In an effort to improve dose intensity, some authors have given some or all of the chemotherapy drugs by the intra-arterial (IA) route [25,75-79]. There are several advantages to administering chemotherapy IA instead of by the conventional IV route, including augmentation of the peak concentration of drug in the region of the tumor and an increase in the local area under the concentration-time curve . Pathologically, metastatic brain tumors are excellent candidates for IA approaches, because they tend to be well circumscribed and non-infiltrative . This is in contrast to most high-grade primary brain tumors, which are very infiltrative and extend beyond the region of contrast enhancement . In addition, MBT universally enhance on CT and MRI imaging, indicating excellent arterial vascularization and impairment of the blood-tumor barrier. Therefore, with metastatic tumors the vast majority of tumor cells receive significant exposure to agents when administered via the localized arterial vasculature. Pharmacologic studies using animal models of IA and IV drug infusion have shown that the IA route can increase the intra-tumoral concentration of a given agent by at least a factor of 3 x to 5.5 x [80,81]. For chemosensitive tumors, improving the intra-tumoral concentrations of drug should augment tumor cell kill and the ability to achieve objective responses .
An important consideration in the application of IA chemotherapy is choosing the proper drug or drugs to be infused. Not all drugs have the appropriate metabolism and pharmacokinetic profile for IA usage. It is important that the drug have a rapid total body clearance, as defined by the concept of Ra, the Regional Advantage (see Chapter 17 for a more detailed explanation) . The Ra is the pharmacological advantage a drug has (or may not have) when administered IA versus the IV route; it is maximized by a rapid (i.e., large) total body clearance. The drugs with the most appropriate Ra for IA chemotherapy of MBT (ranked in descending order) include BCNU > -cisplatin >> carboplatin > etoposide. The two drugs with the highest Ra (i.e., BCNU, cisplatin) are also known to have the most significant neuro-toxicity.
Intra-arterial chemotherapy has been attempted with MBT patients in the past (see Table 35.2), beginning with the 1979 report of Yamada and colleagues . They used IA BCNU (every 4 weeks; in addition to systemic chemotherapy) for nine patients with MBT from lung carcinoma. There were 4 responders, with TTP ranging from 16 to 28 weeks. In a more extensive phase II study, the same investigators used IA BCNU for 35 patients with lung carcinoma and malignant melanoma . Twelve patients had objective responses (34.3 per cent; 6 CR, 6 PR; lung only), with a median survival of 16 weeks. Toxicity included infusional pain, seizures, and confusional episodes. Cascino and co-workers also used IA BCNU (every 5-6 weeks) for 31 patients with MBT that had progressed through radiation therapy . They noted 5 PR (16.2 per cent; 3 lung, 1 breast, 1 melanoma), with a median survival of 17 weeks, and similar toxicity to the Yamada studies. In a more recent report by Madajewicz and associates, a regimen of IA cisplatin and etoposide was administered every three weeks to twenty-eight patients with MBT . There were 6 CR and 6 PR, with a median survival of 28 weeks. Significant neuro-toxicity was noted (e.g., seizures, infusional pain, confusion) in several patients.
At the Ohio State University Medical Center and James Cancer Hospital, Newton and colleagues have recently developed a carboplatin-based IA regimen for treatment of MBT [25,83-85]. The regimen consists of IA carboplatin and intravenous etoposide for two days, every 4 weeks. They report a series of 24 evaluable patients with MBT (11 lung, 9 breast, 2 colon) that have received IA treatment [25,85]. Most of the patients had multifocal metastases and had failed whole-brain radiotherapy. There were 6 CR, 6 PR, and 1 minor response, with a median TTP of 16 weeks overall and 30 weeks in responders. The overall median survival was 20 weeks. The regimen has been well tolerated, with mainly hematological toxicity. Procedural complications and neuro-toxicity during IA administration of carboplatin have been very rare (<1 per cent). Based on these initial encouraging results with IA carboplatin and the previously mentioned activity of temozolomide, a new phase I/II multi-center trial has been opened for accrual [Newton et al. unpublished data]. The regimen consists of IA carboplatin (200 mg/m2 x 2 days) and temozolomide (150 mg/m2 x 5 days) every 4 weeks, for patients with recurrent or symptomatic residual brain metastases. The phase I portion of the protocol has been completed. The regimen has been well tolerated, except for hematological toxicity in heavily pre-treated patients. Several patients have demonstrated PR and SD during MRI follow-up examinations.
Neuwelt and associates have attempted to further dose intensify IA chemotherapy by using it in combination with IA mannitol and osmotic BBB disruption [25,81,86-88]. The rationale for this approach is to augment the general advantages of regular IA treatment by further intentional disruption of the blood-brain and blood-tumor barriers of metastatic tumors (see Chapter 18 for more details). Disruption of the barrier significantly increases intra-tumoral concentrations of drug and may improve response rates [79,81,86]. Initial experience was gained using a regimen of IA methotrexate (1-5 g) and mannitol, IV CTX (15-30 mg/kg), and oral procarbazine (100 mg/day x 14 days) every 4-6 weeks . Several objective responses were noted on CT follow-up in a series of 7 patients with MBT (breast, lung, testicular). In a more recent report of 13 MBT patients by Doolittle and co-workers, the regimen consisted of IA carboplatin and mannitol, IV CTX, and IV etoposide for two days every 4 weeks . Results included 3 CR, 2 PR, and 7 SD; TTP and survival data were not available. The risk of procedural complications and neuro-toxicity is greater with IA treatment in combination with BBB disruption, in comparison to regular IA approaches (e.g., brain swelling, herniation, arrhythmia).
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