Survival rates for children with malignant germ-cell tumours have improved with the advent of platinum-based therapy. However, some patients are refractory to treatment or relapse. Extragonadal germ-cell tumours are more common in children than in adults; many patients are very young, with tumours localised to abdominal or pelvic sites that might be difficult to eradicate. The most common extragonadal germ-cell tumours in this population are sacrococcygeal teratomas. These tumours are usually diagnosed at birth when external lesions predominate. Presacral lesions containing malignant germ-cell tumor elements, such as yolk sac tumours, are noted later in the first years of life.

Although most benign neonatal sacrococcygeal tumours can be treated with resection and observation, malignant tumours require a multidisciplinary approach including chemotherapy with platinum-based compounds and surgery. Survival rates of 80—90% have been achieved with this method.2—4 But surgery, which is essential to survival, is often very difficult to do in these young patients. Long-term longitudinal studies, after initial surgery, have shown that patients are at risk of developing neurological deficits such as bowel and urinary incontinence.5, 6

There are two basic strategies for treating sacrococcygeal tumours with malignant elements: resection, followed by adjuvant chemotherapy4 or neoadjuvant chemotherapy before resection.2 But refractory disease and recurrence are possibilities. These are rare events and patients can respond to further treatment. In The Lancet Oncology, Rüdiger Wessalowski and colleagues7 present a study in which most patients had sacrococcygeal tumours with malignant elements. Patients in this trial7 who had received previous intensive therapy, and whose tumours were refractory or recurrent, received deep regional hyperthermia in conjunction with chemotherapy. The investigators postulate that high-dose intensive therapy alone was not sufficient to treat patients because better local control was needed.

Several studies have assessed hyperthermia in conjunction with radiation and chemotherapy, although significant trials have not been done. In adult trials,8 hyperthermia in the range of 41—43°C in combination with radiation has shown responses in sarcomas. But temperature control is often difficult for deep-seated tumours, and skin burns are often an issue for superficial tumours. In this German MAKEI trial,7 an innovative method was developed. Different sizes of electromagnetic heat applicators were placed in three lucite cylinders (based on patients’ size). The temperature could be safely well maintained.

In paediatric embryonal tumours such as retinoblastoma, localised hyperthermia (laser) has been used successfully in precise approximation with carboplatin.9, 10 Currently, platinum-based compounds are being studied as radiation sensitisers in other paediatric embryonal tumours such as medulloblastoma. Two populations in this study7 might have benefited from this therapy: patients with refractory disease and patients with initial relapse. An aggressive chemotherapy approach is warranted but not sufficient. Surgery is essential, but when? Three therapeutic strategies emerge: surgery followed by hyperthermia and chemotherapy; hyperthermia and chemotherapy followed by surgery; and the addition of external beam radiation therapy. Some patients—for which imaging probably suggested the tumour could be easily resected—had surgery before hyperthermia and chemotherapy. These patients were assessed separately. For the remainder of patients, the question of whether regional hyperthermia improves local control is difficult to answer because of the small population. Moreover, a randomised trial with or without regional hyperthermia would be difficult to do because of the low incidence of this tumour and a much lower incidence of recurrence. Development of evidence-based therapy for many rare paediatric tumours is also complicated in view of their low incidence.

If the nine patients who had surgery before hyperthermia and chemotherapy are excluded, the remaining patients were at higher risk for failure of local control. About half of these patients had no viable tumour at time of surgery. Finally, patients with a viable tumour were salvaged with external beam radiation. These results suggest local control might include stepwise escalation of therapy. Although radiation should be avoided in young children, it may be a viable option if local control has not been achieved.

In summary, these are interesting findings and the investigators have developed a precise delivery method for regional deep hyperthermia and chemotherapy administration. Relapsed and refractory tumours did respond when regional hyperthermia was given with chemotherapy that was identical to that received before recurrence. The procedures were well tolerated with minimal local toxic effects. Therefore, this regimen might be an option for treating rare paediatric tumours. Whether the same technology can be exported to other paediatric centres is not clear, however. The essential element in hyperthermia is temperature control, and until appropriate thermal dosimetry methods are developed and widespread, this procedure might be restricted to a small number of centres.

Source: Lancet