Predicted and actual BCNU concentrations in normal rabbit brain during intraarterial and intravenous infusions

Summary Normal New Zealand White rabbits were used to compare theoretical brain concentrations (based upon pharmacokinetic modeling) with actual experimental concentrations of BCNU following intraarterial (IA) or intravenous (IV) infusions. IA infusion therapy for brain tumor patients has been promising based upon theoretical predictions but of limited effectiveness clinically. Experimentally-measured rabbit carotid artery flow rates (63.9 ± 3.4 ml/min) [mean ± 1 sem] and BCNU systemic clearances (197 ± 10.2 ml/min) predicted a theoretical IA advantage of 4.1 ± 0.2. lpsilateral brain concentrations of BCNU during and after IA infusions (20 mg/min/m² over 15 minutes) were: 16.2 ± 2.9, 19.0 ± 3.9, 20.3 ± 2.8, 4.8 ± 2.5, 2.1 ± 1.5, and 1.7 ± 1.6 g/gm brain at 5, 10, 15, 25, 35, and 45 minutes after infusion start. Mean concentrations at same time points in contralateral hemisphere (IA infusions) were: 7.1 ± 1.8, 9.0 ± 1.8, 10.3 ± 0.7, 4.2 ± 1.4, 2.2 ± 1.2, 2.0 ± 1.5 g/gm brain. Concentrations in either hemisphere during IV infusions were similar to contralateral hemisphere during IA infusions. Comparison of ipsilateral: contralateral hemisphere ratios during and after IA infusions were: 3.2 ± 0.4, 2.6 ± 0.3, 2.2 ± 0.3, 1.1 ± 0.3, 1.0 ± 0.4, and 0.9 ± 0.3 at the same time points. Although these data show higher drug concentrations with IA infusions, actual values were considerably less than predicted by theoretical modeling. This discrepancy between theoretical and experimental results emphasizes need for further study of causes and remedies so that IA therapy can achieve better drug concentrations with less toxicity.     

Phase I clinical trial of intracarotid bis-chloroethylnitrosourea (BCNU) and 2' dioxy-5-fluorouridine (FUDR) in malignant astrocytomas

Summary Systemic chemotherapy has been of limited benefit in the treatment of intracranial neoplasms, due, in part, to the inability to deliver effective drug doses to the neoplasm without systemic toxicity. We have completed a clinical trial of intracarotid BCNU and FUDR using an implantable pump in patients with unilateral malignant astrocytomas (Grade III and IV) in the hope of obtaining better tumor control with less systemic toxicity. Six patients had in-dwelling catheters placed in the internal carotid artery attached to a percutaneous refillable pump (Infusaid 400). The treatment program consisted of bolus BCNU 400 mg every 6 weeks and FUDR by continuous infusion at dosages ranging from 0.5 mg/24 h to 2.5 mg/24 h. The maximum tolerable dose of FUDR was 1 mg/24 h with ipsilateral mucositis and conjunctivitis being dose limiting factors. Flow studies demonstrated significant perfusion of the ipsilateral eye and surrounding face secondary to ophthalmic artery collaterals. No patient had systemic toxicity and the lowest WBC encountered was 2 400 with normal differential and platelets.     

Intra-arterial cisplatin for the treatment of malignant gliomas

Summary Cisplatin (DDP) is a chemotherapeutic agent that has shown efficacy against primary CNS malignancies. Intraarterial (IA) administration of DDP to patients with brain tumors should produce higher peak levels of drug than intravenous (IV) administration of an identical dose and reduce systemic toxicity. Twelve patients with malignant glioma were entered into the study. All had failed irradiation, 11 had failed IA BCNU. Each patient received IA DDP, 58–100 mg/m², into the internal carotid artery at four to six week intervals. One of 12 patients had a partial response of 6 months. The remaining 11 patients had progressive disease [10] or severe complications [1]. Toxicity included seizures in four patients, weakness and/or aphasia in four patients, coma in two patients, and visual deterioration in two patients. IA DDP has very limited efficacy in patients with malignant gliomas after failure of nitrosoureas and is associated with an unacceptable level of toxicity. IA DDP may be more effective when used as initial chemotherapy of malignant gliomas.     

Impact of intra-arterial chemotherapy including internal carotid artery for advanced paranasal sinus cancers involving the skull base

Background:

The most significant problem of intra-arterial chemotherapy for advanced paranasal sinus carcinomas and residual cancers supplied by internal carotid artery (ICA) and involving the skull base is the lack of salvage therapies.

Objective:

The objective of the study was to evaluate the usefulness of intra-arterial chemotherapy including ICA infusion for treating advanced paranasal sinus carcinomas, which have invaded the skull base.

Methods:

Forty-six patients with advanced paranasal sinus carcinomas supplied by ICA were treated by intra-arterial chemotherapy using CDDP and sodium thiosulphate (STS) as a neutraliser of CDDP toxicity. After evaluating CT angiography, 150 mg m⁻² of CDDP was superselectively administered weekly to each feeding artery including ICA four times.

Results:

The 10-year overall survival rate and progression-free survival rate were 70.7 and 60.2%, respectively. Compared with control group without infusing ICA, recurrences at anterior skullbase or anterior ethomoid sinus were significantly diminished. Of 32 patients in which the orbital apex had been invaded, 29 patients were treated with successful preservation of orbital contents. The CT angiography could efficiently determine all feeding arteries supplying the cancers. Consequently, chemotherapy could be administered on schedule, and side effects were minimal and acceptable.

Conclusions:

This new method has promising applications in the treatment of advanced paranasal sinus carcinomas involving the skull base.     

Tissue levels of pirarubicin (THP) in dogs following intra-arterial infusion

The blood and tissue levels of pirarubicin (THP) were studied in dogs by HPLC analysis. The THP (1.5 mg/kg) was infused from the bifurcation of internal iliac artery. We measured the concentration of THP after 1 or 2 hours of intra-arterial infusion (IA) and compared with the concentration of THP administered intravenously (IV). The plasma levels of THP following IA rapidly disappeared the same as for IV. The blood cell level of THP following both IA and IV was significantly higher than the plasma level. The bladder mucosa and muscle levels of THP following IA were about 8 times as high as that of IV. The bladder muscle level of THP 2 hours after IA was about twice as high as after 1 hour and the same as the bladder mucosa level of THP after both 1 and 2 hours. It is considered that THP by the present method may have the transition from the mucosa to the muscle in the bladder. In the other intrapelvic tissues (perivesical adipose tissue, pelvic lymph node and prostate), IA also had higher concentrations compared with IV. However, the extrapelvic tissues (heart, liver and kidney) levels of THP following IA were the same as those for IV. It was concluded that THP was a reasonable agent for IA chemotherapy for bladder cancer.     

Incidence of infusion plan alterations after angiography in patients undergoing intra-arterial chemotherapy for brain tumors

Summary During intra-arterial (IA) chemotherapy of brain tumors, the initial vessels chosen for infusion are based on the vascular distribution of the tumor as revealed by CT or MR imaging. However, angiography may reveal details of vascular anatomy that require an alteration of the vessel infusion plan. The incidence of infusional alterations and the underlying vascular anatomy involved remains unknown in patients with brain tumors undergoing IA chemotherapy. To evaluate this question, we performed a chart, CT/MRI, and angiography review of brain tumor patients receiving IA chemotherapy. Seventy-eight patients were identified with primary (39) and metastatic (39) brain tumors. The cohort consisted of 40 males and 38 females, with a mean age of 47.8 years. During the course of IA treatment, angiographic review identified 5 patients (6.4%) that required an alteration of the vessel infusion plan. In three cases, angiography demonstrated more substantial perfusion of the tumor from a different arterial supply. In two cases, angiography revealed variations in normal anatomy associated with unexpected tumor perfusion. Careful interpretation of angiography at the initiation of each cycle of IA chemotherapy is very important to verify that the appropriate vessels have been chosen for drug infusion, in order to maximize regional dose intensity. In our series, the angiography results necessitated an alteration of the infusion plan in 6.4% of the patient cohort.     

Complications associated with intra-arterial BCNU administered in combination with vincristine and procarbazine for the treatment of malignant brain tumors

Summary We have used intra-arterial (i.a.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) either alone or as part of adjuvant chemotherapy in patients with malignant brain tumors over a 3 year period (1979–1982). The i.a. BCNU technique was used 111 times to infuse 134 arteries in 37 patients. These patients, 28 cases with glial tumor and 9 cases with brain metastasis, received i.a. BCNU in combination with Vincristine and Procarbazine every 6 weeks. Complications encountered were transient and included: periorbital erythralgia or occipital-nuchal pain in 23 (62%), mild confusion and disorientation in 14 (38%), and ipsilateral conjunctival edema in 10 (27%). Reversible myelosuppression was not found. Our findings suggest that BCNU (100 Mg/M²) may be given by i.a. infusion in combination chemotherapy without persistent severe untoward effects with a cumulative dose of 700 mg/M².     

Combination therapy of rat brain tumours using localized interstitial hyperthermia and intra-arterial chemotherapy

Several investigators have reported that a high concentration of drugs in a tumour can be achieved using intra-arterial (IA) chemotherapy. This treatment was highly effective, especially in brain tumours, but the actual therapeutic advantage is still unknown. There are also indications that human malignant gliomas can effectively be treated using interstitial hyperthermia. Therefore, a combined treatment of IA chemotherapy and interstitial hyperthermia should be very promising and this has been studied in a tumour model. Wistar rats with isotransplanted C 6 gliomas in the brain were treated with adriamycin (ADR, 1.0 mg/kg body weight) either infused via the carotid artery (i.a.) or via the tail vein (i.v.), with or without interstitial hyperthermia. Hyperthermia of the tumours was applied using a homemade radiofrequency antenna (RF-heating) and a heating device that maintained the tumour temperature above 40°C. Concentration of adriamycin in tumours after treatment was measured using HPLC. The effectiveness of treatment was determined by the survival time of the animals and histopathological examinations. The highest uptake of adriamycin in the rat C 6 glioma was obtained when the animals were treated with hyperthermia and i.a. ADR infusion ( p <0.01). These animals also showed significantly longer overall survival time (SF50=46 days) in comparison to the other treatments ( p < 0.05). The histological studies demonstrated a necrotic tumour; however, the surrounding normal brain tissue remained intact. Thus, a combination of IA chemotherapy with adriamycin and localized interstitial hyperthermia enhances considerably the efficacy of adriamycin and has a greater antitumour effect for malignant brain tumours. This method is suitable for clinical use, and may be a new strategy for treating gliomas not successfully treated today.     

Combination therapy of rat brain tumours using localized interstitial hyperthermia and intra-arterial chemotherapy.

Several investigators have reported that a high concentration of drugs in a tumour can be achieved using intra-arterial (IA) chemotherapy. This treatment was highly effective, especially in brain tumours, but the actual therapeutic advantage is still unknown. There are also indications that human malignant gliomas can effectively be treated using interstitial hyperthermia. Therefore, a combined treatment of IA chemotherapy and interstitial hyperthermia should be very promising and this has been studied in a tumour model. Wistar rats with isotransplanted C(6) gliomas in the brain were treated with adriamycin (ADR, 1.0 mg/kg body weight) either infused via the carotid artery (i.a.) or via the tail vein (i.v.), with or without interstitial hyperthermia. Hyperthermia of the tumours was applied using a homemade radiofrequency antenna (RF-heating) and a heating device that maintained the tumour temperature above 40 degrees C. Concentration of adriamycin in tumours after treatment was measured using HPLC. The effectiveness of treatment was determined by the survival time of the animals and histopathological examinations. The highest uptake of adriamycin in the rat C(6) glioma was obtained when the animals were treated with hyperthermia and i.a. ADR infusion (p <0.01). These animals also showed significantly longer overall survival time (SF50 =46 days) in comparison to the other treatments (p < 0.05). The histological studies demonstrated a necroti c tumour; however, the surrounding normal brain tissue remained intact. Thus, a combination of IA chemotherapy with adriamycin and localized interstitial hyperthermia enhances considerably the efficacy of adriamycin and has a greater antitumour effect for malignant brain tumours. This method is suitable for clinical use, and may be a new strategy for treating gliomas not successfully treated today.     

Role of high-dose chemotherapy with hemopoietic stem-cell support in the treatment of adult patients with high-grade glioma

Despite surgery, post-operative irradiation and adjuvant conventional chemotherapy, prognosis of high-grade gliomas remains poor. Carmustine (BCNU) has been shown to have limited activity at conventional dosage but is still the standard chemotherapy. Activity of chemotherapy is limited by the blood-brain barrier impermeability and high levels of expression of multidrug resistance proteins on tumor and/or endothelial cells. Despite high response rates, development of intra-arterial chemotherapy remains limited because of frequent acute brain toxicity related to drug administration. High-dose intravenous chemotherapy rescued by autologous hemopoietic stem cell transplantation is an alternative that might increase drug delivery through the blood-brain barrier and tumor control. Several phase I-II trials using high-dose BCNU were published. The maximum tolerated dose seems to be 800 mg/m2 and interstitial pneumonitis and hepatitis are dose-limiting toxicities. Few phase I-II trials of high-dose therapy were published using drug combinations. High response rates in patients with progressive tumor were observed and in adjuvant setting, encouraging results in terms of median survival time and long survivors were published. No phase III trial was reported to date. Future investigations should include randomized trials comparing high-dose and conventional-dose chemotherapy and development of new high-dose regimens that incorporate new drugs such as temozolomide.     

Phase II study of intracarotid or selective intracerebral infusion of cisplatin for treatment of recurrent anaplastic gliomas

Purpose: To assess the response of patients with recurrent malignant gliomas to intra-arterial (IA) cisplatin. Methods: Eligibility criteria included patients with recurrent supratentorial malignant gliomas and measurable, unilateral contrast-enhancing tumor located within the territory of one or two major cerebral arteries. Patients received 75 mg/m² IA cisplatin every four weeks. Depending on individual patients' tumor topography, cisplatin was infused either into the cervical internal carotid artery (ICA) (15 patients), or into one or two major cerebral arteries (26 patients), most often the M1 segment of the middle cerebral artery. Results: Of 40 patients evaluable for tumor response, four patients (10%) were responders and nine patients (22%) had disease stabilization. The median time to tumor progression among the 13 patients with tumor response or stable disease was 23.7 weeks. The response rate did not significantly differ between patients receiving ICA versus selective intracerebral infusion, although the latter group contained a higher proportion of glioblastoma. Tumor progression occurred solely as local failure in 33 patients (82%), with all enhancing tumor still located within the vascular territory infused with IA cisplatin. Ipsilateral vision loss occurred in two patients after ICA cisplatin but in none of the selective infusion patients. Seizures and/or transient or permanent neurologic deterioration occurred in four patients (27%) after ICA cisplatin and in 11 patients (44%) after selective intracerebral infusion. Conclusions: Although this was not a randomized comparison, selective intracerebral artery cisplatin infusion in this group of patients reduced the risk of eye toxicity, but did not produce a better tumor response rate, and carried a higher risk of neurotoxicity relative to ICA infusion.     

Plasma platinum concentration and anti-tumor effects after intra-arterial infusion of lipiodol-CDDP suspension evaluation with VX 2 rabbit liver cancer model and 7.0 Tesla MRI system

To evaluate the usefulness of combination chemotherapy with cisplatin powder, which was newly designed for intra-arterial infusion (IA CALL) and lipiodol, for the VX 2 liver cancer model of the rabbit, sequential change of the plasma platinum concentration within the first 24 hours, as well as the tissue platinum concentration at 24 hours was measured after intra-arterial infusion of IA CALL. The infused materials were either IA CALL alone (C) or the combination of lipiodol+IA CALL (CL). In addition,the reduction rate of the VX 2 tumor was calculated among four therapeutic groups (C, CL, lipiodol alone (L), and saline alone (S)) after one week of intra-arterial infusion on the basis of 7.0 Tesla MR images. Total plasma platinum concentrations within the first 24 hours were kept low in group CL. No increase in the tissue platinum concentration in group CL was observed. On the other hand, the tumor reduction rate tended to be higher in group CL (group CL>group L=group C>group S). These results suggested that the intra-arterial infusion of IA CALL with lipiodol is more effective than that of IA CALL alone.     

Clinical study for determination of the dosage formula for intra-arterial infusion chemotherapy with nedaplatin

Area under the curve (AUC) is a very important parameter for determination of optimal dosage of antineoplastic agents in order to avoid side effects and achieve high effectiveness. Also, even if a certain dosage is administered, measured AUC is different in each individual. Therefore, it is important to determine the formula of the dosage of antineoplastic agents. We treated oral cancer using an intra-arterial infusion chemotherapy with nedaplatin (CDGP). Eighteen patients were treated with CDGP at the Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical University, from October 1998 to June 2002. The correlation among expected AUC, dosage, CDGP clearance and 24 hr creatinine clearance in all chemotherapy was monitored and examined. The obtained formula in the dosage of intra-arterial infusion chemotherapy with Nedaplatin was as follows. dosage = AUC x (0.027 x CCr + 7.17).     

Mature results of a pilot study of pelvic radiotherapy with concurrent continuous infusion intra-arterial 5-FU for stage IIIB-IVA squamous cell carcinoma of the cervix.

PURPOSE: To evaluate the long-term results of continuous infusion intra-arterial 5-fluorouracil (CI IA 5-FU) given with concurrent pelvic radiotherapy (RT) for FIGO stage IIIB-IVA carcinoma of the cervix. METHODS AND MATERIALS: Between 1965 and 1974, 27 patients with extensive FIGO Stage IIIB (22 patients) or Stage IVA (5 patients) squamous cell carcinoma of the cervix were treated with CI IA 5-FU and RT. Twenty-one patients (78%) had bilateral pelvic wall involvement, 25 (93%) had massive tumors (> or =8 cm in diameter), 7 (27%) had involvement of the lower one-third of the vagina, and 15 (56%) presented with hydronephrosis. All patients underwent routine clinical staging, transperitoneal para-aortic lymph node dissection, and bilateral hypogastric artery catheter placement. 5-FU was continuously infused at a dose rate of 10 mg/kg/day on Days 1-15 of RT. The median dose of 5-FU was 376 mg/m2/day (range 270-692). All patients received concurrent pelvic RT to a median dose of 50 Gy at 2.0 Gy per fraction. Only 4 patients received intracavitary RT. The median follow-up of surviving patients was 190 months. RESULTS: The overall 5-year survival rate was 37%. For the 22 patients with FIGO Stage IIIB disease, the 5-year survival rate was 41%. The survival rate for 18 patients treated with only external beam radiation and chemotherapy for Stage IIIB disease was 33%. Four of 10 patients treated with only 50 Gy of external beam radiation and CI IA 5-FU were long-term survivors. Acute complications, including hematologic toxicity and skin reactions, were severe, with 1 death from neutropenic sepsis. Severe late complications were only observed in patients treated with > or =60 Gy of external beam radiation. CONCLUSIONS: While this series is small, the fact that 4 patients with massive Stage IIIB tumors survived after a total radiation dose of only 50 Gy suggests that RT with CI IA 5-FU deserves further study. Modifications in dose, technique, and route of administration should reduce toxicity, and the addition of intracavitary RT should improve the local effectiveness of combined treatment.     

Superselective intra-arterial infusion chemotherapy of high-dose cisplatin for advanced paranasal sinus carcinomas]

Eighteen patients with advanced paranasal sinus carcinomas were treated by "two-route" intra-arterial chemotherapy using cis-diamminedichloroplatinum (CDDP) and sodium thiosulfate (STS) to preserve the hard palate and the eye. In these patients, 100 mg/m2 of CDDP was administered weekly through each feeding artery of the tumor superselectively at 5 mg/min. During infusion of CDDP, STS at a two-hundred fold dose of CDDP was injected through a catheter placed in the brachiocephic vein introduced via the subclavian vein. The complete and partial response rates were 14/18 (78%) and 4/18 (22%), respectively. None of the nine patients following operation showed residual tumors histologically. The peak of the mean total plasma platinum concentration was 5.5 micrograms/ml, and this concentration was rapidly reduced to 1.5 micrograms/ml in 5 hours. The peak of the plasma protein unbound platinum was 3.9 micrograms/ml. This concentration rapidly decreased to almost zero within 5 hours after IA infusion. The mean tumor platinum content achieved by superselective IA infusion was as high as 6.0 micrograms/g tumor, and this decreased rapidly to 2.4 micrograms/g tumor on the 5th day after the 1st intra-arterial infusion. All patients were free from chemotoxicity such as renal, hematological dysfunctions, or gastrointestinal symptoms. Each chemotherapy treatment could be done weekly on schedule. All but one patient was alive for 5-40 months. This new method of chemotherapy appears very effective for advanced paranasal sinus carcinomas.     

Pelvic intra-arterial mitomycin C infusion in previously treated patients with metastatic, unresectable, pelvic colorectal cancer and angiographic determination of tumor vascularity

Thirty patients with unresectable pelvic tumors from recurrent or metastatic colorectal cancer, after failing all conventional chemotherapy or radiotherapy, were treated with mitomycin C (MMC) regional intra-arterial (IA) infusion. MMC at a dose of 20 mg/m2 in 100 mL of 5% dextrose in water was infused for a one-hour period through the regional artery (eg, hypogastric, gluteal) approached percutaneously via the femoral artery. This treatment was repeated every four to eight weeks. Of the 26 patients who could be evaluated, three had objective responses, 14 had tumor stabilization, and nine had no response. Median survival time for the responders (Rs) was 435 days, for stabilized patients (Ss) was 263 days, and for nonresponders (NRs) was 195 days, giving an overall survival time of 239 days. Fourteen patients (2 Rs, 8 Ss, and 4 NRs) had good relief of pain after the IA infusion. Thirty-three pelvic arteriograms (including three patients who had never received IA infusion) showed an avascular tumor of grade 0 in eight patients, a hypovascular tumor of grades 1 and 2 in 16 patients, and a vascular tumor of grade 3 in nine patients. Neovasculatures were mainly derived from the hypogastric artery or its branches (eg, gluteal, obturator, and pudendal artery), and occasionally were found to be derived from the superior hemorrhoidal, lumbar, and sacral arteries. The major side effect after the pelvic infusion was necrotizing cellulitis occurring in the buttock. Myelosuppression was manageable and other toxic effects were mild. Metastatic colorectal cancer occurring in the pelvis was basically a vascular-deficient tumor. Regional IA MMC infusion given intermittently was found effective in palliating pelvic pain and improving the quality of these patients' lives.     

A phase II study of intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer

Background

Based on the convenient oral dosing of erlotinib and the promising results of biologic therapy, we undertook a phase II study with 21 patients with locally advanced (T3–4) lesions combining radiation with intra-arterial (IA) cisplatin and oral daily erlotinib for a 7-week therapy.

Methods

Treatment for the primary tumor and upper neck was given to a total dose of 70 Gy. Chemotherapy with IA cisplatin (150 mg/m²) was given on days 1, 8, 15, and 22 concurrently with radiotherapy. During the 7-week treatment period, patients were given erlotinib 150 mg/day.

Results

Overall survival is 63 %, and the relapse/persistent disease rate stands at 36.8 %. A total of 15.2 % of serious adverse event was considered related to erlotinib.

Conclusion

Our study and several others now demonstrate the feasibility of combining anti-epidermal growth factor receptor (EGFR) therapy with chemoradiation, hint at improved survival outcomes with reduced distant metastatic rates, and suggest that maintenance therapy with anti-EGFR agent may be beneficial.     

Intra-arterial Carboplatin and Intravenous Etoposide for the Treatment of Recurrent and Progressive Non-GBM Gliomas

Recurrent and progressive non-GBM gliomas are a diverse group of brain tumors that often respond poorly to adjuvant chemotherapy treatment. Regional intra-arterial (IA) administration of chemotherapy may result in increased tumor uptake of drug, with improvement in response rates and time to progression (TTP). Twenty-five patients with recurrent or progressive non-GBM gliomas were treated with IA carboplatin (200mg/m²/d) and intravenous (IV) etoposide (100mg/m²/d) for 2 days every 4 weeks. Patients ranged in age from 22 to 68 years (mean 37.8). All but one patient had received standard irradiation, and eight patients had attempted prior chemotherapy. Five of 25 patients had objective responses (20%), while another 15 patients had stable disease (60%), receiving a total of 318 IA treatment procedures. There was one complete response (4.0%), three partial responses (12.0%), one minor response (4.0%), 15 stable diseases (60.0%), and five progressive diseases (20.0%). The median TTP was 24.2 weeks overall and 32 weeks in responders. Overall median survival was 34.2 weeks. Therapy was well tolerated, with mainly hematologic toxicity. Two patients had embolic complications. Although these are preliminary results, IA carboplatin and IV etoposide have modest activity against recurrent and progressive non-GBM gliomas and warrants further study.     

Mixing during Intravertebral Arterial Infusions in an in vitro Model

Regional delivery of drugs can offer a pharmacokinetic advantage in the treatment of localized tumors. One method of regional delivery is by intra-arterial infusion into the basilar/vertebral artery network that provides local access to infratentorial tumors, which are frequent locations of childhood brain cancers. Proper delivery of drug by infused solutions requires adequate mixing of the infusate at the site of infusion within the artery lumen. Our mixing studies with an in vitro model of the vertebral artery network indicate that streaming of drug solution is likely to occur at low, steady infusion rates of 2ml/min. Streaming leads to maldistribution of drug to distal perfused brain regions and may result in toxic levels in some regions while concurrently yielding subtherapeutic levels in adjacent regions. According to our model findings, distribution to both brain hemispheres is not likely following infusion into a single vertebral artery even if the infusate is well-mixed at the infusion site. This outcome results from the unique fluid flow properties of two converging channels, which are represented by the left and right vertebral branches converging into the basilar. Fluid in the model remains stratified on the side of the basilar artery served by the infused vertebral artery. Careful thought and planning of the methods of intravertebral drug infusions for treating posterior fossa tumors are required to assure proper distribution of the drug to the desired tissue regions. Improper delivery may be responsible for some noted toxicities or for failure of the treatments.     

高级别胶质瘤动脉灌注化疗的系统评价

目的评价高级别胶质瘤动脉灌注化疗的疗效及安全性。方法按照Cochrane系统评价方法,检索全世界关于高级别胶质瘤动脉灌注化疗的随机对照试验。采用Cochrane协作网推荐的偏倚评价标准进行偏倚评价,用RevM an5.0.18统计软件进行统计分析。结果此系统评价纳入5个临床试验,共771例患者。各试验异质性突出,发生偏倚的可能性较大。M eta分析的结果显示对于高级别胶质瘤患者（1）动脉组与静脉组的疾病控制率,有效率,1、2、3年生存率差异无统计学意义;（2）毒副反应就全身血液学毒性来讲,静脉组重度白细胞下降比动脉组明显,差异有统计学意义,重度血小板下降静脉组稍多于动脉组,但差异无统计学意义;局部毒副反应则与药物有关,BCNU用乙醇作溶剂进行动脉灌注时脑部和眼部的毒副反应较大,而ACNU动脉灌注的局部耐受性则较好;（3）生存时间给出的是中位数,相关的数据不全以致不能进行合并分析。因纳入比较的试验较少,未能做漏斗图测定发表偏倚。结论现有的证据尚不能证明对于高级别胶质瘤,动脉灌注化疗疗效优于静脉化疗。此系统评价存在诸多局限性,证据强度不足,有待于进一步大样本、高质量的多中心随机对照试验证实其疗效和安全性。