The SMA News recently published a position statement from the Clinical Neuroscience Society (CNS) on chemotherapy wafers (Gliadel). This position statement does not completely clarify the issue of the efficacy of gliadel. Primary brain cancers are difficult to cure because of diffuse infiltration of normal brain tissue and a propensity to local recurrence despite aggressive therapy. Malignant gliomas particularly glioblastoma multiforme are rapidly fatal. Before causing death, they are often crippling and distressing to both the patient and the family. In one recent report, with surgery alone, survival was only 3 months from the initial diagnosis (Jubeliter SJ, 1996). These dismal results have prompted a search for better methods of treatment.

An important step forward in the treatment of malignant gliomas has been the introduction of direct intra-tumoral chemotherapy. This novel concept was developed by a neurosurgeon from Johns Hopkins University and a biotechnology scientist from the Massachusetts Institute of Technology (MIT). The US Food and Drug Administration (FDA) has approved the use of intra-tumoral chemotherapy with BCNU (gliadel) for the treatment of recurrent glioblastoma multiforme – the first new drug therapy for brain tumors to be approved in the last 23 years (Weigart and Brem, 1996).

An important aspect of this novel form of chemotherapy is direct drug delivery to the cancer site, bypassing the conventional intravenous and oral routes of administration. A drawback of conventional routes particularly in relation to the brain is getting enough drug to cross the blood – brain barrier. The higher doses of conventional chemotherapy required to penetrate the blood-brain barrier are associated with side-effects of bone marrow suppression, liver and renal toxicity. The delivery of chemotherapy directly to the tumor site however requires only a fraction of the systemic dose levels to have effective results with concentrations in the brain that are hundreds of times higher than after intravenous administration of the drug (Grosman et al, 1992). Only trace amounts appear in the systemic circulation. All the studies conducted to date, have shown a significantly lower risk of systemic side-effects with intra-tumoral wafer chemotherapy. The development of this wafer technology has been recognised as a major advance in biotechnology. Dr Robert Langer, the scientist from MIT who was primarily responsible for this new technology has been awarded two prestigious international scientific awards – the Gairdner Foundation International Award for Achievement in Medical Sciences and the Lemelson-MIT Prize. Dr Judah Folkman from the Havard Medical School (the distinguished cancer researcher and leader of the team developing anti-angiogenesis factor for cancer treatment) has highly commended Langer’s work and its clinical applications.

The most rigorous clinical study to date on the efficacy of gliadel is a prospective, double-blind, multi-institutional study on 222 patients published in the Lancet in 1995 (Brem et al, 1995). This study was conducted on patients with recurrent malignant gliomas where the survival with conventional treatment was expected to be poor. Among patients with recurrent glioblastomas, 6 month survival with gliadel was 50% greater than in those treated with placebo. The authors reported that "interstitial chemotherapy delivered with polymers directly to brain tumors at the time of surgery seems to be a safe and effective treatment for recurrent malignant gliomas". The only clinically significant side-effect was a slightly increased incidence of local wound pain and poorer wound healing. Since the publication of this study and approval from the FDA, Dr Brem said over 1000 patients have had gliadel treatment.

Dr Henry Brem the Director of Neurosurgical Oncology at Johns Hopkins University, in a letter to the Clinical Neuroscience Society (CNS), pointed out that "given the minimal side effects that are seen in the patients treated with gliadel, it is difficult for me to understand the diminution of value of even a few months of additional life. Furthermore, we have numerous patients that are alive many years after implantation of gliadel for recurrent glioblastoma" (Personal communication).

A second independent prospective randomised study on the efficacy of gliadel was done, but this time for newly diagnosed malignant gliomas was conducted in Europe (Valtonen S et al, 1997). This study showed that median survival was 58 weeks for the gliadel treated group and 40 weeks for the control group (p l 0.05). At one year 63% of the gliadel patients were alive vs 19% for the control group, and at two years 31% of the gliadel group vs only 6% for the control group. Side effects of hemiparesis, convulsions and visual field defects were not significantly different in the two groups. The conclusion was that "adverse events experienced were consistent with those expected in post-operative patients with malignant gliomas". Thus, the addition of gliadel to the operative treatment of these patients did not significantly increase side-effects. This has also been confirmed in a 1998 review on side-effects of gliadel published by the Medical Letter On Drugs and Therapeutics where it was noted that "decreased blood counts and other systemic effects that typically occur with intravenous administration of carmustine have not been reported with Gliadel implants. The adverse effects of implanting the wafers have been an increase in edema at the site of resection and a slight increase in the low incidence of intracranial and wound infections".

REFERENCES

1. Jubeliter SJ. A review of the treatment and survival rates of 138 patients with glioblastoma multiforme, W V Med J 1996; 92[4] : 186-90.

2. Weingart JD, Brem H. Carmustine Implants: Potential in the treatment of Brain Tumors. CNS Drugs 1996; 6[4] : 263-9.

3. Grossman SA et al. The intracerebral distribution of BCNU delivered by surgically implanted biodegradabale polymers. J Neurosurg 1992; 76[4] : 640-7.

4. Brem H et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995; 345: 1008-12.

5. Valtonen S et al. Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study. Neurosurgery 1997; 41: 44-8.

DR PREM PILLAY
CONSULTANT NEUROSURGEON
GLENEAGLES AND MT ELIZABETH HOSPITALS,
SINGAPORE