Chemotherapy

The role of chemotherapy in the treatment of patients with brain metastases has not been clearly defined. Traditionally, it has been assumed that the blood–brain barrier prevented chemotherapeutic agents from entering the central nervous system (CNS).³⁰ However, there is evidence that the blood– brain barrier is partially disrupted within the brain tumours, which is easily recognised by MRI or CT with an intravenous contrast; if the barrier was intact it would prevent the accumulation of contrast inside the lesion. This suggests that other factors also contribute to the generally disappointing results of chemotherapy for brain metastases. These may include the intrinsic resistance to chemotherapy of many tumours that metastasize to the brain and the tendency for brain metastases to develop following the failure of primary chemotherapeutic agents to control the primary disease. Although the results of chemotherapy for brain metastases have generally been disappointing, a number of uncontrolled studies have demonstrated favourable response rates of brain metastases from chemosensitive tumours, such as breast cancer, small cell lung cancer and germ cell tumours.

The development of new chemotherapeutic agents with better penetration (i.e. topotecan, temozolomide (TMZ)) has renewed the interest in using chemotherapy to treat brain metastases.³¹ TMZ is a novel oral alkylating agent with demonstrated activity in primary and recurrent gliomas,^32,33 it crosses the blood–brain barrier ³⁴ and is highly bioavailable after oral administration,³⁵ achieving effective concentrations in the CNS. The adverse event is mainly myelosuppression; however, the incidence of grade 3/4 neutropaenia and thrombocytopaenia is generally less than 10%.³⁶

In a phase II study reported from the Memorial Sloan Kettering Cancer Center, TMZ was administered in patients with recurrent or progressive brain metastases from a variety of primary cancers including non-small cell lung cancer and breast cancer.³⁷ In this trial, 34 evaluable patients received temozolomide. In two patients the brain metastases had a partial response, while in 15 patients the brain lesions remained stable. The median overall survival was 6.6 months. A second study of 28 patients (12 with non-small cell lung cancers), where most patients had received both chemotherapy and whole brain irradiation, found a partial remission in one patient with brain metastases from a non-small cell lung cancer.³⁸

Concurrent administration of TMZ with conventional whole brain irradiation (RT) was investigated in a phase II study from the Metaxas Cancer Hospital, Greece. In this trial, 52 patients with brain metastases from a variety of primary tumours (among whom 31 had non-small cell lung cancer, nine small cell lung cancer and five had breast cancer) were randomised to whole brain irradiation and a total dose of 40Gy with a daily fraction of 2Gy with or without concurrent administration of TMZ.³⁹ TMZ was administered orally at a dosage of 75mg/m2 during radiation treatment and 200mg/m2/d X five days every 28 days for a maximum of six additional cycles. Treatment response was assessed on the basis of CT scanning or MRI two months after completion of radiation treatment according to the World Health Organization (WHO) criteria for response. Fortyfive patients were assessable for response. The objective response rate in the group receiving TMZ (96%) was significantly superior (p=0.017) to that achieved with RT alone (67%). Another measure of treatment efficacy is the requirement for medication to palliate neurologic symptoms. The proportion of patients who required corticosteroids in the TMZ+RT group, two months after the completion of RT, decreased from 100% to 67% compared with a decrease from 100% to 91% in the RT group. Patients treated with TMZ plus RT had a slight improvement in overall survival (8.6 months) compared with RT alone (7.0 months).The addition of TMZ to RT was generally well tolerated. There was no grade 3 or 4 myelosuppression.

In a phase III study ⁴⁰ concurrent administration of temozolomide with whole brain radiotherapy was investigated further. In this trial, 123 patients with brain metastases were randomised to TMZ and RT or RT alone. The total radiation dose was 30Gy, with daily fraction of 3Gy. TMZ was administered with the same schedule as in the previous trial. Treatment response was assessed with CT scanning or MRI three months after completion of the radiation treatment. One hundred and twenty-three patients were assessable for response, among them 103 lung cancer patients. The objective response rate in the group receiving TMZ (50%) was significantly higher (p=0.028) to that achieved with RT alone (31%). The evaluation of lung cancer patients gave similar results, the response rate in the TMZ group (48%) was significantly superior (p=0.031) to that of the RT alone group (27%). The hazard ratio for death from any cause in the temodal group compared with the control group was 0.69 (95%CI: 0.46 -1.02, p=0.06). The median survival in the TMZ+RT group was 7.87 months while in the RT group it was 4.93 months. In the subgroup analysis for the lung cancer patients, median time to progression in the brain was 4.8 months (95% CI: 1.71–9.18) for the RT group, while more than 50% of the patients in the TMZ+RT group were disease-free. There was a significant difference between the two groups (p<0.001).

In summary, metastases in the CNS are common and new treatment modalities are needed. The combination of TMZ with radiation therapy needs to be confirmed in a large phase III international trial.