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03a.Gardner.121-6 5/23/01 8:45 AM Page 121 High-Dose Chemotherapy With Autologous
Stem Cell Rescue for the Treatment
of Patients With Brain Tumors
Sharon Gardner, Jonathan Finlay
New York University Medical Center, Department of Pediatric Oncology, ABSTRACT
Despite the use of surgery, irradiation, and standard-dose chemotherapy, the majority of patients with malignant brain tumors succumb to their disease. Over thepast 15 years, investigators from several institutions have used high-dose chemo-therapy with autologous stem cell rescue (ASCR) to try to improve survival in thesepatients. One of the earliest studies was a 2-drug regimen using thiotepa andetoposide in patients with recurrent brain tumors (Finlay JL, et al. J Clin Oncol14:2495–2503, 1996). The overall response rate was 23% in 35 patients withradiographically measurable disease who survived at least 28 days after autologousbone marrow rescue. Subsequent studies have used several different combinations ofchemotherapy, including thiotepa/etoposide with and without carboplatin,thiotepa/busulfan, thiotepa/cyclophosphamide, and cyclophosphamide/melphalan.
Responses have been seen in patients with a variety of recurrent brain tumorsincluding medulloblastoma, primitive neuroectodermal tumor (PNET), high-gradeglioma, and central nervous system (CNS) germ cell tumors. Because of theseencouraging results, high-dose chemotherapy with ASCR has more recently beenused in young children newly diagnosed with brain tumors to avoid radiation therapywith its associated long-term sequelae in very young children. Responses withdurable event-free survival were seen in children with medulloblastoma, PNET, andependymoma. This approach is presently being examined by cooperative groups.
There are 2 studies using sequential courses of high-dose chemotherapy with ASCRin children newly diagnosed with brain tumors currently under way within theChildren’s Oncology Group (COG). Future studies include examining the use ofhigh-dose chemotherapy with ASCR vs. standard-dose therapy in a randomizedsetting and incorporating new agents such as temozolomide as part of the cytore-ductive regimen. In addition, the use of high-dose chemotherapy with ASCR may becombined with other approaches including immunomodulation and gene therapy.
03a.Gardner.121-6 5/23/01 8:45 AM Page 122 INTRODUCTION
Brain tumors are the second most common malignancy in children and the most common solid tumor. They occur with a frequency of 24.5 per million children peryear.1 In adults, the incidence of CNS tumors per 100,000 population is 6.5 at 35years, increasing to 70 by 70 years of age.2 In the past 10 years, the survival ratesfor many malignancies, particularly pediatric tumors, have significantly improved.
However, the survival of many children and adults with malignant brain tumorsremains poor.
Over the past 15 years, investigators from several different institutions have used high-dose chemotherapy with autologous stem cell rescue in the treatment of patientswith malignant brain tumors. The drugs considered to have the best tumoricidalactivity against brain tumors are alkylating agents such as thiotepa, melphalan, BCNU,cyclophosphamide, and the platinum compounds. These drugs are particularly wellsuited for use at high doses with autologous stem cell support because of their steeplinear-log dose-response curve. In addition, the principal dose-limiting toxicity formany of these drugs is bone marrow suppression. These drugs are cell-cyclenonspecific and therefore are not schedule dependent. Furthermore, the addition ofnonalkylating agents, such as etoposide, synergistically enhances tumor kill.
One of the earliest studies using combination chemotherapy at high doses was a 2-drug regimen using thiotepa and etoposide with autologous bone marrowrescue in patients with recurrent brain tumors.3 The study was piloted at theUniversity of Wisconsin–Madison in 1986 and became a cooperative group studyin the Children’s Cancer Group in 1988. Of 35 patients with radiographicallymeasurable disease who survived at least 28 days after autologous bone marrowrescue, the overall response rate (complete and partial responses) was 23%.
Objective responses were seen in 4 of 14 assessable patients with high-gradeglioma and in 2 of 6 patients with PNET.
In 1988, a 3-drug regimen using BCNU in addition to thiotepa and etoposide was initiated. Although responses were seen, the toxic mortality rate as a result ofmultiorgan system failure was unacceptably high.4 In 1989, a third study usingcarboplatin with thiotepa and etoposide was opened at Memorial Sloan KetteringCancer Center. There have been approximately 70 patients with brain tumorsrecurrent or refractory after irradiation and/or conventional-dose chemotherapytreated with this approach. Because of encouraging results seen in patients withrecurrent brain tumors, this approach has more recently been used in infants andyoung children newly diagnosed with malignant brain tumors in an attempt to limitand, if possible, avoid the use of irradiation because of its long-term effects on thegrowth and development of young children.
Preliminary results of the 3-drug regimen (carboplatin, thiotepa, and etoposide) in patients with recurrent brain tumors as well as the use of high-dose 03a.Gardner.121-6 5/23/01 8:45 AM Page 123 chemotherapy with ASCR in infants and young children newly diagnosed withmalignant brain tumors are presented. In addition, results of studies using high-dose chemotherapy performed by other investigators are discussed.
MATERIALS AND METHODS
Recurrent Malignant Brain Tumors in Children and Young Adults:
Study of Carboplatin, Thiotepa, and Etoposide
Patients with high-risk brain tumors that had either recurred or proven resistant to conventional chemotherapy and radiation therapy were considered eligible forthis study. Patients had to have minimal residual disease before undergoing thehigh-dose chemotherapy. This could be achieved with either surgery or standard-dose chemotherapy.
Cytoreduction consisted of carboplatin as a 4-hour infusion on days –8, –7, and –6. The carboplatin was initially administered at a dose of 500 mg/m2 per day; itwas subsequently dosed using the Calvert formula with an area under the curve of7 per day calculated from the urine creatinine clearance collected before each doseof carboplatin.5,6 Thiotepa was administered at a dose of 300 mg/m2 per day as a3-hour infusion on days –5, –4, and –3. The etoposide was administered on thesame days as the thiotepa at a dose of 250 mg/m2 per day over 3 hours each day.
Autologous stem cells, initially from bone marrow and more recently fromperipheral blood, were reinfused on day 0.
Newly Diagnosed Malignant Brain Tumors in Children
Յ6 Years of Age: Intensive Induction Chemotherapy
Followed by Consolidation With High-Dose Carboplatin,
Thiotepa, and Etoposide With Autologous Stem Cell Rescue
Eligibility criteria included all children <3 years of age newly diagnosed with a malignant brain tumor irrespective of residual disease or neuraxis dissemination. Inaddition, children 3 to 6 years of age with poor-risk tumors, including 1) all high-grade gliomas, brain-stem tumors, and supratentorial PNETs, 2) medulloblastomaswith neuraxis dissemination, and 3) ependymomas with residual disease and/orneuraxis dissemination, were eligible.
Patients received 5 cycles of induction chemotherapy including cisplatin, vincristine (first 3 cycles only), cyclophosphamide, and etoposide. Patients who hadresponsive disease or no evidence of disease after completion of the induction phaseproceeded with consolidation chemotherapy. The consolidation phase consisted ofhigh-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue asdescribed above for patients with recurrent brain tumors. Children who had no 03a.Gardner.121-6 5/23/01 8:45 AM Page 124 evidence of disease before consolidation did not receive any irradiation. Childrenwith unresectable disease before consolidation received involved-field irradiationapproximately 6 weeks after the high-dose chemotherapy.
Recurrent Malignant Brain Tumors in Children and Young Adults:
Study of Carboplatin, Thiotepa, and Etoposide
Seventy patients with malignant brain tumors that had recurred or were refractory to irradiation and/or standard-dose chemotherapy were treated withcarboplatin, thiotepa, and etoposide at Memorial Sloan Kettering Cancer Center orNew York University Medical Center between 1989 and 2000. Diagnoses includedmedulloblastoma (n = 17), other PNET (n = 13), malignant glioma (n = 25), germcell tumor (n = 6), ependymoma (n = 5), and other (n = 4). Ages ranged from 1 to45 years (median, 14 years). Thirty-seven patients were rescued with bone marrow,30 received peripheral blood, and 3 received both bone marrow and peripheralblood stem cells. Carboplatin was dosed using the Calvert formula in 22 patientswho received bone marrow and in all patients who received peripheral blood stemcells. Overall, the toxic mortality rate was 11 of 70 (16%); however, in the past 5years, the toxic mortality rate has been 1 of 33 (3%).
The 4-year event-free survival for patients with recurrent malignant glioma rescued with bone marrow was 10%. For patients with medulloblastoma andsupratentorial PNET, the 4-year event-free survival was 35%. Five of 6 patientswith recurrent CNS germ cell tumors are alive without evidence of disease, 4, 12,15, 36, and 45 months after stem cell rescue.
Newly Diagnosed Malignant Brain Tumors in Children
<6 Years of Age: Intensive Induction Chemotherapy
Followed by Consolidation With High-Dose Carboplatin,
Thiotepa, and Etoposide With Autologous Stem Cell Rescue
Between 1992 and 1997, 75 children <6 years of age were enrolled in Head Start I. Diagnoses included medulloblastoma (n = 17), other PNETs (n = 21), epen-dymoma (n = 12), high-grade glioma and rhabdoid tumors (n = 19), and brain-stemtumors (n = 6).
The median overall survival for the entire cohort was 25 months, with an estimated 6-year overall survival of 32%. The median event-free survival for theentire cohort was 14 months, with an estimated 3-year event-free survival rate of29%. Patients with completely resected tumors had a better survival than those withincomplete resection (4-year overall survival of 57% vs. 30% [P=.03] and 2-year 03a.Gardner.121-6 5/23/01 8:45 AM Page 125 event-free survival of 54% vs. 25% [P=.06], respectively). Survival in patients <3years of age was not inferior to that in older children (median overall survival of39 vs. 32 months, respectively; P1=.4). Prognosis varied greatly between histologicsubtypes. The estimated 4-year overall survival was 57% for medulloblastoma,38% for PNET, 47% for ependymoma, and 16% for brain-stem tumors.
DISCUSSION
Most patients with recurrent malignant brain tumors have a dismal outcome with standard-dose therapy. Not too long ago, some investigators suggested thatroutine surveillance scans in patients who had completed therapy for medullo-blastoma were not even warranted, since no patients with recurrent diseasesurvived.7 However, the use of autologous bone marrow and, more recently,peripheral blood stem cells has allowed the administration of much higher doses ofchemotherapy. In addition, improvements in supportive care and the use ofautologous peripheral blood stem cells have significantly decreased toxicityassociated with this therapy.
As expected, the best responses in the 3-drug regimen (carboplatin, thiotepa, and etoposide) were seen in patients with brain tumors, which tend to be morechemosensitive. These included medulloblastoma, supratentorial PNET, and germcell tumors. Other investigators have found similar results. Mahoney et al.8 reportedthe results of a pilot study from the Pediatric Oncology Group using escalating dosesof cyclophosphamide and fixed doses of melphalan with autologous bone marrowrescue for children with recurrent or progressive malignant brain tumors. Responseswere seen in 7 of 18 evaluable patients including 4 patients with medulloblastoma,2 with germinoma, and 1 with ependymoma. The French have also seen responsesin children using the combination of thiotepa and busulfan. Kalifa et al.9 reported a75% response rate in previously treated patients with medulloblastoma/PNET.
Bouffet et al.10 recently presented the results of the French Pediatric OncologySociety using high-dose etoposide and thiotepa for patients with refractory andrecurrent malignant intracranial germ cell tumors. Six of 11 evaluable patients hadresponses (3 CR and 3 PR).
The treatment of very young children with malignant brain tumors is partic- ularly challenging because of the aggressive nature of their tumors and alsobecause of the potential long-term sequelae associated with treating these patientsat such a young age. Preliminary results of the Head Start therapy indicate that asignificant number of children newly diagnosed with malignant brain tumors canachieve durable remissions without the use of radiotherapy or prolongedmaintenance chemotherapy.11 This is particularly true for children with medullo-blastoma, supratentorial PNET, and ependymoma. Additional studies are needed toconfirm these results. At the present time there are 2 studies underway in COG for 03a.Gardner.121-6 5/23/01 8:45 AM Page 126 children newly diagnosed with malignant brain tumors involving high-dosechemotherapy with autologous stem cell rescue.
Unfortunately, there are still patients with malignant brain tumors for whom the use of high-dose chemotherapy has not yet proven to be effective. These includepatients with recurrent ependymoma or recurrent brain stem tumors and patientsnewly diagnosed with malignant gliomas. For these patients, modifications in thepresent high-dose regimens as well as other approaches are needed. Future studiesinclude the use of other cytoreductive agents including the new oral alkylatingagent temozolomide as well as intravenous busulfan. In addition, other approachesincluding the use of antiangiogenesis agents as well as immunomodulation andgene therapy, with and without high-dose chemotherapy, are being explored.
REFERENCES
1. Duffner PK, Cohen ME, Myers MH, Heise HW. Survival of children with brain tumors: SEER program 1973–1980. Neurology 36:597–601, 1986.
2. Annegers JF, Schoenberg BS, Okazaki H, Kurland LT. Epidemiologic study of primary intracranial neoplasms. Arch Neurol 38:217–221, 1981.
3. Finlay JL, Goldman S, Wong MC, et al. Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNStumors. J Clin Oncol 14:2495–2503, 1996.
4. Papadakis V, Dunkel IJ, Cramer LD, et al. High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the treatment of high risk central ner-vous system tumors. Bone Marrow Transplant 26:153–160, 2000.
5. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748–1756, 1989.
6. Newell DR, Pearson AD, Balmanno K, et al. Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. J Clin Oncol 11:2314–2323, 1993.
7. Torres CF, Rebsamen S, Silber JH, et al. Surveillance scanning of children with medul- loblastoma. N Engl J Med 330:892–895, 1994.
8. Mahoney DH, Strother D, Camitta B, et al. High-dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors inchildren: a pilot Pediatric Oncology Group study. J Clin Oncol 14:382–388, 1996.
9. Kalifa C, Hartmann O, Demeocq F, et al. High-dose busulfan and thiotepa with autolo- gous bone marrow transplantation in childhood malignant brain tumors: a phase II study.
Bone Marrow Transplant 9:227–233, 1992.
10. Bouffet E, Baranzelli MC, Patte C, et al. High dose etoposide and thiotepa for refractory and recurrent malignant intracranial germ cell tumours (CNS-GCT). 9th InternationalSymposium on Pediatric Neuro-Oncology [abstract]. Neuro-Oncology 2:S72, 2000.
11. Mason WP, Grovas A, Halpern S, et al. Intensive chemotherapy and bone marrow res- cue for young children with newly diagnosed malignant brain tumors. J Clin Oncol16:210–221, 1998.

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