Carboplatin before and during radiation therapy for the treatment of malignant brain stem tumours: A study by the Société Française d'Oncologie Pédiatrique
Institut de Cancérologie Gustave Roussy, Villejuif, Île-de-France, France European Journal of Cancer
(Impact Factor: 5.42).
05/2002; 38(6):815-9. DOI: 10.1016/S0959-8049(02)00029-1
Childhood malignant brain stem tumours have a very poor prognosis with a median survival of 9 months despite radiotherapy. No chemotherapy has improved survival. However, carboplatin has been reported to have activity in glial tumours as well as antitumour synergy with radiation. Our aims were to test the response rate of these tumours to carboplatin alone and to evaluate the efficacy on survival of carboplatin alone followed by concurrent carboplatin and radiotherapy. Patients younger than 16 years with typical clinical and radiological presentation of infiltrating brain stem tumour, as well as histologically-documented cases in the atypical forms, were eligible. Two courses of carboplatin (1050 mg/m2 over 3 days) were administered initially. This treatment was followed by a chemoradiotherapy phase including five weekly carboplatin courses (200 mg/m2) and conventional radiotherapy. 38 eligible patients were included. No tumour response was observed after the initial phase. This schedule of first-line carboplatin followed by concurrent carboplatin and radiotherapy did not improve survival.
Available from: Adam Glaser
- "A number of chemotherapeutic approaches have also been tried with limited or no effect. These have included radiosensitisers such as carboplatin   , standard chemotherapy such as etoposide (oral and intravenous )  , vincristine and high dose chemotherapy such as busulfan and thiotepa with stem cell support  . Temozolomide is an oral alkylating agent which crosses the blood brain barrier  and is used widely in the treatment of high grade gliomas, both in adults and children. "
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ABSTRACT: Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28 d) of temozolomide was studied with the aim of overcoming O6-methylguanine methyltransferase (MGMT) mediated resistance.
Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m2) after which up to 12 courses of 21 d of adjuvant temozolomide (75–100 mg/m2) were given 4 weekly. The trial used a 2-stage design and passed interim analysis.
At diagnosis median age was 8 years (2–20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10–100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5–11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis.
This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.
Available from: PubMed Central
- "Of note, these survival rates are higher than those reported in more recent trials; this is likely related to the inclusion of non-DIPG patients. DIPG has been studied in a large number of clinical trials including those evaluating cytotoxic agents, high-dose chemotherapy with stem cell rescue (Dunkel et al., 1998; Bouffet et al., 2000), neoadjuvant chemotherapy (Doz et al., 2002), biologic response modifiers (Warren et al., 2006, 2011a,b) and radiation sensitizers, none of which demonstrated significantly improved outcome. Contemporary studies limiting enrollment to patients with DIPG generally report progression-free survival (PFS) of 5–8 months and 2-year overall survival rates of <10% (Pollack et al., 2007, 2011; Gururangan et al., 2010; Haas-Kogan et al., 2011; Table 1). "
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ABSTRACT: Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.
Available from: Lorenza Gandola
- "This difference remained for smaller numbers of patients when histological samples were reviewed, and new, correct nosological entities were therefore assigned (Packer, 1996). Since the 1989 publication, chemotherapy has been added to radiotherapy in different schedules: as a preradiant " sandwich " phase (Kedar et al., 1994; Kuhl et al., 1998; Pendergrass et al., 1987; Wolff, et al. 2002a), concomitantly (Doz et al., 2002; Massimino et al., 2000a; Wolff et al., 2002b), and as maintenance (Finlay et al., 1995). High-dose chemotherapy has already been explored for relapsing or newly diagnosed malignant glioma (Finlay et al., 1996), either in preradiant or postradiant schedules, with the aim of tumor reduction before delivering radiotherapy (Heideman et al., 1993), or as radiation treatment consolidation (Bouffet et al., 1997; Finlay, 1996). "
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ABSTRACT: Childhood malignant gliomas are rare, but their clinical behavior is almost as aggressive as in adults, with resistance to therapy, rapid progression, and not uncommonly, dissemination. Our study protocol incorporated sequential chemotherapy and high-dose thiotepa in the preradiant phase, followed by focal radiotherapy and maintenance with vincristine and lomustine for a total duration of one year. The induction treatment consisted of two courses of cisplatin (30 mg/m2) plus etoposide (150 mg/m2) x 3 days and of vincristine (1.4 mg/m2) plus cyclophosphamide (1.5 g/m2) plus high-dose methotrexate (8 g/m2), followed by high-dose thiotepa (300 mg/m2 x 3 doses), with harvesting of peripheral blood progenitor cells after the first cisplatin/etoposide course. From August 1996 to March 2003, 21 children, 14 females and 7 males, with a median age of 10 years were enrolled, 18 presenting with residual disease after surgery. Histologies were glioblastoma multiforme in 10, anaplastic astrocytoma in nine, and anaplastic oligodendroglioma in two; sites of origin were supratentorial areas in 17, spine in two, and posterior fossa in two. Of the 21 patients, 12 have died (10 after relapse, with a median time to progression for the whole series of 14 months; one with intratumoral bleeding at 40 months after diagnosis; and one affected by Turcot syndrome for duodenal cancer relapse). Four of 12 relapsed children had tumor dissemination. At a median follow-up of 57 months, overall survival and progression-free survival at four years were 43% and 46%, respectively. Sequential and high-dose chemotherapy can be afforded in front-line therapy of childhood malignant glioma without excessive morbidity and rather encouraging results.
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