Michaelyn A. Page

Age influences chemotherapy response in astrocytomas.

Objective In patients with cerebral astrocytomas treated with nitrosourea-based chemotherapy, to determine whether age is predictive of response, time to progression, survival, or rate of complications. Design Retrospective analysis of neuroimaging studies and clinical data. Setting University hospital with a busy neuro-oncology service. Patients One hundred forty-eight patients with pathologically confirmed malignant astrocytomas or recurrent astrocytomas. Results Partial response occurred in 39% of patients aged <40 years, in 17% of those aged 40 to 59, and in only 5% of those aged ≤60 (p < 0.001). Median time to progression after chemotherapy was 23 weeks in patients aged <60 and 6 weeks in patients aged ≤60 (p < 0.001). Median survival after chemotherapy was 43 weeks in patients aged <60 but only 24 weeks in patients aged ≤60 (p < 0.001). Differences between age groups in response rate, time to progression, and survival persisted with adjustment for tumor grade. The risk of myelosuppressive complications requiring hospitalization was significantly related to age (p = 0.03); such complications occurred in 35% of patients aged ≤60 and 16% of patients under 60 years. Conclusion Age is strongly predictive of the likelihood of a response to chemotherapy, time to progression, survival, and risk of myelosuppressive complications. Patients aged ≤60 have a lower chance of benefit and an increased risk of myelosuppressive complications from chemotherapy for astrocytomas compared with younger patients.

Procarbazine chemotherapy in the treatment of recurrent malignant astrocytomas after radiation and nitrosourea failure

The Brain Tumor Study Group has shown procarbazine (PCB) to be as effective an adjuvant treatment as 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). We treated 35 patients with recurrent malignant astrocytomas after radiation and nitrosourea failure with successive courses of PCB 150 mg/m2/d for 28 days every 8 weeks. After 2 courses, 2 patients had complete responses, 7 had partial responses, 11 had stable disease, and 15 had progression. Significantly more patients receiving PCB had complete or partial responses or stable disease than a similar group of patients in a previous trial who received intraarterial (IA) cisplatin (DDP). There is a significant advantage in time to disease progression for those receiving PCB compared with those receiving IA diaziquone (AZQ). Our results suggest that PCB is a more effective 2nd agent than IA DDP or AZQ following radiation and nitrosourea failure.

Intra-arterial cisplatin for the treatment of malignant gliomas

SummaryCisplatin (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.

Results of re-irradiation of primary intracranial neoplasms with three-dimensional conformal therapy

We evaluated the potential of three-dimensional conformal therapy for re-irradiation of selected intracranial neoplasms and reviewed the retreatment of 20 patients at the University of Michigan between May 1988 and August 1991. All patients had previously undergone a full course of external beam radiotherapy (RT) to a median dose of 5,940 cGy (range 5,100-6,500 cGy), including five whole brain treatments. All recurrences were unsuitable for brachytherapy or radiosurgery. Various histologies were retreated, including 14 high-grade gliomas. Median time to re-irradiation was 38 months (range 9 months to 19 years, 6 months). RT was delivered with complex plans designed using fully integrated computed tomography/magnetic resonance imaging (CT/ MRI) tumor volume information, and regions of previous parenchymal treatment were avoided if possible. Composite (initial+retreatment) dose-volume histograms (DVH) of dose to nontarget brain allowed comparison of alternative plans to select beam orientations which minimized normal brain irradiation. Mean target dose of re-irradiation was 3,600 cGy (range 3,060-5,940 cGy). Total cumulative dose ranged from 8,060 to 11,940 cGy. Median survival was 9 months, and 1-year actuarial survival was 26%. After retreatment, 8 of 12 patients (67%) had steroid dose decrement and neurologic improvement at 4-48 months (median duration 14 months). Radiographic regression or stabilization of disease was noted in 11 of 16 patients (68%). Re-irradiation with highly conformal three-dimensional planning provides frequent clinical improvement with acceptable morbidity and should be considered in selected patients with recurrent intracranial neoplasms.

Intra-arterial bromodeoxyuridine radiosensitization of malignant gliomas

In the 1950s it was first observed that mammalian cells exposed to the halogenated deoxyuridines were more sensitive to ultraviolet light and radiation than untreated cells. This prompted early clinical trials with bromodeoxyuridine (BUdR) which showed mixed results. More recently, several Phase I studies, while establishing the feasibility of continuous intravenous (IV) infusion of BUdR, have reported significant dose limiting skin and bone marrow toxicities and have questioned the optimal method of BUdR delivery. To exploit the high mitotic activity of malignant gliomas relative to surrounding normal brain tissue, we have developed a permanently implantable infusion pump system for safe, continuous intraarterial (IA) internal carotid BUdR delivery. Since July 1985, 23 patients with malignant brain tumors (18 grade 4, 5 grade 3) have been treated in a Phase I clinical trial using IA BUdR (400-600 mg/m2/day X 8 1/2 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy/day in 6 1/2 weeks). Following initial biopsy/surgery the infusion pump system was implanted; BUdR infusion began 2 weeks prior to and continued throughout the 6 1/2 week course of radiotherapy. There have been no vascular complications. Side-effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Myelosuppression requiring dose reduction occurred in one patient. An overall Kaplan-Meier estimated median survival of 20 months has been achieved. As in larger controlled series, histologic grade and age are prognostically significant. We have shown in a Phase I study that IA BUdR radiosensitization is safe, tolerable, may lead to improved survival, and appears to be an efficacious primary treatment of malignant gliomas.

Comparison between BCNU and procarbazine chemotherapy for treatment of gliomas

SummaryWe compared sequential single-agent BCNU and procarbazine (PCB) chemotherapy in 31 patients with gliomas [grade IV (10), grade III (15), grade II (6)]. Patients had failed surgical biopsy ± resection and radiation therapy. All patients were treated initially with BCNU 150-300mg/m2 by intra-arterial or intravenous route every 6 weeks. After CT evidence of tumor progression, all patients received PCB 150mg/m2/day for 28 days every 8 weeks. Patient responses to BCNU were CR (0), PR (7), SD (12), progression (12), and to PCB CR (2), PR (9), SD (6), and progression (14). Kaplan-Meier estimates of median time to failure for all patients were shorter for BCNU, 5.0 months (range 1.5–20), than for PCB, 6.0 months (range 2–50+). There was a statistically significant difference (Mantel-Cox test, p=0.02) in the distribution of time to disease progression between the two drugs, especially for grade III tumors (p= 0.02). The cumulative proportion of patients without disease progression at 6 months was 26% while on BCNU, compared to 48% while on PCB; at 12 months the cumulative proportions were 3% for BCNU compared to 35% for PCB. Although there was no formal washout period between administration of the two drugs, no carryover effect was evident. These data provide further evidence that PCB has significant activity against malignant glioma and may, in fact, be more effective than BCNU.

Use of Implantable Pump Systems for Intraarterial, Intraventricular and Intratumoral Treatment of Malignant Brain Tumors

Significant advances in the development of implantable continuous infusion pumps have made available devices which are reliable and attractive for trials of regional chemotherapeutic treatment of various types of tumors involving the central nervous system. Since oftentimes tumors of the brain or CSF pathways respond in a dose-related fashion to either chemotherapy or radiation, it is reasonable to try to increase exposure on a regional basis, thus limiting systemic exposure and complications. It is this desire to increase regional exposure that has lead our group and others to utilize continuous infusion of various agents within the carotid arterial system, the ventricular system and even directly within the tumor itself. This paper will review our experience at the University of Michigan as well as the work of other investigators.

Radiosensitization with carotid intra‐arterial bromodeoxyuridine ± 5‐fluorouracil biomodulation for malignant gliomas

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR ±5-FU over 8½ weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 834 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system. The 2-year survival rate was 21% with the original and 28% with the modified grading system. The dose-limiting toxicity was a reversible unilateral focal forehead dermatitis, blepharitis, and conjunctivitis. Continuous IA halopyrimidine infusion may enhance the effectiveness of radiation in the treatment of malignant glioma.

The Ocular Effects of Intracarotid Bromodeoxyuridine and Radiation Theraphy in the Treatment of Malignant Glioma

Since July 1985, 23 patients have been entered into a phase I/II clinical trial using intraarterial 5-bromodeoxyuridine (BUdR) (400-600 mg/m2 daily for 8.5 weeks) and focal external beam radiotherapy (59.4 Gy at 1.8 Gy daily in 6.5 weeks) in the treatment of malignant gliomas (Kernohan grades 3 and 4). The side effects in all patients have included varying degrees of anorexia, fatigue, ipsilateral forehead dermatitis, blepharitis, and conjunctivitis. Mucopurulent conjunctivitis and exposure keratitis developed in several patients and spontaneous corneal perforation developed in one. Eyes from two individuals examined at autopsy showed significant changes. Animal studies that predated clinical trials using rhesus monkeys did not predict the ophthalmologic complications seen in human subjects.

Mucocutaneous complications of intraarterial 5-bromodeoxyuridine and radiation

5-Bromodeoxyuridine (BUDR), a halopyrimidine thymidine analogue, is incorporated into the DNA of dividing cells and causes photoradiosensitization. Twenty-five patients with malignant astrocytomas were treated with continuous intracarotid BUDR radiosensitization and radiotherapy for 8 1/2 weeks. Unique dose-limiting mucocutaneous complications were encountered. Ipsilateral facial dermatitis with epilation of eyebrows and eyelashes, ocular irritation, and bilateral nail dystrophy developed in all patients. Less common reactions included oral ulceration in six patients, body exanthem on the trunk in five, and atypical erythema multiforme major in one.