Nimotuzumab in combination with chemotherapy for patients with malignant gliomas / 中华肿瘤杂志

<p><b>OBJECTIVE</b>Nimotuzumab is a humanized monoclonal antibody targeted against epidermal growth factor receptor (EGFR). Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. The aim of the present study was to evaluate the efficacy and side effects of nimotuzumab in combination with chemotherapy for patients with malignant gliomas.</p><p><b>METHODS</b>The patients received 200 mg of nimotuzumab infusion intravenously over 60 minutes once weekly for the first eight weeks and then once every two weeks until unacceptable toxicity or tumor progression occurred. Individualized chemotherapy was administered based on O(6)-methylguanine-DNA methyltransferase (MGMT) expression and previous chemotherapy responses in combined with nimotuzumab.</p><p><b>RESULTS</b>Fourteen patients received a total of 122 times of nimotuzumab ranging from 2 to 20 (median 7.5 times). Combined chemotherapy regimens included: continuous 21-day temozolomide (10 cases), standard 5-day temozolomide (2 cases), teniposide plus cisplatin (1 case), and teniposide plus nimustine (1 case). Partial response (PR) and stable disease (SD) were found in 3 patients (21.4%)and 6 patients (42.9%), respectively. Disease control rate (PR + SD) was 64.3%. The median progression-free survival (PFS) was 4 months (95%CI: 0.7 - 7.3) and PFS at 6 months was 30.6%. The most common toxicities include grade I-II neutropenia (2 cases), thrombocytopenia (2 cases), lymphopenia (1 case), nausea and vomitting (3 case) and asymptomatic transaminase increase (1 case). One patient developed grade IV neutropenia and thrombocytopenia. One patient developed nimotuzumab-related acneiform rash.</p><p><b>CONCLUSIONS</b>Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.</p>

Effects of Hydroxychloroquine Co-administered with Chemotherapeutic Agents on Malignant Glioma Cell Lines: in vitro Study

OBJECTIVE: Anti-malaria drugs may modulate tumor resistance to chemotherapeutic agents, but it has not been proven effective in the treatment of malignant gliomas. The aim of this study was to determine whether adequate pre-clinical data on co-administration of chemotherapeutic agents with anti-malaria drugs on malignant cell lines could be obtained that would warrant its further potential consideration for use in a clinical trial for malignant gliomas. METHODS: Two malignant glioma cell lines (U87MG, T98G) were treated with chemotherapeutic agents alone or with anti-malaria drugs. Cells were incubated with drugs for 4 days. Following the 4-day incubation, drug sensitivity assays were performed using 3-(4, 5-dimethyl-2-thiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay following optimization of experimental conditions for each cell lines and cell viability was calculated. RESULTS: In all of four chemotherapeutic agents(doxorubicin, vincrisitne, nimustine, and cisplatin), the cell viability was found to be markedly decreased when hydroxychloroquine was co-administered on both U87MG and T98G cell lines. The two way analysis of variance(ANOVA) yielded a statistically significant two-sided p-value of 0.0033(doxorubicin), 0.0005(vincrisitne), 0.0007(nimustine), and 0.0003(cisplatin) on U87MG cell lines and 0.0006(doxorubicin), 0.0421(vincrisitne), 0.0317(nimustine), and 0.0001(cisplatin) on T98G cell lines, respectively. However, treatment with chloroquine and primaquine did not induce a decrease in cell viability on both U87MG and T98G cell lines. CONCLUSION: Our data support further consideration of the use of hydroxychloroquine prior to systemic chemotherapy to maximize its tumoricidal effect for patients with malignant gliomas.

Clinical Study: Phase II Study of Continuous ACNU (nimustine) and CDDP (cisplatin) Infusion Followed by Conventional Radiotherapy in Patients with High Grade Astrocytomas

OBJECTIVE: This study is aimed at evaluating the efficacy and the toxicity of a 72-hour continuous intravenous infusion of ACNU and CDDP before radiotherapy in adult patients with newly diagnosed anaplastic astrocytoma and glioblastoma. METHODS: Forty-three adult patients with a postoperative Karnofsky performance status greater than 60 were entered into this protocol without any prior treatment. Two cycles of preradiation chemotherapy were performed at 6-week intervals. Conventional radiotherapy was begun 6 weeks later. Magnetic resonance (MR) imaging studies were conducted pre- and postoperatively, and follow-up MR images at the beginning of each treatment and every three months after radiotherapy completion. Response rate, survival rate, prognostic factors and complications were evaluated. RESULTS: Among 43 patients mentioned above, twenty-one patients completed two cycles of chemotherapy. One patient showed complete remission, ten partial response, seven stable disease and three progressive disease. The median survival time was 15.9 months. Overall response rate was 22.3%. Twenty-seven showed pancytopenia, including two bleeding tendencies, one intracerebral hemorrhage resulting to death, and another two infections. Considering the prognostic factors, only a mutated p53 level of under 20%(% of tumor cells containing mutated p53) was correlated with survival prolongation. Prognostic factor of age under 45 was the only significant factor of extending the time to progression. CONCLUSION: This treatment protocol shows favorable results of preradiation chemotherapy using ACNU and CDDP.

Posterior Leukoencephalopathy Syndrome Following Intravenous Chemotherapy for Medulloblastoma in a Child

Posterior leukoencephalopathy syndrome(PLES) is a rare neurological complication which is associated with malignant hypertension, pre-eclampsia, and some drugs including immunosuppressive agents. A 9-year-old boy who had cerebellar medulloblastoma showed seizure on the seventeenth day after intravenous chemotherapy including ACNU and vincristine. Radiologic findings were consistent with those of PLES due to vasospasm. After hypertensive therapy, the symptoms were improved. We present a case of PLES with medulloblastoma which developed following chemotherapy with the regimen of medulloblastoma in a child.

Results of Combined Chemotherapy and Radiotherapy for Advanced Intraocular Retinoblastoma

PURPOSE: To report the result of combined chemotherapy and radiotherapy for 5 retinoblastoma patients. METHODS: Retrospective study of 5 patients (8 eyes) who were diagnosed with retinoblastoma of group III to V in the Reese-Ellsworth (R-E) classification was done. After 6 cycles of chemotherapy consisting of Vincristine, VP-16 (Etoposide) and Carboplatin, Radiotherapy (4500Gy/5weeks) was done. Neoaedjuvant therapy consisting of Nimustine and Carboplatin was done, and supplementary laser photocoagulation was done in 1 case. Mean follow-up period is 33 months. RESULTS: Significant reduction of tumor size and regression were observed in five eyes of R-E classification group V, and slight reduction of tumor size and regression were observed in three eyes of R-E classification groups III and IV. There was no recurrence and no new mass was detected. CONCLUSIONS: Combined chemotherapy, radiotherapy and supplementary therapy may save eyeballs which were diagnosed with retinoblastoma, even R-E classification group V.

Phase III Randomized Trial of ACNU in Addition to Surgery and Radiotherapy for Patients with Supratentorial Malignant Gliomas / 대한암학회지

No abstract available

BCNU-CDDP Continuous Infusion Chemotherapy in Recurrent Oligodendroglioma

Eight patients with recurrent oligodendroglioma were treated with 1.3-bis(2-chloroethyl) nitrosourea(BCNU) and CDD continuous infusion chemotherapy. They were 5 with benign oligodendrogliomas and 3 with anaplastic oligodendrogliomas. All the recurrent tumors had been treated with surgery and radiotherapy. Four patients had already received chemotherapy with ACNU. Seven of them showed response to continuous infusion chemotherapy. The time from the response to progression was 15 to 67 weeks. No severe complication of the chemotherapy was found. In conclusion, BCNU-CDDP continuous infusion chemotherapy is an effective treatment modality in recurrent oligodendrogliomas.

Effect of High-Dose Tamoxifen on Malignant Gliomas

In vitro studies have shown that the nonsteroidal antiestrogen tamoxifen can suppress deoxyribonucleic acid(DNA) synthesis and cell proliferation in cultured human gliomas. This growth suppression is independent on its antiestrogenic properties. Tamoxifen may act through the inhibition of the enzyme protein kinase C(PKC), which transduces mitogenic signals from the cell surface to the nucleus. In order to evaluate the therapeutic response and side effect of high-dose tamoxifen, we performed a clinical study of 28 patients with malignant gliomas who were treated with high-dose tamoxifen in our hospital between February 1991 and January 1993. An effect was defined as a statistically improved survival times/rates. In patients who were assigned to receive high-dose tamoxifen, it was first administered at standard antiestrogen doses(20mg orally bid/day) to observe for any side effect and if tolerated, the dose was increased weekly to achieve target doses(100mg orally bid/day) over a 1 month period. We compared the survival times/rates between anaplastic astrocytomas and glioblastoma mutiformes. Although the median survival time was slightly longer in anaplastic astrocytomas than that of glioblastoma multiformes, there was no statistical difference of survival curves between two groups at the p=0.05 level. We also examined the survival times/rates of malignant gliomas according to treatment modalities(radiotherapy alone, radiotherapy plus ACNU, and radiotherapy plus tamoxifen). Although the survival rate and time were slightly higher in radiotherapy plus tamoxifen group than those of another treatment groups, we could not find the statistical significance of survival curves between three treatment groups(p>0.05). High-dose oral tamoxifen appeared to be well tolerated in most patients. Five patients developed anorexia following dose escalation of tamoxifen. Another complications were amenorrhea, nausea/vomiting, and constipation. There were no changes in hematological studies that could be attributed to tamoxifen. We think that high-dose tamoxifen cah be administered safely to malignant gliomas patients. Our results were not impressive. We conclude that the definition of the true efficacy of high-dose tamoxifen in patients harboring malignant gliomas is not possible from this limited study, and a further large scale, randomized trial of this agent is necessary.

Effect of ACNU Chemotherapy on Malignant Glioma

In order to determine if there was an enhancing therapeutic effect of ACNU(1-4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride, nimustine chloride given in addition to radiotherapy, we performed a randomized clinical study of irradiation alone and combination of irradiation with ACNU in the treatment of malignant gliomas. Thirty-seven patients who were treated in our hospital from August 1990 to September 1992 were included in this study. An effect was defined as a statistically improved survival times. Radiotherpy with a total dose of 5000 to 6500 rads was applied to the whole brain and to a generous field surrounding the tumor. Patients who were assigned to receive chemotherapy were given ACNU intravenously at a dose of 1-2mg/kg. The survival rates of patients with anaplastic astrocytoma and glioblastoma multiforme at 18 months after the surgery were 0% and 37% for radiotherapy alone, and 66.7% and 40.1% for radiotherapy plus ACNU, respectively. The median survival times of patients with anaplastic astrocytoma and glioblastoma multiforme were 14 and 15 months for radiotherapy alone, and 19 and 16 months for radiotherapy plus ACNU, respectively. The survival rates of patients with malignant gliomas(anaplastic astrocytoma plus glioblastoma multiforme) at 18 months were 5.5% for radiotherapy alone and 45.4% for radiotherapy plus ACNU, and the median survival times were 15 and 16 months, respectively, Althouh the survival rate of patients with malignant gliomas at initial 6 months was much higher in radiotherapy plus ACNU than in radiotherapy alone, the differences between survival curves were not significant at the p=0.05 level. This study demonstrated that, although the use of ACNU during radiotherapy suppressed malignant gliomas more than radiotherapy alone, the survival time was not extended significantly. It is necessary to continue to search for an effective chemotherapapeutic regimen to prolong survival of patients with malignant gliomas.

Medulloblastoma Involving Brain Sterm: Case Report

Six patients with medulloblastoma involving brain stem were treated with surgical excision, irradiation or chemotherapy consisting of ACNU, vincristine and procarbazine from 1982 to 1993. All 6 patients were treated by surgical excision. Chang's staging was from T3b to T4 and radiation therapy was done in 5 patients and chemotherapy was performed in 4 patients. Mena follow up period was 25 months(range 1 to 87 months). The result of treatment for medulloblastomas invading brain stem was unfavorable in general, but radiation therapy combined aggressive chemotherapy after surgical resection could show a good result in some cases.

Phase III Randomized Trial of ACNU in Addition to Surgery and Radiotherapy for Patients with Malignant Glioma of the Brain: A Preliminary Report

No abstract available.

Intravenous vs Selective Intraarterial ACNU Chemotherapy on Malignant Gliomas

In 17 cases of glioblastoma multiforme and 3 cases of anaplastic astrocytoma, ACNU chemotherapy was performed by intravenous(10 cases) and supraophthalmic or superselective intraarterial(10 cases) injection postoperatively combined with radiation therapy. The postoperative median survival time in 17 cases of glioblastoma multiforme was 15 months(7 cases alive), and those for intravenous(8 cases) and intraarterial(9 cases) were 16.3 months(2 case alive) and 13 months(5 cases alive) respectively. 3 cases of anaplastic astrocytoma(2 cases intravenous, 1 case intraarterial) are all alive and the average postoperative follow-up period was 22.5 months. The survival rate of patients with gliobalstoma multiforme at 18 months after operation was 47.6%, and those for intravenous and intraarterial were 57.6% and 36.5%. In an analysis of performance status at the time of 3 months following surgery, there was remarkable improvement of quality of life in 70% of glioblastoma multiforme treated. In postoperative 12 months, about 50% of gliobalstoma multiforme patients could carry their normal daily life. Systemic side effects such as leukopenia and thrombocytopenia occurred little more frequently in intravenous group than intraarterial group. But more serious local neurological complication such as visual loss(1 case) and leucoencephalopathy(1 case) occurred in intraarterial group. Platelet count were decreased maximally in the fourth week after ACUN administration.