Regional deep hyperthermia for salvage treatment of children and adolescents with refractory or recurrent non-testicular malignant germ-cell tumours: an open-label, non-randomised, single-institution, phase 2 study.

BACKGROUND: Although the survival of children and adolescents with malignant germ-cell tumours has improved greatly in recent years, the outcome remains poor for those with refractory or recurrent malignant germ-cell tumours. We aimed to determine whether objective tumour response could be achieved in patients with refractory or recurrent malignant germ-cell tumours with PEI-regional deep hyperthermia as salvage treatment. METHODS: Patients with refractory or recurrent non-testicular malignant germ-cell tumours after standard cisplatin-based chemotherapy were treated prospectively with PEI chemotherapy (cisplatin 40 mg/m(2), delivered intravenously on days 1 and 4; etoposide 100 mg/m(2), intravenously on days 1-4; and ifosfamide 1800 mg/m(2), intravenously on days 1-4) plus simultaneous 1-h regional deep hyperthermia (41-43°C) on days 1 and 4. Patients received three to four treatment courses at 21-day intervals until residual tumour resection was possible; they subsequently received one or two additional courses of PEI-regional deep hyperthermia. Local radiotherapy was given for incompletely resected tumours. Chemotherapy and hyperthermia toxic effects were assessed using WHO grading. The primary endpoint was the proportion of patients who had an objective response as assessed with Response Evaluation Criteria in Solid Tumors version 1.0 guidelines. Secondary endpoints were the event-free survival and overall survival after 5 years. This ongoing PEI-regional deep hyperthermia study (Hyper-PEI protocol) is registered at the German Cancer Society, number 50-2732. FINDINGS: 44 patients aged 7 months to 21 years (median 2 years 7 months) with refractory or recurrent malignant germ-cell tumours (nine patients with poor response, 23 patients with first relapse, 12 patients with multiple relapses) were included in this study. We identified 34 yolk sac tumours, eight embryonal carcinomas, one choriocarcinoma, and one dysgerminoma by histology analysis. Of the 35 patients who had sufficient clinical and radiographical data available for response assessment, 30 (86%) had an objective response to treatment (16 patients had complete remission and 14 had partial remission). 5-year event-free survival was 62% (95% CI 45-75), and 5-year overall survival was 72% (95% CI 55-83). The median follow-up of surviving patients was 82 months (range 9-195). WHO grade 3-4 neutropenia and thrombocytopenia occurred in all 181 chemotherapy cycles. Granulocytopenic fever, which required intercurrent hospital admission, was noted in 29 (66%) of 44 patients after 53 (29%) of 181 courses. Five patients experienced treatment-related grade-3 acute renal toxic effects. INTERPRETATION: A multimodal strategy integrating PEI-regional deep hyperthermia and tumour resection with or without radiation can successfully treat children and adolescents with refractory or recurrent malignant non-testicular germ-cell tumours. The long-term prognosis of patients with poor response or after first relapse was almost similar to those receiving first-line treatment. This strategy merits further investigation. FUNDING: Deutsche Krebshilfe eV, Bonn, Elterninitiative Kinderkrebsklinik Düsseldorf eV, the Barbara and Hubertus-Trettnerstiftung, and the Marie Quendt Fund.

Hyperthermia associated osteonecrosis in young patients with pelvic malignancies.

INTRODUCTION: Progressive and non-juvenile avascular osteonecrosis (AVN) is a rare condition in children. During the last decade, some data indicate that regional deep hyperthermia therapy (RHT) combined with either chemo- and / or radiotherapy in malignancies is associated with AVN in young patients. In this study, we present our data on AVN following RHT in children with intra-pelvic malignancies. MATERIAL AND METHODS: Localization, extent of AVN, and associated joint effusions were evaluated via MRI and X-ray findings in 37 patients treated with RHT and chemotherapy +/- additional radiotherapy for intra-pelvic malignancies in our study. AVN was classified in accordance to the Association Research Circulation Osseus (ARCO). In addition, the recurrence of sarcoma after RHT, the number of total joint replacements, and level of activity including sport activities were recorded in all patients. The mean follow-up was 6.2 years (SD: 4.1, range: 1-12 years). RESULTS: Eight out of 37 pediatric patients treated with RHT and chemotherapy +/- additional radiotherapy showed AVN of the femoral head within our follow-up period. Five out of the eight children developed bone marrow edema within 6 months after RHT procedure and three additional patients within the first year. All patients except one showed a rapid progression of AVN from ARCO stage 0 to the post-collapse-stages III and IV in our study. Seven out of eight AVN patients survived without evidence of further malignancy. Although advanced stages of AVN were observed in our patient group, they were able to still maintain a high quality of life. No patients in our group have undergone total hip replacement thus far. CONCLUSION: Based on our findings, we hypothesize a high risk of AVN in young children who receive RHT for pelvic sarcoma. However, further clinical investigation needs to be done to prove our hypothesis.

Disseminated pilocytic astrocytoma involving brain stem and diencephalon: a history of atypical eating disorder and diagnostic delay.

The association of weight loss and pediatric brain tumors that affect the diencephalon or brain stem with weight loss is a recognized, but not fully understood phenomenon. Tumors located in the hypothalamic region may induce the diencephalic syndrome (DS), which is characterized by profound emaciation with almost complete loss of subcutaneous fatty tissue. Tumors that compress or infiltrate the brain stem rarely cause both psychological disturbance and emaciation. The clinical presentation may be different, depending on the location of the lesion and age of the patient. In this report we present an unusual case of severe emaciation in a 4(9)/(12)-year-old girl with a juvenile pilocytic astrocytoma of the hypothalamic region and brain stem with neuroaxis dissemination. This case illustrates the importance of considering intracranial mass-lesions in the differential diagnosis of weight loss, psychological disturbance and atypical eating disorder. We discuss the importance of tumor multifocality and the role of patient age in the clinical presentation with reference to the literature.

Role of heat treatment in childhood cancers: distinct resistance profiles of solid tumor cell lines towards combined thermochemotherapy.

BACKGROUND: Since information on the efficacy of hyperthermia in combination with chemotherapy on pediatric tumors is limited, we performed a systematic analysis on the synergistic effects of a combined application of heat and chemotherapy on 20 tumor cell lines derived from patients with neuroblastomas, Ewing tumors, germ cell tumors (GCT), and osteosarcomas. METHODS: Cisplatin (cDDP), a cross-linking agent, and etoposide (VP-16), a topoisomerase II inhibitor, were examined either alone or in combination with heat (42 degrees C, 43 degrees C) by using the XTT-assay 1. RESULTS: Our data demonstrate that heat stress at 43 degrees C for 1 hr, but not at 42 degrees C, leads to a notable cytotoxic effect on the different tumor cells. The comparison of mean survival fractions reveals values between 62% for neuroblastoma cells and 76% for Ewing tumor cells. Analyzing the sensitivity to chemotherapy alone, our results show that cDDP (5 microg/ml) reduces cell growth to 47% in Ewing tumor cells, to 61% in neuroblastoma cells, to 75% in GCT cells, and to 76% in osteosarcoma cells. Treatment with VP-16 (10 microg/ml) decreases cell survival to mean values between 58% (neuroblastomas) and 77% (osteosarcomas). Simultaneous application of heat and chemotherapy enhances synergistically cDDP cytotoxicity in all tumor types tested, whereas the efficacy of VP-16 is only slightly influenced by additional application of hyperthermia. The cytotoxicity of cDDP (5 microg/ml) can be increased by a factor of between 1.5 and 2.5 at 42 degrees C and from 2.6 to 14.0 at 43 degrees C. Furthermore, the results show that the sensitivity to heat (43 degrees C) as well as the sensitivity to chemotherapy and combined thermochemotherapy varies considerably between cell lines of the same tumor group. CONCLUSIONS: Simultaneous application of hyperthermia synergistically enhances the cytotoxicity of the alkylating agent cDDP, but not of the topoisomerase II inhibitor VP-16, in a defined spectrum of cell lines from different pediatric tumor entities.

Sensitization of human Ewing's tumor cells to chemotherapy and heat treatment by the bioflavonoid quercetin.

BACKGROUND: The bioflavonoid quercetin, a polyphenolic compound widely distributed in the plant kingdom, has been demonstrated to exert cytostatic activity against a variety of tumor cells in vitro and in vivo. It may be useful in cancer therapy as a thermosensitizer by increasing the cell killing effect of hyperthermia and chemotherapy because of its ability to suppress heat-shock protein expression. MATERIALS AND METHODS: We investigated the effect of quercetin combined with two cytotoxic agents, cDDP (cis-diamminedichloroplatinum II) and VP-16 (etoposide), under various heat-shock conditions in two Ewing's tumor cell lines SK-ES-1 and RD-ES, using XTT-assay and Western blot analysis. RESULTS: Induction of thermotolerance by a sublethal heat-shock (42 degrees C, 1 hour) led to a transient resistance against subsequent heat treatment alone or combined thermochemotherapy with the crosslinking agent cDDP or the topoisomerase II inhibitor VP-16. Quercetin (> or = 50 microM) applied for 24 hours inhibited cell proliferation, increased the cytotoxic activity of cDDP or VP-16 alone or combined with simultaneous hyperthermia and suppressed the development of thermotolerance. Hyperthermia (43 degrees C, 45 degrees C for 1 hour) induced high expression of the inducible form of HSP70, whereas HSP27, which is constitutively expressed at normothermic conditions, is only slightly induced by 43 degrees C and nearly completely suppressed at 45 degrees C. Induction of thermotolerance is accompanied by an elevated expression of both HSP70 and HSP27. Quercetin (> or = 50 microM), alone as well as in combination with thermochemotherapy, inhibited the expression of both HSP70 and HSP27. CONCLUSION: These data suggest that the bioflavonoid quercetin potentially may be useful in clinical trials for optimizing the efficacy of hyperthermia in combination with chemotherapy.