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Paediatric Drugs 2006Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite... (Review)
Review
Strategies for the treatment of childhood cancer have changed considerably during the last 50 years and have led to dramatic improvements in long-term survival. Despite these accomplishments, CNS tumors remain the leading cause of death in pediatric oncology. Astrocytic tumors form the most common histologic group among childhood brain tumors. They are a heterogeneous group that from a practical therapeutic point of view can be subdivided into low-grade astrocytomas (LGA), optic pathway gliomas (OPG), high-grade astrocytomas (HGA), and brainstem gliomas (BSG). This article focuses on the practical application of treatments that lead to long-term survival, improved quality of life, and reduced long-term complications. Improvement in therapy has led to better outcomes for patients with LGA and OPG. Careful follow-up without any treatment is indicated for a small percentage of patients diagnosed with LGA with an indolent course including children with neurofibromatosis type 1 (NF1). Surgery is the main recommended treatment for children with resectable LGA. Radiation therapy is generally recommended for children with progressive LGA, or after failure of chemotherapy, accomplishing tumor control at 10 years in over 60% of patients. Cytotoxic chemotherapy is usually reserved for children who have had treatment failure with surgery and radiation therapy. It is also offered for children who are too young to be treated with radiation or to defer or avoid radiotherapy. Carboplatin and vincristine achieve 5% complete and 28% partial responses but the use of vincristine is criticized due to poor penetration of the CNS. A regimen of tioguanine, procarbazine, mitolactol, lomustine, and vincristine is frequently administered as an alternative to carboplatin and vincristine in LGA. The introduction of temozolomide has allowed better responses, including a 24% complete response rate compared with 0-5% complete response rates with the previous regimens. OPG are usually histologically LGA, and are treated with similar chemotherapy regimens. OPG is the most common type of brain tumor associated with NF1. Tumor growth in some of these patients is slow with no treatment recommended for an extended period of time. The prognosis for children with the remaining types of astrocytomas remains poor. Surgical resection is typically the first step in the treatment of HGA followed in older children by radiation therapy. The data regarding chemotherapy are mixed. Combination chemotherapy before or after radiation, including cisplatin, carmustine, cyclophosphamide, and vincristine or carboplatin, ifosfamide, cyclophosphamide, and etoposide has provided disappointing results. Clinical trials with temozolomide and agents directed against single targets have not shown substantially better results, but it is hoped that currently conducted studies will provide better outcomes. Diffuse intrinsic BSG are among the most difficult-to-treat brain tumors. Surgical treatment is not recommended for diffuse intrinsic BSG and standard radiation therapy is typically given in children aged >3 years. None of the numerous chemotherapy regimens, including temozolomide, has provided a significant response rate or an improvement in survival. It is expected that newer agents affecting multiple targets such as AEE-788 and antineoplastons, and combinations of single-targeted agents with chemotherapy will provide better results. Careful evaluation of histology, location of the tumor, patient age, and consideration of treatment-related morbidity play an important part in selecting between clinical observation, surgery, radiation, chemotherapy, or investigational agents. The goals of treatment for astrocytic tumors should extend well beyond objective responses and increased survival. Improvement of quality of life is an equally important objective of treatment. Radiation therapy and chemotherapy result in serious late toxicities.
Topics: Astrocytoma; Central Nervous System Neoplasms; Child; Clinical Trials as Topic; Combined Modality Therapy; Humans; Meta-Analysis as Topic
PubMed: 16774296
DOI: 10.2165/00148581-200608030-00003 -
Blood Feb 2006Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free... (Randomized Controlled Trial)
Randomized Controlled Trial
Relapse is a major obstacle in the cure of acute myeloid leukemia (AML). The Pediatric Oncology Group AML Study 9421 tested 2 different strategies to improve event-free survival (EFS) and overall survival (OS). Patients were randomized to receive standard-dose DAT (daunorubicin, cytarabine, and thioguanine) or high-dose DAT during induction. To interfere with P-glycoprotein (P-gp)-dependent drug efflux, the second randomization tested the benefit of cyclosporine (CsA) added to consolidation chemotherapy. Of the 282 children randomly assigned to receive standard DAT induction, 248 (87.9%) achieved remission compared to 253 (91%) of the 278 receiving high-dose DAT (P = ns). Children with HLA-identical sibling donors who achieved a complete remission received an allogeneic bone marrow transplant as consolidation. For the 83 patients receiving a matched related donor bone marrow transplantation (BMT), the 3-year disease-free survival (DFS) is 67%. Of the 418 children who achieved remission and went on to consolidation with and without CsA, the DFS was 40.6% and 33.9%, respectively (P = .24). Overexpression of P-gp was infrequent (14%) in this pediatric population. In this study, intensifying induction with high-dose DAT and the addition of CsA to consolidation chemotherapy did not prolong the durations of remission or improve overall survival for children with AML.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Cyclosporine; Disease-Free Survival; Doxorubicin; Female; Humans; Immunosuppressive Agents; Infant; Karyotyping; Leukemia, Myeloid, Acute; Leukocyte Count; Male; Mitolactol; Remission Induction; Survival Analysis; Tamoxifen; Treatment Outcome
PubMed: 16254147
DOI: 10.1182/blood-2004-08-3218 -
Anticancer Research 2004This prospective semi-randomized study was undertaken to assess the effects and effectiveness of alkylating drugs in a preoperative setting. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
BACKGROUND
This prospective semi-randomized study was undertaken to assess the effects and effectiveness of alkylating drugs in a preoperative setting.
PATIENTS AND METHODS
During a 6-year period preceding February 2000, 80 patients with Stage II-IVa (AJCC 2002) squamous cell cancer of the oral cavity were treated. Thirty patients (Group N) received a combination of bleomycin, vincristine and methotrexate (BVM). In the alkylating group, thirty patients (Group A/M) received BVM and mitolactol (dibromodulcitol), while twenty patients (Group A/C) received BVM and cisplatin. Patients underwent surgery within 3 weeks after chemotherapy. Clinical response rate and tumour-free survival were investigated.
RESULTS
Clinical complete response was 30%-36% (Group N-A). Partial response was 57%-56% (Group N-A). Side-effects were moderate and reversible. Nausea, anaemia and leucopenia were observed in the alkylating (A) group, while other side-effects (alopecia, mucositis, gastritis) were similar in both groups. The observation time was 36 months. Regional disease-free survival showed a significant difference, favouring the non-alkylating (N) group (p=0.03). A higher metastasis rate was observed in the alkylating (A) group.
CONCLUSION
Cisplatin and mitolactol in combination with BVM showed higher local control and lower disease-free survival than BVM alone. That was mostly due to a higher rate of regional metastatis formation in the alkylating-treated patients. This may be a late side-effect caused by the immunosuppressive and myelosuppressive effect of alkylating agents.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Disease-Free Survival; Female; Humans; Male; Methotrexate; Middle Aged; Mitolactol; Oropharyngeal Neoplasms; Prospective Studies; Treatment Failure; Vincristine
PubMed: 15330214
DOI: No ID Found -
International Journal of Molecular... Nov 2003E-cadherin, an intercellular adhesion molecule, is important in cell growth and differentiation. Adhesion between cells is thought to decrease as cancers develop and...
E-cadherin, an intercellular adhesion molecule, is important in cell growth and differentiation. Adhesion between cells is thought to decrease as cancers develop and disseminate. Knowledge of the effect of cell adhesion on proliferation and chemosensitivity may help individualize cancer treatment. Lovo and MCF-7 cells, which express E-cadherin, and PC-3 cells, which do not, were used in this study. Proliferation and chemosensitivity were measured in two-dimensional (2-D) culture and three-dimensional (3-D) culture. Protein and mRNA expression of E-cadherin, catenin, and cyclin-dependent kinase inhibitors were determined. Growth of Lovo and MCF-7 but not PC-3 cells was markedly suppressed in 3-D relative to 2-D. MCF-7 cells express high levels for E-cadherin, catenin, and p27 in 3-D, but catenin and p27 expression was decreased by exposure to anti-E-cadherin neutralizing antibody. Chemosensitivity of PC-3 was similar in 2-D and 3-D, but chemosensitivity of Lovo and MCF-7 was less in 3-D than 2-D. Moreover, the presence of anti-E-cadherin antibody increased chemosensitivity of MCF-7 in 3-D. E-cadherin affected the regulation of cell proliferation and differentiation, and decreased chemosensitivity. Chemosensitivity of cancer is affected by the state of cell adhesion and expression of intercellular adhesion molecules. Consideration of intercellular adherence characteristics in different chemosensitivity tests is likely to improve their reliability.
Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cadherins; Cell Adhesion; Cell Cycle Proteins; Cell Division; Cell Line, Tumor; Cell Size; Cisplatin; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinase Inhibitor p57; Cyclin-Dependent Kinases; Cyclins; Cytoskeletal Proteins; Doxorubicin; Drug Resistance, Neoplasm; Enzyme Inhibitors; Fluorouracil; Humans; Inhibitory Concentration 50; Mitolactol; Mitomycins; Nuclear Proteins; RNA, Messenger; Trans-Activators; Tumor Suppressor Proteins; alpha Catenin; beta Catenin
PubMed: 14532995
DOI: No ID Found -
Neoplasma 2002Our aim was to investigate the effect of BCNU and DBD combined chemotherapy in patients with recurrent malignant gliomas. Forty-six patients were treated with combined...
Our aim was to investigate the effect of BCNU and DBD combined chemotherapy in patients with recurrent malignant gliomas. Forty-six patients were treated with combined chemotherapy. Out of 26 patients with anaplastic astrocytomas 11 were originally low-grade where no postoperative radiotherapy was applied. Fifteen patients with anaplastic astrocytoma responded well to the chemotherapy and 9 survived longer than one year. Median survival time was 14 months. Complete response of recurrent glioblastoma did not occur and only 4 patients survived longer than one year. Median survival time was 7 months. Ratio of patients with response and stable disease was 70 and 55 %, respectively. BCNU and DBD combination proved to be an effective combination for recurrent malignant gliomas. It was remarkable that patients' survival with primary or secondary lower grade astrocytoma were significantly longer than that in patients with glioblastomas. Treatment of lower grade tumors, even at their malignant recurrences is promising.
Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Brain Neoplasms; Carmustine; Female; Glioblastoma; Humans; Male; Middle Aged; Mitolactol; Time Factors; Treatment Outcome
PubMed: 12458335
DOI: No ID Found -
Ideggyogyaszati Szemle Jan 2002At the Hungarian National Institute of Neurosurgery 73 recurrent supratentorial malignant tumours were treated by chemotherapy during the last ten years. Chemotherapy... (Clinical Trial)
Clinical Trial
At the Hungarian National Institute of Neurosurgery 73 recurrent supratentorial malignant tumours were treated by chemotherapy during the last ten years. Chemotherapy was applied after postoperative radiotherapy but in some cases following reoperation only. All cases were clinically and by CT or MRI verified recurrences. Forty-three patients received BCNU-DBD (dibromodulcitol) treatment (23 anaplastic astrocytoma--AA, and 20 glioblastoma multiforme--GM): day 1. BCNU 150 mg/sq.m. in i.v. infusion, day 2. dibromdulcitol 1000 mg/sq orally was given. This course was repeated every six weeks, altogether 2-8 times. Sixteen patients with AA responded with complete or partial regression but only 6 did with GM. Median survival was 14 and 7 months, the difference proved to be significant, p = 0.0091. PCV combination (procarbazine, CCNU, vincristine) was applied to 16 patients with AA and 14 cases with recurrent oligodendroglioma (O). Treatment started with vincristine 1.5 mg/sq.m. i.v. (2.0 mg maximum), the next day CCNU 100 mg/sq.m. was given, followed by procarbazine 60 mg/sq.m. on days 8-22. and finished by the same dose of vincristine on day 30. The course was repeated after one month, mostly six times. Six patients with AA did not respond; in cases of oligodendroglioma all but one responded with complete or partial improvement. It is remarkable that no significant difference was found between the survivals of BCNU-DBD or PCV treated AA patients. Chemotherapy of supratentorial malignant glioma recurrences with nitroso-ureas and their combination proved to be efficacious. It also seems, that in recurrent cases lower grade gliomas show better response rate than glioblastomas.
Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Carmustine; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Glioblastoma; Humans; Male; Middle Aged; Mitolactol; Neoplasm Recurrence, Local; Procarbazine; Radiotherapy, Adjuvant; Reoperation; Supratentorial Neoplasms; Survival Analysis; Treatment Outcome; Vincristine
PubMed: 12122942
DOI: No ID Found -
Zhonghua Zhong Liu Za Zhi [Chinese... Jan 2000To study the results of combination chemotherapy of uterine sarcoma after operation and recurrent tumor. (Clinical Trial)
Clinical Trial
OBJECTIVE
To study the results of combination chemotherapy of uterine sarcoma after operation and recurrent tumor.
METHODS
One hundred seventy-four cases of three major pathological subtypes of uterine sarcomas were treated in the Cancer Hospital from 1960 to 1996. Clinical data were analyzed of 51 cases of uterine sarcomas treated with postoperative adjuvant chemotherapy and 38 cases with recurrent tumors received 98 courses of chemotherapy. They were divided into 4 groups according to the adjuvant chemotherapy regimen: single drug, VAC, VAD, and other regimens. Chemotherapy regimens for recurrent tumors were VAD, PA/PAC, and other combination regimens including etoposide, ifosfamide, cisplatin, adriamycin.
RESULTS
The 5-year survival rate of stage I-II uterine sarcoma patients was 54.9% receiving adjuvant chemotherapy. It was 72.7% in VAD group which was significantly higher than that in other regimen groups. The survival rate was related to the number of chemotherapy course. The chemo-sensitivity of various pathological types of recurrent uterine sarcomas was not different.
CONCLUSION
The 5-year survival rate does not improve in patients with stage I-II uterine sarcomas given postoperative chemotherapy. VAD is among the best regimens and at least 3 courses should be performed. The results of new treatment regimens such as EPA, IA, etc., must await further clinical observation.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Doxorubicin; Drug Therapy, Combination; Etoposide; Female; Humans; Mitolactol; Mitomycins; Neoplasm Recurrence, Local; Postoperative Period; Retrospective Studies; Sarcoma; Survival Rate; Uterine Neoplasms
PubMed: 11776610
DOI: No ID Found -
Japanese Journal of Cancer Research :... Nov 2001SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various...
SNF4435C and D, novel immunosuppressants produced by a strain of Streptomyces spectabilis, were examined for their reversing effects in vitro on various multidrug-resistant (MDR) tumor cells overexpressing P-glycoprotein. These two compounds in the range of 3-10 microM completely reversed the resistance of MDR variant cells, mouse leukemia P388 cells [vincristine (VCR)-resistant P388/VCR and adriamycin (ADM)-resistant P388/ADM], human myelogenous leukemia K562 cells (VCR-resistant K562/VCR and ADM-resistant K562/ADM) and human ovarian cancer A2780 cells (ADM-resistant AD(10)), against VCR. Both compounds moderately potentiated the sensitivity of the MDR cells to ADM but the reversal was not complete. SNF4435C and D significantly increased the intracellular accumulation of VCR in AD(10) cells as potently as verapamil, cyclosporin A (CysA) and FK506, whereas the compounds exerted no effect on the accumulation of VCR in the drug-sensitive parent cells. Moreover, SNF4435C improved the chemotherapeutic efficacy of VCR in the treatment of P388/VCR-bearing mice. When 10 mg/kg SNF4435C was administered intraperitoneally to the mice concurrently with 0.2 mg/kg VCR for every 5 days, a treated/control (T/C) value of 143% was obtained. These results suggest that the compounds are useful candidates or tools for MDR modification in cancer chemotherapy.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Division; Dose-Response Relationship, Drug; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Female; Humans; Inhibitory Concentration 50; Mice; Mitolactol; Mitomycins; Neoplasm Transplantation; Neoplasms; Nitro Compounds; Pyrones; Tumor Cells, Cultured; Vincristine
PubMed: 11714449
DOI: 10.1111/j.1349-7006.2001.tb02145.x -
Cell Biology International 2001A-431 squamous cell carcinoma cells were treated in vitro with either 4 Gy radiation of 15 (or 45) microg/ml dibromodulcitol (DBD), as well as with combined 4 Gy...
A-431 squamous cell carcinoma cells were treated in vitro with either 4 Gy radiation of 15 (or 45) microg/ml dibromodulcitol (DBD), as well as with combined 4 Gy irradiation and DBD, with the latter as either a pretreatment or post-treatment. DBD alone or in combination with radiation had a greater effect on cell proliferation than the effect of radiation alone. The difference is due to a higher level of apoptosis induced by DBD, especially in conjunction with radiation. Such a combination may therefore be useful in the treatment of squamous cell carcinoma, which in general responds poorly to radiation therapy.
Topics: Antineoplastic Agents, Alkylating; Apoptosis; Carcinoma, Squamous Cell; Cell Division; Combined Modality Therapy; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Screening Assays, Antitumor; Gamma Rays; Humans; Mitolactol; Mitosis; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein; Tumor Cells, Cultured; Tumor Suppressor Protein p53
PubMed: 11448098
DOI: 10.1006/cbir.2000.0707 -
Neuro-oncology Jan 2000We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and... (Clinical Trial)
Clinical Trial
We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Glioma; Humans; Lomustine; Male; Mitolactol; Procarbazine; Survival Analysis; Thioguanine; Treatment Outcome; Vincristine
PubMed: 11302250
DOI: 10.1093/neuonc/2.1.22