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ObjectiveTo determine whether a fraction of patients with primary CNS lymphoma (PCNSL) had been cured by systemic and intraventricular methotrexate- and cytarabine-based chemotherapy (Bonn protocol) after a very long-term follow-up of nearly 20 years.MethodsSixty-five patients (median age 62 years, range 27–75; median Karnofsky performance score 70, range 20–90) had been treated with systemic and intraventricular polychemotherapy without whole brain radiotherapy from September 1995 until December 2001. All patients still alive in 2019 were contacted and interviewed on their current life situation.ResultsMedian follow-up for surviving patients was 19.6 years (17.5–23.3 years). Out of 65 patients, 11 (17%) were still alive. Six of those never experienced any relapse. For the whole study population, median overall survival (OS) was 4.4 years (95% confidence interval [CI] 2.9–5.9); for patients ≤60 years, 11.0 years (95% CI 4.8–17.0). The 10-year OS rate for the entire cohort was 29% and the estimated 20-year OS rate was 19%. Four late relapses were observed after 9.8, 10.3, 13.3, and 21.0 years.ConclusionAt a median follow-up of 19.6 years, 17% of patients were alive and free of tumor; however, even after response for decades, an inherent risk of relapse, either systemic or cerebral, characterizes the biology of PCNSL.Classification of evidenceThis work provides Class III evidence that PCNSL treatment with methotrexate-based polychemotherapy including intraventricular therapy is associated with long-term disease control in some patients.

Background Survival in recurrent ependymomas in children and adolescents mainly depends on the extent of resection. Studies on repeated radiotherapy and chemotherapy at relapse have shown conflicting results. Methods Using data from the German multi-center E-HIT-REZ-2005 study, we examined the role of local therapy and the efficacy of chemotherapy with blockwise temozolomide (TMZ) in children and adolescents with recurrent ependymomas. Results Fifty-three patients with a median age of 6.9 years (1.25–25.4) at first recurrence and a median follow-up time of 36 months (2–115) were recruited. Gross- and near-total resection (GTR/NTR) were achieved in 34 (64.2%) patients and associated with a markedly improved 5-year overall survival (OS) of 48.7% vs. 5.3% in less than GTR/NTR. Radiotherapy showed no improvement in OS following complete resection (OS: 70 (CI: 19.9–120.1) vs. 95 (CI: 20.7–169.4) months), but an advantage was found in less than GTR/NTR (OS: 22 (CI: 12.7–31.3) vs. 7 (CI: 0–15.8) months). Following the application of TMZ, disease progression was observed in most evaluable cases (18/21). A subsequent change to oral etoposide and trofosfamide showed no improved response. PF-A EPN were most abundant in relapses (n = 27). RELA-positive EPN (n = 5) had a 5-year OS of 0%. Conclusion The extent of resection is the most important predictor of survival at relapse. Focal re-irradiation is a useful approach if complete resection cannot be achieved, but no additional benefit was seen after GTR/NTR. Longer-term disease stabilization (>6 months) mediated by TMZ occurred in a small number of cases (14.3%).

Diffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence. The study included patients between 3 and 20 years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150 mg/m2 weekly for 12 weeks. Radiotherapy at total dose of 54 Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3). All 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8 months and median overall survival (OS) was 9.4 months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression. Concomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

Background Severe neurotoxicity has been observed after systemic high-dose and intrathecal methotrexate (MTX) treatment. The role of biochemical MTX-induced alterations of the folate and methyl-transfer pathway in the development of neurotoxic symptoms is not yet fully elucidated. Procedure MTX, 5-methyltetrahydrofolate, calcium folinate, S-adenosylmethionine, and S-adenosylhomocysteine were measured in the cerebrospinal fluid (CSF) of 29 patients with acute lymphoblastic leukemia (ALL) who were treated with high-dose MTX (5 g/m2) followed by calcium folinate rescue (3 × 15 mg/m2) and/or intrathecal (8–12 mg) MTX. Two patients developed subacute MTX-associated neurotoxicity. CSF was obtained by lumbal puncture 1–3 weeks after administration of MTX and shortly after the occurrence of neurotoxicity. The analytes were measured using HPLC assays with UV and/or fluorescence detection. Results In non-toxic patients, CSF concentrations of 5-methyltetrahydrofolate and S-adenosylmethionine were in the normal range 2 weeks after administration of high-dose and intrathecal MTX followed by rescue. In contrast, when these patients received intrathecal MTX without rescue, 5-methyltetrahydrofolate concentrations were significantly decreased 12 days after the first MTX administration. S-adenosylmethionine concentrations were significantly decreased up to 45 days. The two patients suffering from neurotoxicity had decreased levels of 5-methyltetrahydrofolate and S-adenosylmethionine during or following toxicity. S-adenosylhomocysteine was determined in all samples of neurotoxic patients but was below the limit of quantification in most samples of non-toxic patients. Calcium folinate was not detected; MTX was present only in samples obtained during its infusion. Conclusion Intrathecal MTX without folinate rescue as well as MTX-associated neurotoxicity are likely to be associated with specific alterations of the folate and methyl-transfer pathway. Pediatr Blood Cancer 2009;52:26–32. © 2008 Wiley-Liss, Inc.

Methotrexate-Associated Biochemical Alterations in a Patient with Chronic Neurotoxicity Intrathecal and/or high-dose intravenous administration of methotrexate (MTX) in the treatment of malignancies such as acute lymphoblastic leukaemia (ALL) has been associated with cases of mild to severe neurotoxicity. The pathogenic mechanism of neurotoxicity is not clear, possibly MTX-associated biochemical alterations of the folate and methyl-transfer metabolic pathways play an important role. We report a case of an adult patient treated for ALL relapse with signs of chronic leukoencephalopathy associated with MTX administration. In order to assess alterations in the folate and methyl-transfer pathway we determined 5-methyltetrahydrofolate (5-methyl-THF), S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in the cerebrospinal fluid (CSF) of the patient. Three CSF samples were obtained by lumbar punction within a four-month period. Concentrations of the metabolites were measured using validated bioanalytical methods based on HPLC with UV and fluorescence detection. The results showed two-fold lower 5-methyl-THF levels (29.3-31.8 nmol/L) in all obtained samples compared to reference values. SAM concentrations were even more than five-fold lower in two samples (5-34.2 nmol/L). SAH concentrations were in the range 7.5-14.3 nmol/L. Our patient had pronounced alterations in the folate and methyltransfer pathway which indicate that MTX-associated biochemical alterations of these pathways may play an important role in the development of leukoencephalopathy.

The aim of this study was to evaluate feasibility and toxicity of bevacizumab (Avastin), a monoclonal antibody directed against the vascular endothelial growth factor in children and young adults.Fifteen patients (male: n = 8; female: n = 7; median age, 14.6 years) received bevacizumab for recurrent or progressive solid tumors (carcinoma: n = 3; neuroblastoma: n = 2; astrocytoma grade III: n = 2; rhabdomyosarcoma: n = 2; nephroblastoma: n = 2; benign vascular tumors: n = 2; synovial sarcoma: n = 1; and malignant hemangiopericytoma: n = 1) on a compassionate basis. Bevacizumab was administered at 5-10 mg/kg body weight intravenously every 2-3 weeks. Most patients received chemotherapy in addition to bevacizumab. Duration of bevacizumab therapy ranged from 1.5 to 23 months.Bevacizumab-related side-effects were mild and included hypertonia (n = 2), proteinuria/hematuria (n = 2), epistaxis (n = 2), local erythema (n = 1), and defective wound healing and ascites (n = 1). Radiographic objective responses (partial responses) were observed in two patients with astrocytoma grade III and in one patient each with neuroblastoma and pleomorphic rhabdomyosarcoma, respectively.Bevacizumab seems to have a good acute safety profile and some antitumor activity in heavily pretreated children and young adults with recurrent solid tumors. Prospective clinical trials are urgently needed to further evaluate the safety and efficacy of bevacizumab in pediatric patients.

Systemic administration of etoposide is effective in treating metastatic, recurrent or refractory brain tumors, but penetration into the cerebrospinal fluid is extremely poor. This study was designed to determine the safety and toxicity profile of intraventricular etoposide administration and was affiliated with the prospective, multicenter, nonblinded, nonrandomized, multi-armed HIT-REZ-97 trial. The study enrolled 68 patients, aged 1.1-34.6 (median age 11 years). Adverse events that could possibly be related to intraventricular etoposide therapy were documented and analyzed. Intraventricular etoposide was simultaneously administered with either oral or intravenous chemotherapy in 426 courses according to three major schedules varying in dosing (0.25-1 mg), frequency of administration (bolus injection, every 12 or 24 h), course duration (5-10 days) and length of interval between courses (2-5 weeks). Potential treatment-related adverse effects included transient headache, seizures, infection of the reservoir, nausea and neuropsychological symptoms. Hematological side effects were not observed. One patient, with history of multiple prior therapies, who received long-term intraventricular and oral etoposide treatment developed acute myeloid leukemia as a secondary malignancy. Overall intraventricular etoposide is well tolerated. The results of this study have warranted a phase II trial to determine the effectiveness of this regimen in disease stages with very limited therapeutic options.

Until now, studies confirming the safety of glycopeptide restriction in the empirical treatment of prolonged fever and neutropenia included only nine children. In an open-label observational study, the use of teicoplanin in paediatric oncology patients was investigated. A period of unrestricted use (2001-2003) was compared with a second period (2004) following implementation of a restrictive treatment guideline. Empirical first-line treatment consisted of piperacillin/tazobactam; in 2004, fosfomycin was added after 72 h as the second-line combination instead of teicoplanin. In total, 213 episodes (n=163 in 2001-2003; n=50 in 2004) managed with teicoplanin or fosfomycin (only 2004) were eligible. Empirical treatment of fever of unknown origin with teicoplanin was reduced by 97%. In 2004, the mean length of stay was 0.4 days shorter, no infection-related death occurred and no vancomycin-resistant enterococci were detected. Restriction of empirical glycopeptides is safe in paediatric cancer patients after first-line treatment with piperacillin/tazobactam. Fosfomycin appears to offer a feasible and cost-saving alternative in second-line combination therapy.

The methotrexate (MTX) rescue agent carboxypeptidase G2 (CPDG2) rapidly hydrolyses MTX to the inactive metabolite DAMPA (4-[[2,4-diamino-6-(pteridinyl)methyl]-methylamino]-benzoic acid) and glutamate in patients with MTX-induced renal failure and delayed MTX excretion. DAMPA is thought to be an inactive metabolite of MTX because it is not an effective inhibitor of the MTX target enzyme dihydrofolate reductase. DAMPA is eliminated more rapidly than MTX in these patients, which suggests a nonrenal route of elimination. In a phase II study (May 1997-March 2002), CPDG2 was administered intravenously to 82 patients at a median dose of 50 U kg(-1) (range 33-60 U kg(-1)). Eligible patients for this study had serum MTX concentrations of10 microM at 36 h or5 microM at 42 h after start of MTX infusion and documented renal failure (serum creatinineor =1.5 times the upper limit of normal). Immediately before CPDG2 administration, a median MTX serum level of 11.93 microM (range 0.52-901 microM) was documented. Carboxypeptidase G2 was given at a median of 52 h (range 25-178 h) following the start of an MTX infusion of 1-12 g m(-2) 4-36 h(-1) and resulted in a rapid 97% (range 73-99%) reduction of the MTX serum level. Toxicity related to CPDG2 was not observed. Toxicity related to MTX was documented in about half the patients; four patients died despite CPDG2 administration due to severe myelosuppression and septic complications. In conclusion, administration of CPDG2 is a well-tolerated, safe and a very effective way of MTX elimination in delayed excretion due to renal failure.

Purpose: To evaluate response rate, response duration, overall survival (OS), and toxicity in primary CNS lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From September 1995 to July 2001, 65 consecutive patients with PCNSL (median age, 62 years) were enrolled onto a pilot and phase II study evaluating chemotherapy without radiotherapy. A high-dose methotrexate (MTX; cycles 1, 2, 4, and 5) and cytarabine (ARA-C; cycles 3 and 6)–based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ARA-C. Results: Sixty-one of 65 patients were assessable for response. Of these, 37 patients (61%) achieved complete response, six (10%) achieved partial response, and 12 (19%) progressed under therapy. Six (9%) of 65 patients died because of treatment-related complications. Follow-up is 0 to 87 months (median, 26 months). The Kaplan-Meier estimates for median time to treatment failure (TTF) and median OS were 21 months and 50 months, respectively. For patients older than 60 years, median survival was 34 months, and the median TTF was 15 months. In patients younger than 61 years, median survival and median TTF have not been reached yet; the 5-year survival fraction is 75%. Systemic toxicity was mainly hematologic. Ommaya reservoir infection occurred in 12 patients (19%), and permanent cognitive dysfunction possibly as a result of treatment occurred in only two patients (3%). Conclusion: Primary chemotherapy based on high-dose MTX and ARA-C is highly efficient in PCNSL. Response rate and response duration in this series are comparable to the response rates and durations reported after combined radiotherapy and chemotherapy. Neurotoxicity was infrequent.

Though liposomal amphotericin B has been available in Germany since 1992, efficacy and safety of this formulation of amphotericin B are still not well-documented in children. As far as gastrointestinal side-effects are concerned, an elevated alkaline phosphatase and elevated transaminases have been reported. In our department, liposomal amphotericin B had been used since 1994 to treat patients with proven or suspected fungal infections in a daily dose of 1-3 mg kg-1. Additionally, patients with high-dose chemotherapy and autologous stem cell support received liposomal amphotericin B prophylactically in a dose of 1 mg kg(-1) three times per week. We performed a retrospective analysis of all 31 patients who had received liposomal amphotericin B by 1999. In five patients, an isolated transient elevation of the serum lipase level during, or shortly after, the therapy with liposomal amphotericin B was detected. Three of these patients showed clinical signs of pancreatitis, with one patient displaying slightly elevated transaminases. So far, elevated levels of serum lipase have not been described as a possible side-effect of a liposomal amphotericin B therapy. The pathogenesis of this elevation is unclear. As possible reasons, an enzyme induction due to fat overload or a toxic damage of the pancreatic tissue by the liposomes or amphotericin B itself are discussed.

High-dose methotrexate (HDMTX) is a component of many cancer treatment regimens. Despite careful management, delayed renal clearance, followed by extremely high serum levels with potentially life-threatening toxicity can occur. In the present study, we report our results of carboxypeptidase-G2 (CPDG2) rescue in 8 patients with delayed methotrexate elimination and renal impairment after HDMTX therapy for lymphoma or osteosarcoma. A dose of 50 U/kg CPDG2 was administered. MTX plasma levels decreased rapidly and recovery of renal function was observed in all patients. No patient developed severe WHO grade 4 MTX toxicity. CPDG2 provides an alternative route of MTX elimination by converting it to inactive and non-toxic metabolites. CPDG2 rescue was well tolerated, safe and very effective in preventing severe or life-threatening MTX toxicity.

The objective was to evaluate response rate, response duration, and toxicity after systemic and intraventricular chemotherapy in primary CNS lymphoma (PCNSL). From September 1995 to September 1998, 20 consecutive patients with PCNSL (median age 64, range 27 to 71 years) were enrolled in a pilot study evaluating chemotherapy without radiotherapy. A high dose methotrexate (MTX) (cycles 1, 2, 4, 5) and cytarabine (ara-C) (cycles 3, 6) based systemic therapy (including dexamethasone, vinca alkaloids, ifosfamide, and cyclophosphamide) was combined with intraventricular MTX, prednisolone, and ara-C. Complete response was achieved in 11 and partial remission in two patients; in one response could not be determined. Four patients showed progressive disease and two (70, 71 years) died from treatment related complications. Observation time was 2 to 59 months (median 31.5 months). Kaplan-Meier estimate for median time to treatment failure (TTF) was 20.5 months, and for median survival 54 months. Systemic toxicity was mainly hematological. Ommaya reservoir infection occurred in four patients and acute transient MTX induced encephalopathy in two (subacute in another). Cognitive dysfunction possibly due to treatment was seen in only one patient after relapse and after a total of 12 cycles (six at relapse). In conclusion, primary chemotherapy based on high dose MTX and ara-C is highly efficient in PCNSL. Toxicity is manageable in patients younger than 70years.

This trial assessed the efficacy and safety of meropenem versus ceftazidime as empirical monotherapy for febrile neutropenia in paediatric cancer patients. In a prospective randomized study, 172 evaluable febrile episodes in the meropenem arm and 170 episodes in the ceftazidime arm were analysed for the clinical and microbiological response dependent on the kind of infection. About half the episodes were classified as fever of unknown origin (FUO) and the remainder as microbiologically or clinically documented infections. The most frequently documented infections in both arms were bacteraemias (22.1 versus 26.5%), predominantly caused by Gram-positive organisms (57.9 versus 71.1%). The success rate of the initial monotherapy differed significantly between the two arms and was 55.8% in the meropenem and 40.0% in the ceftazidime arm (P = 0.003). In addition, a significantly longer duration of fever and of antimicrobial therapy was observed in the ceftazidime arm than in the meropenem arm (median 5 versus 4 days, P = 0.022, and 7 versus 6 days, P = 0.009, respectively). With respect to the kind of infection, differences between the two arms were significant only in episodes classified as FUO but not in documented infections. In both arms, side effects were minimal. Despite the greater response rate for meropenem in FUO, the fact that ceftazidime has been proven to be as effective as meropenem in documented infections in the present study suggests that both drugs are useful as empirical monotherapy in febrile paediatric cancer patients.

As the systemic administration of etoposide is effective in the treatment of relapsed and metastatic brain tumours, a pilot trial was designed to study the feasibility of intraventricular administration of etoposide in such patients. 14 patients aged 2.1 to 33.2 years were treated with intraventricular etoposide simultaneously with either oral or intravenous chemotherapy with trofosfamide or carboplatin and etoposide. In 59 courses (1–12/patient) 0.5 mg etoposide was administered daily via an indwelling subcutaneous reservoir for 5 consecutive days every 2–5 weeks over a period of 0–11 months. During 15 courses in 5 patients serial CSF samples were obtained and etoposide levels were determined by reversed-phase HPLC. Side effects included transient headache and bacterial meningitis, each during 2 courses. Pharmacokinetic data analysis in the CSF (11 courses, 4 patients) revealed a terminal half-life of 7.4±1.2 hours and an AUC of 25.0 ± 9.5 μg h ml–1(mean ± standard deviation). The volume of distribution at steady state and total clearance exhibited a large interindividual variability with mean values of 0.16 l and 0.46 ml min–1respectively. Intraventricularly administered etoposide is well tolerated. CSF peak levels exceed more than 100-fold those achieved with intravenous infusions. Further studies should be focused on optimizing the dose and schedule and on determining the effectiveness of intraventricularly administered etoposide. © 2001 Cancer Research Campaign http://www.bjcancer.com

After cisplatin / 5-fluorouracil chemotherapy for nasopharyngeal carcinoma, an 18-year female patient developed aortobifemoral embolism. Besides chemotherapy, additional risk factors for arterial thromboembolic events were smoking, contraceptive medication and adjuvant antiemetic treatment with dexamethasone. Thrombophilia screening was negative. Thromboembolic complications during or after cisplatin have been reported in a frequency of 17.6 % in lung cancer patients, and in 8.4 % of patients with germ cell tumors. The incidence of arterial thromboembolic events was 9.3 % and 1.7 %, respectively. The pathogenesis of cisplatin induced thromboembolism is thought to be caused by endothelial damage leading to endothelial cell dysfunction, increased von Willebrand factor plasma levels, and hypomagnesaemia.

A phase II trial was designed to explore the potential feasibility and efficacy of a reinduction therapy consisting of fludarabine, cytarabine, idarubicin and granulocyte colony stimulating factor (G-CSF) for acute myelogenous leukaemia (AML) patients with poor prognosis. Twenty-three patients aged 1 2-17.5 years with refractory (n=3), relapsed (n=19) or secondary (n=11) AML were treated with the IDA-FLAG regimen, a combination therapy of idarubicin (days 2-4, 12 mg/m2/d), fludarabine (days 1-4, 30 mg/m2/d), cytarabine (days 1-4, 2000mg/ m2/d) and G-CSF (day 0 up to ANC > 1 x 10(9)/l, 400 microg/m2/ d). They received a total of 3 7 courses of IDA-FLAG and/or FLAG (IDA-FLAG without idarubicin). 17/23 patients achieved a complete remission (CR) with a median duration of 13.5 months (1-39 months), one patient showed a partial remission, and five were nonresponders while in CR, 11 patients underwent bone marrow or PBSC (peripheral blood stem cells) transplantation. Overall, nine patients remain in continuous complete remission with a median duration of 17.5 months (9.5-39 months). The toxicity of the IDA-FLAG courses was more severe than for the FLAG courses with marked neutropenia and thrombocytopenia (for IDA-FLAG: median 22.5 and 25 d respectively; for FLAG: median 10.5 and 14 d respectively). Pulmonary infections were the main nonhaematological toxicity. One patient died in CR from invasive aspergillosis. The IDA-FLAG regimen produced a CR of >12 months in more than half of the patients and can be recommended as a therapeutic option prior to allogeneic or autologous bone marrow transplantation.

Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with both radiotherapy and vinorelbine, a pilot phase 2 protocol was launched that combined nimotuzumab with concomitant radiation and vinorelbine. An amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR + PR + SD) according to the RECIST. This report concerns the outcome of this strategy as a whole. Vinorelbine 20 mg/m(2) was administered weekly, with nimotuzumab 150 mg/m(2) in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Vinorelbine 25 mg/m(2) and nimotuzumab were given every other week thereafter until the tumor progressed or for up to 2 years. Re-irradiation consisted of 19.8 Gy, fractionated over 11 days. Baseline and latest MRIs were assessed blindly by an outside neuroradiologist. Twenty five children (mean age 7.4 years) were enrolled as of August 2009 (median follow-up 29 months). A response was observed in 24/25 patients (96 %). The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. Eleven of 16 locally-relapsing patients were re-irradiated. One-year PFS and OS rates were 30 ± 10 % and 76 ± 9 %, respectively; 2-year OS was 27 ± 9 %; the median PFS and OS were 8.5 and 15 months, respectively. This strategy generated interesting results and warrants further investigation.

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.

Intensive chemotherapy has improved the prognosis of patients with AML. The success rate of relapse treatment correlates with the length of first remission. Thus early relapses and primarily refractory diseases have a grave prognosis. New chemotherapeutic regimens could be useful for those patients. Patients treated for newly diagnosed or relapsed AML with polychemotherapy regimen of the AML-BFM-studies containing induction, consolidation and high-dose cytarabine combined with mitoxantrone (HAM) and relapsed within 2 up to 31 months after the first CR entered a pilot trial, the so called IDA-FLAG regimen. This regimen includes G-CSF (day 0 up to ANC > 1000/microliter, 400 micrograms/m2.d), fludarabine (day 1-4, 30 mg/m2.d), high-dose cytarabine (day 1-4, 2000 mg/m2.d) and idarubicin (day 2-4, 12 mg/m2.d). 10 patients aged 1,8 to 28,1 years (mean = 9,6 years) having the first (n = 8) or second relapse (n = 1) of AML or an acute blastcrisis of myelodysplastic syndrome (n = 1) (FAB classification: M1/M2 = 3, M4/M5 = 5, M7 = 1, CMML = 1) received 14 courses. Overall, 7 patients achieved CR with a mean duration of 8,9 months (1-22 months), one patient showed a partial remission and two were nonresponders. 4 patients are in continuous CR for 7,5 to 22 months (mean = 13,2 months). 3 patients got a bone marrow transplantation (allogenic = 2, autologous = 1) in CR following this treatment. Toxicity was considerable, mainly bone marrow aplasia with leucopenia < 1000/microliter for 15 to 40 days (mean = 26,1 days), neutropenia < 500/microliter for 14 to 39 days (mean = 26,0 days) and thrombocytopenia < 30,000/microliter for 14 to 90 days (mean = 36,5 days). Further important side effects were fever, mucositis and pneumonia. One patient died from an fulminant aspergillus sepsis during long-term neutropenia. The sequential administration of G-CSF, fludarabine, cytarabine and idarubicin is effective in treatment of relapsed AML in childhood and an advisable option prior to allogenic or autologous bone marrow transplantation. With regard to the unfavorable prognosis of relapsed or refractory AML the toxicity of this regimen seems acceptable.

In spite of new alkylating medication and recently accumulated knowledge about genomics, the prognosis of malignant gliomas remains poor. The introduction of single substances interfering with tumour proliferation dynamics has been disappointing and the lessons learned indicate that a complicated network of proliferation needs time consuming, in-depth analysis in order to more specifically treat now distinguishable subgroups of a disease, which too long was thought of as a uniform entity.The clinical trials using the EGFR antibody nimotuzumab in the treatment of malignant gliomas are reviewed. Pending conformation in future studies the antibody might be part of the treatment of MGMT-negative, EGFR-amplified, not completely resected gliomas of adulthood and juvenile DIPG (pontine gliomas). Upcoming genomic results of the different tumour entities may suggest certain combination partners of the antibody. Recent studies of nimotuzumab indicate the reason for the lack of toxicity, which is the most attractive argument for its clinical use besides modest efficacy.We await the final results on the use of the antibody together with vinorelbine and radiation therapy for the therapy of DIPG. Adult patients with MGMT-negative, EGFR amplified, not totally resected GBM may also profit from this combination therapy. TK-inhibitors combined with the antibody and irradiation may be an option for a therapeutic trial in paediatric patients.

Diffuse intrinsic pontine gliomas (DIPG) have a poor prognosis: the median survival rate is less than one year. Radiotherapy is the only effective treatment affording an overall survival of 6 - 9 months. So far, no improvement has been achieved with the addition of single/poly-chemotherapy regimens. An urgent need is to advance in this field, from both the biological and the clinical points of view.Among the few studies providing biological information on DIPG, Gilbertson's group demonstrated a significant increase in EGFR expression. The activity of nimotuzumab, a humanized anti-EGFR monoclonal antibody, was therefore studied within a Phase II trial in 47 relapsing pediatric patients with DIPG and high-grade gliomas, showing an interesting, persistent response, especially in the first group treated. A multicenter exploratory study combining nimotuzumab and radiotherapy showed disease control and an overall patient survival similar to previous experiences along with an improvement in the quality of patient survival and no severe side effects.We recommend considering this combination in the armamentarium against DIPG. It might be improved by adding other target drugs/low-toxicity chemotherapy regimens with a synergistic effect with the anti-EGFR component.

Objective To evaluate long-term progression-free survival and overall survival, quality of life, and cognitive function in primary central nervous system lymphoma after systemic and intraventricular chemotherapy without radiotherapy. Methods A long-term follow-up was conducted on surviving primary central nervous system lymphoma patients having been enrolled in a pilot/phase II trial between September 1995 and December 2001. Initially, 65 patients (median age, 62 years) had been treated with systemic and intraventricular chemotherapy without radiotherapy. All living patients were contacted, and a neurological examination, comprehensive neuropsychological testing, quality-of-life assessment, and imaging were performed. Results Twenty-one of all 65 patients (32 %) and 17 of 30 patients 60 years or younger (57%), respectively, were still alive at median follow-up of 100 months (range, 77–149 months). Nineteen of 21 patients completed all investigations; 1 was lost to follow-up. In three patients, an exclusively extraneural relapse of a high-grade non-Hodgkin's lymphoma was diagnosed after 9, 31, and 40 months, respectively. All of them experienced complete remission to high dose. Neither late neurotoxicity nor compromise of quality of life was found in any of the patients examined. Interpretation Primary polychemotherapy based on high-dose methotrexate (MTX) and cytarabine (Ara-C) is highly efficient in treatment of primary central nervous system lymphoma. About half of patients 60 years or younger can obviously be cured with this regimen without long-term neurotoxic sequelae or quality-of-life compromise. ANN NEUROL 2010;67:182–189

BACKGROUND: A systemic and intraventricular polychemotherapy regimen (the Bonn protocol) without radiotherapy resulted in durable responses in 75% of patients

The trial ALL-BFM 95 for treatment of childhood acute lymphoblastic leukemia was designed to reduce acute and long-term toxicity in selected patient groups with favorable prognosis and to improve outcome in poor-risk groups by treatment intensification. These aims were pursued through a stratification strategy using white blood cell count, age, immunophenotype, treatment response, and unfavorable genetic aberrations providing an excellent discrimination of risk groups. Estimated 6-year event-free survival (6y-pEFS) for all 2169 patients was 79.6% (± 0.9%). The large standard-risk (SR) group (35% of patients) achieved an excellent 6y-EFS of 89.5% (± 1.1%) despite significant reduction of anthracyclines. In the medium-risk (MR) group (53% of patients), 6y-pEFS was 79.7% (± 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation. Omission of preventive cranial irradiation in non–T-ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk (HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% (± 3.2%). Compared without previous trial ALL-BFM 90, consistently favorable results in non-HR patients were achieved with significant treatment reduction in the majority of these patients.

Piperacillin-Tazobactam (Pip-Taz) is an evidence-based empirical treatment of febrile neutropenia in adolescents and adults. No data are available in pediatric cancer patients

Pediatric oncologists from Germany systematically reviewed the literature, considering the use of urokinase in pediatric oncology patients published since 1998 and came to the following conclusions. The use of urokinase to prevent central venous access device (CVAD)–related infections in pediatric cancer patients represents an evidence-based approach, at least in external, tunneled catheters (eg, Hickman, Broviac). The effectiveness of urokinase prophylaxis in decreasing infections and thrombotic events is probably related not only to the concentration and timing of the urokinase intervention but also to the type of CVAD, and perhaps to the intensity of the concomitant chemotherapy program. Urokinase can safely and effectively be used on CVADs with malfunctioning or intraluminal occlusion in a dose of 5000 IU/mL or as salvage 3-hour infusion with 1000 IU/kg/hour. Hitherto, adjuvant treatment with urokinase in the management of CVADs with intraluminal infection still relies on case reports and small case series. In this field, a randomized controlled study is necessary.

Summary. Despite its common adverse effects intravenous (i.v.) amphotericin B is an indispensable antifungal drug in childhood oncology. We report here on three cases of painful cyanotic Raynaud's phenomenon after i.v. administration or inhalation of amphotericin B. A liposomal i.v. preparation of amphotericin B was well tolerated by the infants. Spasms of peripheral vessels mediated by thromboxane A2 could be responsible for the Raynaud's phenomenon. Hence, inhibitors of prostaglandin synthesis are suggested for therapy. Zusammenfassung. Trotz seiner bekannten Nebenwirkungen bei intravenoser Applikation ist Amphotericin B ein unverzichtbares Therapieelement in der Behandlung schwerer Mykosen in der Kinderonkologie. Wir berichten uber drei Falle von schmerzhaftem, zynotischem Raynaud-Phanomen in zeitlichem Zusammenhang mit intravenoser und inhalativer Verabreichung von konventionellem Amphotericin B. Die intravenose Gabe von liposomalem Amphotericin B wurde ohne Nebenwirkungen toleriert. Thromboxan A2-vermittelte Gefasspasmen durften verantwortlich sein fur das Raynaud-Phanomen. Eine logische Therapieoption ware demzufolge die Verabreichung von Inhibitoren der Prosta-glandinsynthese.

The prognosis for young children with medulloblastoma is poor, and survivors are at high risk for cognitive deficits. We conducted a trial of the treatment of this brain tumor by intensive postoperative chemotherapy alone.After surgery, children received three cycles of intravenous chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide) and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved. Leukoencephalopathy and cognitive deficits were evaluated.Forty-three children were treated according to protocol. In children who had complete resection (17 patients), residual tumor (14), and macroscopic metastases (12), the five-year progression-free and overall survival rates (+/-SE) were 82+/-9 percent and 93+/-6 percent, 50+/-13 percent and 56+/-14 percent, and 33+/-14 percent and 38+/-15 percent, respectively. The rates in 31 patients without macroscopic metastases were 68+/-8 percent and 77+/-8 percent. Desmoplastic histology, metastatic disease, and an age younger than two years were independent prognostic factors for tumor relapse and survival. Treatment strategies at relapse were successful in 8 of 16 patients. There were no major instances of unexpected toxicity. In 19 of 23 children, asymptomatic leukoencephalopathy was detected by magnetic resonance imaging. After treatment, the mean IQ was significantly lower than that of healthy controls within the same age group but higher than that of patients in a previous trial who had received radiotherapy.Postoperative chemotherapy alone is a promising treatment for medulloblastoma in young children without metastases.

Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. 'Concentration x time' schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach. In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy).

Despite its wellknown adverse effects, Amphoterin B is an integral part of any supportive therapy in haematology/oncology. We report on a thirteen year old boy with acute myelogenous leukemia and suspected fungoid pneumonia. Shortly after iv or inhalative application of Amphotericin B he repeatedly presented with a Raynaud phenomenon of his toes, which ceased after switching to Ambisome (liposomal unilamellar encapsuled Amphotericin B). Since there is evidence that thromboxane A2-mediated arteriolar spasms of renal vessels provoke the wellknown increase in serum creatinine after Amphotericin B, and in different species pulmonal vasoconstriction has been observed, we speculate that a similar mechanism is responsible for the observed Raynaud phenomenon. Thus we suggest inhibitors of prostaglandine synthesis for therapy.

Following years of successful treatment of children with refractory or relapsed acute myelogenous leukemia (AML) with the Idarubicin (IDA)-FLAG regimen in this study a combination therapy of liposomal daunorubicin (DaunoXome), fludarabine, cytarabine and G-CSF (DNX-FLAG) was emphasized on the assumption that the liposomal anthracyc-line would have lower cardiotoxicity than the non-liposomal one. This pilot trial was designed to explore the potential feasibility and efficacy of this reinduction therapy prior to BMT/PBSCT.

Acute, subacute and chronic neurotoxicity have been observed after the administration of high-dose and/or intrathecal methotrexate (MTX). Acute toxicity is usually transient without permanent damage. Subacute and chronic toxicity are associated with changes in the brain and/or the spinal cord which may be progressive and even lead to coma and death in severe cases. It is believed that MTX can induce direct toxic effects to the CNS by damaging the neuronal tissue. Moreover, MTX interferes with the metabolic pathways of folates, excitatory amino acids, homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, adenosine and biopterins, inducing biochemical alterations which have been associated with neurotoxic symptoms. It has been suggested that acute toxicity is partly mediated by adenosine, whereas homocysteine, S-adenosylmethionine/S-adenosylhomocysteine, excitatory amino acids and biopterins may play an important role in the development of subacute and chronic toxicity. A better understanding of the pathogenesis of MTX neurotoxicity would offer the possibility of developing new therapeutic strategies for its treatment or prevention.

BACKGROUND In the past 20 years, a dramatic improvement in the prognosis of patients with hepatoblastoma (HB) has been achieved by combining surgery with chemotherapy in several national and international trials. A worldwide, unsolved problem remains the treatment of patients with advanced or metastatic HB. METHODS The German Cooperative Pediatric Liver Tumor Study HB 94 was a prospective, multicenter, single-arm study. The study ran from January 1994 to December 1998. The protocol assessed the efficiency of chemotherapy consisting of cisplatin, ifosfamide, and doxorubicin (CDDP/IFO/DOXO) and/or etoposide and carboplatin (VP16/CARBO). The prognostic significance of the surgical strategy, pretreatment factors, and tumor characteristics for disease free survival (DFS) were analyzed. RESULTS Sixty-nine children with HB were treated in the HB 94 study. The median follow-up of survivors was 58 months (range, 32–93 months). Fifty-three of 69 patients (77%) remained alive, and 16 of 69 patients (23%) died. Long-term DFS was as follows: 26 of 27 patients had Stage I HB, 3 of 3 patients had Stage II HB, 19 of 25 patients had Stage III HB, and 5 of 14 patients had Stage IV. A complete resection of the primary tumor was achieved in 54 of 63 patients (86%). Six children (8%) had no surgical treatment. Twenty-two tumors were resected primarily, and 41 children underwent surgery after initial chemotherapy. Two children underwent liver transplantation. There was no perioperative death. Forty-eight children received primary chemotherapy with CDDP/IFO/DOXO. Forty-one of 48 children achieved partial remission after CDDP/IFO/DOXO. Eighteen children with advanced or recurrent HB underwent VP16/CARBO chemotherapy, with a response achieved by 12 children. The relevant pretreatment prognostic factors were growth pattern of the liver tumor (P = 0.0135), vascular tumor invasion (P = 0.0039), occurrence of distant metastases (P = 0.0001), initial α-fetoprotein level (P = 0.0034), and surgical radicality (P < 0.0001). CONCLUSIONS The current results underline the necessity of preoperative chemotherapy in all children with HB. Complete tumor resection is one of the main prognostic factors. Cancer 2002;95:172–82. © 2002 American Cancer Society. DOI 10.1002/cncr.10632

10020 Background: Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG has prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with vinorelbine and radiotherapy, a pilot phase 2 protocol launched in 2009 combined nimotuzumab with concomitant radiation and vinorelbine. A protocol amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR+PR+SD) according to the RECIST. This report concerns the outcome of this whole strategy. Methods: Vinorelbine 20 mg/m2 was administered weekly, with nimotuzumab 150 mg/m2 in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Then vinorelbine 25 mg/m2and nimotuzumab were given every other week until the tumor progressed or for up to two years. Re-irradiation consisted of 19.8 Gy, fractionate...

The beta-lactam/beta-lactamase inhibitor combinations are a good choice for empirical antimicrobial therapy in febrile neutropenic patients, because their antibacterial spectra include both gram-negative and gram-positive pathogens. This trial was initiated to assess the efficacy and safety of piperacillin with the beta-lactam inhibitors sulbactam (PSG group) or tazobactam (PTG group) and gentamicin as initial therapy in febrile neutropenia of pediatric patients. In a prospective study, 239 episodes of fever and neutropenia were analyzed for the clinical and microbiological response dependent on infection etiology and treatment group: 66.5% of episodes were classified as fever of unknown origin (FUO) and 33.5%, as microbiologically or clinically documented infections; 19.2% of all episodes were due to bacteremia, predominantly caused by gram-positive organisms (69.6%). The response to the initial therapy was 55.2% overall and 65.4% in episodes of FUO with a significant higher success rate in the PSG group than in the PTG group (70.1% vs. 52.4%, P=0.039), and 35.0% in documented infections. In episodes with documented infection longer duration of fever and antimicrobial therapy was recorded than for FUO episodes. Four patients died of causes related to infection. Fever relapse occurred in 26 episodes (11.1%), predominantly in patients who were still neutropenic. Toxic side effects were minimal. The initial therapy of piperacillin with sulbactam or tazobactam in combination with gentamicin is well tolerated, and its efficacy is comparable to that of other combination therapies or of monotherapy with beta-lactam antibiotics in pediatric neutropenic cancer patients.

The prognosis of refractory, relapsed or secondary AML is poor and effective reinduc tion regimens are rare. Allogeneic or autolo gous bone marrow transplantation (BMT or ABMT) offers a chance for long-term survival in these cases. Thus, a phase II trial of a com bination therapy with fludarabine, HD-ARA C, idarubicin and G-CSF was designed to study the feasibility and efficacy in the treatment of poor prognosis AML of childhood as a possible option prior to BMT or ABMT.

prophylaxis, receive a biweekly schedule of 2.5 mg/kg L-AmB (AmBisome; i.e., on Monday and Thursday; 5 mg/kg/week). The AmBisome prophylaxis is given as a 1-hour infusion [2] . The availability of an outpatient care team with highly experienced oncologic nurses and an attending physician (on call) enabled us to offer LAmB as home care infusion to 16 paediatric cancer patients. The median age was 6 years (10 months to 19 years); 5 patients were male; the underlying malignant diseases were ALL (n = 9), AML (n = 2), B-NHL (n = 1), systemic histiocytosis (n = 1), neuroblastoma (n = 4) and primitive neuroectodermal tumors of the CNS after high-dose chemotherapy (n = 1). In 10 of 16 patients (63%) there was a relapse of the disease. L-AmB was administered for the following indications: primary prophylaxis (n = 11), secondary prophylaxis after an IFI in their recent medical history (n = 2) or as ongoing treatment of histologically confirmed IFI of the lung, the sinus or the CNS (n = 3) [5] . In total, 147 single doses (1–6 mg/kg/dose) of L-AmB were administered (1–55/patient) as a 1to 2-hour infusion through a Broviac (n = 13) or port (n = 3) central venous catheter, because all high-risk paediatric patients have such a long-term central venous device in place. In all patients, the first dose of L-AmB was administered in the hospital or in the Kruger et al. [1] recently presented results of haemopoietic stem cell transplantation in patients with a history of invasive or systemic fungal infection (IFI) in Acta Haematologica . Their strategy of secondary prevention was either administration of liposomal amphotericin B (L-AmB) or an early switch to L-AmB after administration of azoles. Mehta et al. [2] recently published a pharmacokinetic study of high-dose (10 mg/kg) weekly AmBisome TM prophylaxis in 14 young children (median age 3 years; range 4.5 months to 9 years and 9 months). The authors concluded that weekly administration of AmBisome provided sufficient plasma concentration of the free active drug (non-lipid-complex amphotericin). We discussed the pros and cons of our current practice of itraconazole prophylaxis in the management of high-risk patients [3] and would like to communicate our uncontrolled experience with biweekly L-AmB prophylaxis as home care infusion in paediatric cancer patients, who do not tolerate itraconazole or who do not achieve protective itraconazole plasma concentrations. Low-dose L-AmB (50 mg L-AmB every other day) has been used to reduce the incidence of IFI in patients with haematological malignancies and prolonged neutropenia ( 1 10 days) [4] . In our unit, those patients at high risk of IFI, who are not eligible for itraconazole Accepted after revision: March 9, 2007 Published online: May 29, 2007

We report on an 18.5-year-old woman with osteosarcoma and delayed methotrexate (MTX) elimination due to renal failure after high-dose MTX, in whom rescue with high doses of folinic acid caused intolerable side effects. In this life-threatening clinical situation, the patients was rescued by the administration of recombinant carboxypeptidase G2, a bacterial enzyme that rapidly hydrolyzes MTX into inactive metabolites. This is the first report on the successful clinical use of this alternative catabolic route for the elimination of MTX.

8557 Background: To evaluate survival, quality of life and neurotoxic sequelae in long-term survivors with primary central nervous system lymphoma (PCNSL) after systemic and intraventricular chemotherapy with deferred radiotherapy. Patients and Methods: From 09/1995 to 12/2001, 65 patients with PCNSL (median age 62 years) were enrolled in a pilot/phase II study evaluating chemotherapy without radiotherapy; thirty patietns were younger than 60 years. A high-dose methotrexate (MTX) (cycles 1,2,4,5) and cytarabine (ara-C) (cycles 3,6) based systemic therapy (including dexamethasone, vinca-alkaloids, ifosfamide and cyclophosphamide) was combined with intraventricular MTX, prednisolone and ara-C. All living patients were contacted, a neurological examination, comprehensive neuropsychological testing, Quality of Life (QoL) - Assessment (EORTC QLQ-C30 (Version 3.0) und EORTC QLQ-BN20) and imaging were performed. Results: Twenty-one of 65 patients (32 %) are alive. Of these, 17 patients were younger than 60 years...

8579 Background: Methotrexate (MTX) is the most efficient chemotherapeutic drug in primary central nervous system lymphoma (PCNSL); it directly interferes with methionine metabolism. Patients and Methods: Eight functional polymorphic variants influencing methionine metabolism were investigated in 65 PCNSL patients and were analyzed for their impact on the occurrence of confluent CNS white matter changes (WMC) (Pearson’s Chi-square test and multinominal regression analysis) and for their influence on survival (univariate Log Rank and multivariate COX regression analyses). Results: Twenty/65 (31%) patients developed WMC, which was significantly predicted by the genotype of methylenetetrahydrofolate reductase c.1298A>C (p.E429A; patients with WMC, AA/AC/CC: 0.80/0.10/0.10; patients without WMC: 0.40/0.47/0.13; nominal logistic regression: χ2=11.54; p=0.003). In addition, the transcobalamin 2 variant c.776C>G (p.P259R) influenced the occurrence of WMC (patients with WMC: 0.20/0.45/0.35; patients without WMC: ...

2058 Background: Despite multimodal therapy children with newly diagnosed intrinsic pontine glioma (PG) have a dismal prognosis. Recently novel therapeutic approaches were taken in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase III trial was designed following the excellent results of a phase II study in resistant diffuse intrinsic pontine gliomas (ASCO 2007; 2006) to explore the feasibility and efficacy of the monoclonal anti-EGFR antibody (Nimotuzumab) in the primary treatment of these patients. Methods: Pediatric patients with newly diagnosed PG with radiologically proven disease and a life expectancy of minimum 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for twelve weeks, concomitantly with radiotherapy at weeks 3 to 8 to a total dose of 54 Gy. In case of non-PD a consolidation therapy of 150 mg/m2 of nimotuzumab biweekly followed until dis...

2006 Background: Despite multimodal therapy most children with high grade gliomas (HGG), including glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and intrinsic pontine glioma (PG) have an infaust prognosis if they relapse or are refractory to the primary treatment. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (nimotuzumab) in the treatment of these patients. Patients and Methods: Pediatric patients with GM, AA or PG with radiologically proven progressive disease following primary or relapse treatment and a life expectancy of less than 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for six weeks, and in case of non-PD a consolidation therapy of 4 infusions in a 3 week interval. The response was documented by MRI in week 8 and 21 and only clinically in rapidly progresssive disease. Results: Between June 2004 and April 2006 47 patients aged 4 to 17 years (median 11 years) were enrolled in this study. 46 patients were evaluable for response. According to RECIST 14 out of 46 patients showed objective responses (PR n=4, SD n=10) in the MRI as the best response with a median change in the largest diameter of the index lesion of -11% (-50% to +16%). The PR/SD were seen in 2/13 patients with GM, 2/11 with AA and 10/22 with PG. Thirteen patients continued with the consolidation therapy and showed 4 PR, 3 SD and 6 PD in week 21. The median overall survival was 4.4 months (0.3–25.4 months) and was significantly better for repsonders (median 10 months) than for nonresponders (median 4.0 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of nimotuzumab is well tolerated and safe. Nimotuzumab has cytotoxic efficacy in heavily pre- treated relapsed HGG. Based on this data a phase III trial with nimotuzumab in newly diagnosed diffuse intrinsic pontine gliomas concomittent with radiotherapy was introduced in first quarter 2006. No significant financial relationships to disclose.

1522 Background: Children and adolescents suffering from high grade gliomas (HGG) have a poor prognosis when they relapse during or after primary treatment. Thus novel therapeutic approaches as the inhibition of growth-signalling pathways are needed. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (Nimotuzumab) in the treatment of these patients. Methods: Pediatric patients with glioblastoma multiforme, anaplastic astrocytoma or intrinsic pontine glioma (PG) with radiologically proven progressive disease following primary or relapse treatment were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 Nimotuzumab for six weeks, and in case of non-PD a subsequent consolidation therapy of four infusions in a three week interval. The response was documented by MRI in week 8 and 21. Results: Between June 2004 and August 2005 34 patients aged 5.0 to 17.4 years (median 10.9 years) were enrolled in this study. According to RECIST 12 out of 34 patients showed response (PR n=1, SD n=11) in the MRI of week 8 after the induction therapy with a median change in the largest diameter of the index lesion of −5% (−39 to +16%) accompanied by clinical deterioration in four and markedly clinical improvement in two patients. Surprisingly, 9 PR/SD were seen in the 14 patients with PG. Eight patients continued with the consolidation therapy. So far 5 out of 8 Patients are evaluable for response after consolidation therapy and showed three PR, one SD and one PD in week 21. Eight patients with consolidation therapy are free of progression for a median of 7.5 months (1.2–13.2 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of Nimotuzumab is well tolerated and safe. It has cytotoxic efficacy in heavily pre-treated relapsed HGG, especially in intrinsic pontine glioma. A phase III study for patients with newly diagnosed PG is warranted. [Table: see text]

In primary CNS lymphoma (PCNSL) irradiation alone is no longer the primary treatment and combination with chemotherapy has significantly improved response and survival. However, patients treated with combined modality therapy suffer from significant neurotoxicity. Therefore, studies with chemotherapy alone have been carried out. We recently reported on a phase II multicenter trial to evaluate event-free survival, overall survival, response rate, response duration and toxicity of combination chemotherapy in patients with previously untreated PCNSL. 65 consecutive patients with histologically proven PCNSL received a total of 6 courses of combination chemotherapy with 3 different courses of chemotherapy. In patients with response these 3 cylces were repeated. The combination chemotherapy included high-dose methotrexate (MTX) (5g/m2, course 1,2,4,5) and cytarabine (ara-C) (3g/m2/d, d1-2, courses 3,6) combined with dexamethasone (courses 3–6), vinca alkaloids and ifosfamide alternating with cyclophosphamide. In addition, MTX, prednisolone and ara-C were applied via an Ommaya or Rickham reservoir in each course. The study population included 65 consecutive patients with a median age of 62 years with a range between 27 and 75. 62 patients are evaluable for response. There were 9% therapy-related deaths mainly due to neutropenic infections. Ommaya reservoir infections occurred in 12/64 (19%) and acute transient MTX related encephalopathy in 2 (subacute in 1) patients. The 5-year-survival of patients below 61 years was 75%, of patients of 61 years or older 17% (Pels H et al., J Clin Oncol21(24), 2003). The results for patients younger than 60 years could be superior to previously reported therapy regimes. The survival rates for patients above 60 years are comparable to those reported for combined radiochemotherapy. However, in contrast to radiochemotherapy permanent treatment-associated neurotoxicity is infrequent. Based on these data we constructed a follow-up trial. Patients below the age of 61 are treated as in the antecedent protocol without intraventricular therapy. Patients above 60 are treated in a protocol modified by the addition of procarbazine in 2 cycles and a maintenance therapy with procarbazine. First results of this follow-up trial will be presented.

Thirty-six children and adolescents received 42-h methotrexate (MTX) infusions in doses of 5.5-22 g/m2 as a single drug or as part of a combination chemotherapy for relapsed childhood leukemias or solid tumors. In a total of 109 courses serum MTX concentrations were maintained at 2 x 10(-5) -2 x 10(-4) M for 42 h before leukovorin rescue was started. There were responses in one of two hemangiopericytomas, two of five Ewing's sarcomas, and six of eight rhabdomyosarcomas. In ALL, NHL, and neuroblastomas, responses were seen with 42-h MTX infusions as part of a combination chemotherapy. The major toxicities were mucositis in 45%, nausea and vomiting in 35%, and hepatic toxicity in 25% of the courses. Bone marrow depression as well as neuro- and nephrotoxicity were rare. Long-term MTX infusions in high doses are strongly recommended for the treatment of relapsed childhood malignancies because of their efficacy and mild toxicity.

Eleven young patients with relapsed childhood malignancies received continuous infusions of 5-10 mg/m2/day doxorubicin. 30 infusions were given via a central venous access until signs of mucositis showed up (7-52 days). Other toxicity was low, both bone marrow depression and fever and neutropenia occurred in 7/30 and 5/30 courses of therapy, respectively. No signs of liver or cardiac toxicity were seen in these heavily pretreated patients. In 8/11 patients tumor regression was documented, though only two partial remission were noted. Continuous infusions of doxorubicin are an effective and relatively non-toxic treatment for relapsed childhood malignancies. Since this form of therapy enables good quality of life and medical care on ambulatory basis, a phase II-study of low-dose doxorubicin for relapsed tumors is justified.