Hyperthermia for the treatment of patients with malignant germ cell tumors: a phase I/II study in ten children and adolescents with recurrent or refractory tumors.

BACKGROUND: Extracranial nontesticular germ cell tumors (GCTs) are rare malignancies in children and adolescents. Cisplatin-containing regimens and complete tumor resection are important determinants for a favorable outcome; however, patients with recurrent tumors that cannot be eradicated by surgical procedures and chemotherapy have a poor prognosis. Noninvasive electromagnetic technologies for superficial and regional deep hyperthermia (RHT) are under investigation to enhance local tumor control in various malignancies. The objectives of this Phase I/II study were to examine 1) whether RHT can be used in combination with platinum-based chemotherapy with acceptable toxicity in children and adolescents and 2) whether this combined regimen can induce objective tumor response in patients with malignant nontesticular GCT that persisted or recurred locoregionally after validated, intensive, cisplatin-based chemotherapy +/- surgery as unsuccessful first-line treatment. METHODS: The authors studied the effects of RHT induced by electromagnetic waves in combination with platinum-based chemotherapy in ten children and adolescents with recurrent or refractory GCTs. RESULTS: Seven of ten patients with recurrent or refractory GCTs had objective responses. Of these, two patients had a partial response and five patients had a complete response. CONCLUSIONS: The results of the current study found that combined RHT and platinum-based chemotherapy can be used in children and adolescents. This regimen was found to induce objective tumor response in 70% of study patients with recurrent or refractory GCTs. The results thus far are encouraging and the study has been extended to patients with a poor response to first-line treatment.

Treatment results in children and adolescents with loco-regional recurrences of abdominal germ cell tumors (GCTs): a pilot-study with PEI chemotherapy and regional deep hyperthermia (RHT) in comparison to a matched cohort.

In this study treatment results in children and adolescents (n = 32) suffering from loco-regional abdominal relapses of germ cell tumors (GCT) (7 embryonal carcinoma, 17 Yolk sac tumors, 8 immature teratomas) aged from 1;0 to 23;3 years (mean = 10;11 years) were evaluated. In this pilot study 9 patients were treated with cisplatinum (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) (PEI) +/- radiation in combination with regional deep hyperthermia (RHI). In sedation RHT was induced by non-invasive heat applicators (Sigma-40 and Sigma 60, BSD Medical Corporation, Utah, USA). In 7 out of these 9 patients with recurrent GCT a tumor response (5 CR, 2 PR, 1 SD, 1 PD) was found. In addition, in 2 patients a complete tumor resection could be achieved inspite of 2 previous incomplete tumor resections each. Five out of 9 patients are living event-free after an observation period ranging from 8 to 40 months (median = 15 months). Treatment results of this RHT study population were compared with treatment results in patients with recurrent GCT, who received conventional relapse therapy (chemotherapy/ surgery +/- radiation) alone. In this matched cohort 5 out of 23 patients are living event-free after an observation time ranging from 1 to 120 months (median = 8 months). According to Kaplan-Maier life table analysis, patients with relapse therapy combined with RHT have an event-free survival (EFS) of 0.41 +/- 0.33 whereas the matched cohort without RHT have an EFS of 0.16 +/- 0.25. The difference in treatment results of both groups is significant (Wilcoxon/p = 0.03). From the data presented in this study we conclude that children with loco-regional recurrences of extracranial non-testicular GCT have an unfavorable prognosis, unless local tumor control can be achieved. The additional application of RHT in combination with conventional therapy (PEI chemotherapy +/- radiation) can improve local tumor control and EFS in GCT patients with loco-regional recurrences. Therefore, based upon these results in the future MAKEI trial RHT will be applied to GCT patients with poor response to neoadjuvant chemotherapy alone as first line treatment.