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The incidence of central nervous system neoplasias ranges from 3.8 to 5.1 cases per 100,000 inhabitants. In the presence of recurrence, the treatment is problematic; chemotherapy is experimental, primarily because the response is palliative and of limited duration. This article analyses the new drugs that have been introduced in the treatment of these patients in the latest years, the objective response, the time to progression and the mean survival time. The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years. New approaches to the chemotherapy treatment are necessary. Enrolment of patients into rigorous, well-conducted, clinical trials, both at tumour diagnosis and after tumour recurrence, will generate new information regarding investigational therapies and may offer improved therapies for patients with malignant gliomas.

Controlled delivery of chemotherapeutic agents by biodegradable polymers is a new strategy that has been added to the arsenal available for the treatment of malignant neoplasms. This approach is particularly suitable for the management of brain tumours because of the constraints imposed by the blood brain barrier (BBB). The use of polymers for local drug delivery minimises systemic toxicity, while achieving prolonged elevation of intratumoural drug concentrations that results in improved efficacy. In addition, this strategy broadens the spectrum of drugs available for the treatment of neoplasms in the central nervous system to include agents whose efficacy is significantly limited by systemic toxicity or inability to penetrate the BBB. In this review, we discuss the rationale and background for the use of this novel approach. We also summarise the clinical trials and laboratory investigations leading to the development of local delivery of anti-neoplastic agents from biodegradable polymers for the treatment of malignant gliomas.

The management of low-grade oligodendrogliomas and oligoastrocytomas has been further complicated by recent reports documenting the chemosensitivity of these tumours. Preliminary results suggest that low-grade oligodendroglial tumours are less dramatic and predictable in their response to chemotherapy than their anaplastic counterparts. Nonetheless, the use of chemotherapy as initial treatment for these indolent neoplasms has inherent appeal, particularly if this strategy permits the delay or elimination of cranial irradiation. Before the use of chemotherapy becomes standard initial therapy for these neoplasms, further efforts will be required to describe in greater detail the susceptibility of these tumours to chemotherapy, document the delayed toxicities of chemotherapy for low-grade oligodendrogliomas, identify the most therapeutic agents or regimens, and correlate clinical and radiographic response with molecular markers of chemosensitivity.

Brain metastases (BrM) are estimated to occur in 20% to 40% of cancer patients, and two-thirds of them become symptomatic during their lifetime. Although every solid tumour may spread to the brain, the risk of developing BrM is higher in lung cancer, breast cancer and melanoma patients. Several findings suggest that the incidence of BrM is rising as a result of advances in imaging procedures and improvements in therapy, which leaves more cancer patients at risk as survival increases. The prognosis of patients with BrM is dependent on the type of the primary tumour. Breast cancer patients have better prognosis than those with BrM from lung, melanoma or colorectal cancer. Patients with BrM from renal cell carcinoma tend to have a poor prognosis. The optimal treatment of patients with BrM continues to evolve. Several factors interfere with the therapeutic strategy, such as histology of primary tumour, patient compliance, localisation, size and number of BrM, and outcome of extracranial disease. Generally, surgery or stereotactic radiotherapy followed by whole brain radiotherapy (WBRT) are indicated in patients with controlled extracranial disease and good performance status presenting an isolated BrM. Adding chemotherapy in this subset of patients is controversial. Supportive care associated with WBRT remains the standard treatment for all patients with multiple symptomatic BrM or with isolated symptomatic BrM in the presence of uncontrolled extracranial disease. For potentially chemosensitive patients with asymptomatic multiple or isolated BrM with disseminated disease, chemotherapy represents the optimal starting therapy.

Current neurological opinion favours the extensive surgical removal of supratentorial glioma, when feasible, without injury to normal structures. Several recent studies relate the extent of surgical resection to the length and quality of survival. Better surgical results due to microsurgical techniques and operative facilities suggest the re-evaluation of the role of surgery in the overall management of glial tumours.

Treatment outcome for patients with chronic hepatitis C virus infection has greatly improved during the last years with the development of interferon (IFN) and ribavirin combination therapy. The final decision to treat or not, however, is complex and should be based on several factors such as the age of the patient, the general health, the risk of developing cirrhosis and the probability of a cure with treatment. Combination therapy with standard doses (IFN-a 3 x 106 IU three times per week plus ribavirin 1000-1200 mg daily in two divided doses) for six (up to 12) months significantly improves the sustained biochemical and virological response rates 2-3 times as compared to IFN alone given during 12 months. Combination therapy has thus become standard therapy for na ve patients and relapse patients after a prior IFN treatment course. For patients with favourable baseline viral characteristics (genotype 2 and 3 irrespective of viral load) six months combination therapy is sufficient whereas patients with unfavourable viral baseline characteristics (genotype 1 with high baseline viral load) will need 48 weeks combination treatment. In addition, for patients with compensated cirrhosis, combination therapy is superior and better tolerated than IFN monotherapy. For the future better optimised treatment schedules and dosing regimens for IFN in combination with ribavirin need to be worked out and individualised according to genotype to further improve treatment results. Utilisation of new IFN formulas such as pegylated IFN and consensus IFN in combination regimens will probably improve treatment further.

The hepatitis C virus (HCV) infects some 170 million people worldwide and is responsible for approximately 20% of cases of acute hepatitis and 70% of cases of chronic hepatitis. Acute hepatitis is icteric in only 20% of patients and is rarely severe. Eighty five per cent of the infected patients develop chronic infection which is generally asymptomatic. Among the HCV chronic carriers, 25% have persistently normal serum alanine aminotransferase (ALT) levels despite having detectable HCV-ribonucleic acid in serum, 75% have elevated ALT levels. While the majority of patients with mild chronic hepatitis have a slowly progressive liver disease, the patients with moderate or severe chronic hepatitis may develop cirrhosis within a few years. In patients with HCV-related cirrhosis, the incidence of hepatocellular carcinoma is 2-5% per year. HCV-related end-stage cirrhosis is currently the first cause of liver transplantation. Treatment with the combination of interferon-alpha and ribavirin induces a sustained virological response in roughly 40% of the patients. The virological response is associated with a biochemical response and histological improvement. It is believed that the decrease of necroinflammatory liver lesions induced by anti-viral therapy in responders, is associated with a decreased risk of development of cirrhosis and hepatocellular carcinoma

An important group of patients with chronic hepatitis C do not respond to interferon (IFN) therapy. Compared with untreated patients with chronic hepatitis C, non-responders have a higher percentage of cirrhosis, are more frequently infected by genotype 1 and usually have a viral load above 2 x 106 copies/ml. Also, patients with cirrhosis have lower life expectancy and higher risk of clinical complications, and therefore, are most in need of effective treatment strategies. There is no evidence that the re-treatment of non-responders with a standard regimen of IFN or more prolonged IFN therapy achieves a sustained biochemical or virological response. Between 20% and 40% of non-responder patients treated with IFN therapy for more than two years had an hepatic improvement in liver histology associated with a decrease in hepatitis C virus-ribonucleic acid levels. In contrast, combination therapy with IFN and ribavirin for six months now results in sustained response rates between 6% and 29% depending on the viral genotype and the presence or absence of cirrhosis. Patients infected with genotype 2 and 3 have a higher probability of achieving a sustained virological response than those infected by genotype 1. Currently, different studies are underway to determine whether high-dose IFN and/or induction therapy combined with ribavirin for more prolonged periods of time could increase the sustained response rate in non-responders. No other drugs appear to be efficacious in these patients, except the combination of IFN, ribavirin and amantadine which has shown interesting results in a preliminary trial but they need to be confirmed in further studies. These findings suggest that combination therapy is beneficial and can be recommended for some non-responder patients until other new therapies are available.

Hepatitis C virus (HCV) infection is an important clinical problem, with a world-wide prevalence of approximately 1-2%. HCV infection is associated with an increased risk for the development of severe liver disease. HCV is inherently resistant to anti-viral therapy with interferon (IFN). The virus circulates in infected individuals as a mixture of related, yet genetically distinct variants, or quasispecies. Many studies have implicated HCV quasispecies in IFN responsiveness. Effective containment of HCV quasispecies mutation and selection through more aggressive therapy (e.g. daily induction), combination therapy (e.g. IFN plus ribavirin), or longer lasting therapy (e.g. pegylated IFN) is required for IFN responsiveness. Recently, several HCV proteins including the non-structural 5A and envelope gene 2-glycoprotein have been implicated in HCV anti-viral resistance. It is likely that multiple HCV genes disrupt IFN-induced anti-viral responses at many levels and that these virus-host cell interactions are associated with IFN resistance. Characterisation of HCV-encoded mechanisms of anti-viral resistance has important implications for the development of new anti-virals.