Concomitant treatment of brain metastasis with Whole Brain Radiotherapy [WBRT] and Temozolomide [TMZ] is active and improves Quality of Life

Brain metastases [BM] represent an important cause of morbidity and mortality in cancer patients, and are the most common intracranial tumor, occurring in approximately 10% to 30% of adult patients with cancer [1]. The risk of developing brain metastasis varies according to primary tumor type. Approximately half of all brain metastases occur due to lung cancer. More than 80% of brain metastases are detected after the primary tumor has been diagnosed; less frequently brain metastasis represent the first manifestation of neoplasia and/or are diagnosed at the same time as the primary tumor. The incidence of these metastases has increased in recent years for several reasons and they are associated with poor prognosis. The median survival time of untreated patients is approximately 1 month [1]. Often these patients have severe neurologic symptoms with a decrease in survival and quality of life.

Treatment choices are limited: only patients with a single brain metastasis benefit from surgery or radiosurgery. Frequently the palliative approaches focused on symptomatic care remain the standard treatment to relieve neurologic symptoms, primarily with the use of corticosteroids and anti-convulsant [2]. However, single metastases are rare and whole brain radiotherapy remains the standard treatment for most [3]. WBRT improves specific neurologic symptoms in the majority of patients [4], but response duration is short and the treatment may be associated with late complications. Phase III trials of the Radiation Therapy Oncology Group (RTOG) showed that treatment of brain metastasis with WBRT results in a median survival of 4 to 6 months and improves the neurologic function in most patients. No difference in median survival or 1-year survival has been seen between various dose groups, including a comparison between standard fractionation (30 Gy in 10 daily fractions) and accelerated hyperfractionation (1.6 Gy twice daily to 54.4 Gy) [5].

Patients with brain metastases represent a heterogeneous population. The Radiation Therapy Oncology Group classification derived from a recursive partitioning analysis (RPA) identified three groups of patients according to prognostic factors related to tumour based on Karnofsky performance score, primary tumor status, presence of extra-cranial metastases and age. Patients with KPS ≥70, age < 65 years, no extra-cranial metastases and controlled primary tumor are considered Class I and have a median survival of 7.1 months; patients with KPS< 70 are class III with a median survival of 2.3 months. All other patients belong to class II with a median survival of 4.2 months [6]. Most patients are in class II and III and the WBRT remain standard treatment.

The role of systemic chemotherapy in the management of BM is limited and controversial. The limited ability of most chemotherapeutic agents to cross the blood-brain barrier is believed to be one of the principal reasons these agents are less active against disease in the central nervous system than against extra-cranial, systemic disease [7]. Importantly, most patients have received most of the standard chemotherapy agents by the time they develop brain metastases and this increases tumor resistance. In newly diagnosed brain metastases, the tumors are responsive as the primary systemic cancer, as demonstrated by several phase II studies. The response rates ranging from 50% with 80% in patients with primary breast and lung cancer reported in some studies are associated to severe adverse events [8]. Results of a few phase III studies comparing chemotherapy alone with combined chemotherapy and WBRT do not allow firm conclusions [9], and studies comparing chemotherapy alone to WBRT alone are lacking. Nevertheless, it appears reasonable to consider chemotherapy for brain metastases in specific situations, such as chemosensitive primary tumor, or systemic metastases requiring chemotherapy. In fact, most patients are in class II and III and WBRT remains standard treatment.

Temozolomide (TMZ), an oral imidazotetrazinone methylating agent has demonstrated schedule-dependent activity in several cancers, including gliomas [10]. TMZ is rapidly absorbed and is spontaneously cleaved in vivo to monoethyl triazenoimidazole carboxamide (MTIC), a reactive DNA methylating species. The cytotoxicity of MTIC is thought to be caused by methylation of the O⁶ position of guanine [11]. TMZ is highly bio-available after oral administration, has excellent central nervous system penetration, and reaches the brain in therapeutic concentrations [12]. Myelosuppression is the primary toxicity associated with TMZ, but it is non-cumulative, and manageable in the majority of patients.

We have previously reported the results of a phase II study demonstrating that the temozolomide/pegylated doxorubicin regimen was well tolerated with encouraging activity in brain metastases from solid tumors [13]. Previous studies have reported on the use of TMZ in the setting of recurrent or progressive brain metastasis with modest results [14, 15]. The concomitant use of TMZ and WBRT is well tolerated and in a randomised phase II trial, showed a significantly higher response rate in patients receiving TMZ and radiotherapy versus radiotherapy alone [16, 17], confirming the in vitro data on the combination of temozolomide with radiation [18].

The primary aim of this study was to confirm the efficacy and safety of the combination of TMZ and WBRT in patients with previously untreated BM from solid tumours. The primary end points were conventional clinical symptoms evaluation and neuro-imaging response criteria. We also evaluated the impact of this treatment combination on the quality of life of the patients enrolled in the study, overall survival, progression free survival, safety and tolerability.

The clinical studies evaluating the role of chemotherapy in BM have been mostly non randomised Phase II trials. The results have been often divergent due to variability in several factors, including tumor histology, presenting stage, previous use of chemotherapy, etc. [25]. Two randomized phase III studies have confirmed the efficacy of chemotherapy in BM. One, of concurrent chemotherapy plus radiotherapy in BM from non-small-cell lung cancer [26], suggested that the timing of WBRT, with respect to chemotherapy with cisplatin and vinorelbine did not influence survival. The other, evaluating effect of adding WBRT to teniposide in small cell lung cancer, resulted in a better response rate and longer time to BM progression but had no impact on survival [27]. Several trials of TMZ plus radiation therapy have been conducted in patients with newly diagnosed brain metastases. Previous studies demonstrated that TMZ treatment is safe and well-tolerated when combined with RT but no significant improvements in survival was noted, compared to WBRT alone. Improvement in neurologic functional status has been reported with the combination, but there are no significant data about the influence on overall responses and QoL. In fact, the efficacy and safety of temozolamide concurrently with WBRT for patients with newly diagnosed brain metastases was evaluated in recent trials. The largest of these trials demonstrated a significant improvement of response rate and trend toward improved survival in the arm of combined therapy (8.3 vs. 6.3 months; p = 0.179) that was however not statistically significant [7]. Our data, revealing a 44% overall response rate (CR+PR) with 8,5% CR rate and the 76% brain disease control rate, appear encouraging. Patients treated with WBRT and TMZ had a slight improvement in OS as compared to the study of Antonadou et al. that yielded a median OS time of 8.6 months in the arm of concomitant treatment with WBRT and temozolamide [16]. More recently, a phase II trial of temozolomide and cisplatin followed by whole brain radiotherapy in NSCLC patients with brain metastases demonstrated a median OS of 5 months [28].

The responses were independent from the type of the primary tumor, gender and previous chemotherapy. In details, also the inclusion of brain metastases from breast cancer in the analysis did not change these results (data not shown). Furthermore, in our series KPS <70, age >65 years, presence of other extra-cranial metastases and RPA class III represent unfavourable factors for response. We have also demonstrated that KPS and age influence PFS and OS.

The results of this study suggest that the combination of WBRT and TMZ has a significant clinical activity in patients with brain metastases from solid tumours. The overall objective response plus stabilization rate of 78,9% is similar to that typically achieved with WBRT alone (61–91%). However, the responses achieved in this study were also reasonably durable with a median progression free survival of 9 months. Moreover, the median survival of 13 months is good for such an advanced-staged patient population. These results appear better than others obtained in previous trials; a possible explanation is the presence in our series of a high number of patients in the I and II RPA class.

This regimen was generally well tolerated by almost all patients, including elderly patients (>70 years) (12/59). The addition of daily TMZ to WBRT resulted in only one grade 4 hematologic toxicity. When neutropenia or thrombocytopenia developed, it resolved quickly and resulted in only minor treatment delays up to one week, with only one patient requiring dose reduction to 125 mg/m² of TMZ. In our series of patients we observed a considerable improvement in QoL, measured using the FACT-G and FACT-Br questionnaires. These data confirm previous results which showed an amelioration of QoL also in patients who did not obtain an objective response.

The results of our QoL analysis shows a high level of satisfaction among patients who have undergone TMZ plus WBRT treatment for brain metastases and provides excellent support for its acceptability. The benefits of treatment-related efficacy were not affected by symptoms caused by the toxic effect. The results of the present study support the efficacy and safety of WBRT and TMZ in the treatment of patients with BM from a variety of solid tumors and confirm that this combination can also offer significant palliation for BM, improving global QoL. Though the presented data looks promising, this will need to be further validated within the settings of a randomized trial.