Brain metastasis are one of the most common type of intracranial metastases and are 10 times more common as compared to primary malignancy of brain.[2] Brain metastasis commonly develop from primary tumors of lung, breast, and melanoma.[3,4] Presence of metastasis to brain is poor prognostic feature and whole brain radiotherapy (WBRT) is most commonly indicated for management of such patients.[7] Temozolomide (TMZ), an orally administered chemotherapeutic agent that cross the blood– brain barrier has shown to have additive effect in management of brain metastasis.[11] The present study aimed at assessing and comparing radiological, clinical response and side effects before and after treatment in two groups i.e. cases (WBRT with TMZ) and controls (WBRT alone).
Brain metastasis is commonly observed following primary cancers affecting lung, breast, and melanoma. Other malignancies less commonly associated with brain metastasis included prostate and head and neck cancers.[3,4] Primary cancer histology is an important determinant of aggressiveness of cancer. In present study, majority of cases (47.1) as well as controls (52.9%) presented with brain metastasis following carcinoma breast followed by Ca lung (29.4% cases and 23.5% controls). Other primary sites were Ca oropharynx, Ca rectum, ca urinary bladder, Melanoma, Ca cervix and Ca gastroesophageal junction. In present study, as majority of patients had breast cancer, the histology in majority of cases (41.2%) and controls (52.9%) was intraductal carcinoma whereas about 23.5% and 35.3% cases and controls respectively were adenocarcinoma. However, two groups comparable with respect to primary histology (p>0.05). Previous literature mainly included brain metastasis following primary lung cancer or primary breast cancer or ovarian cancers individually. In another meta-analysis by Xin et al [15] and Lv et al[16] included patients with brain metastases (BM) from non-small-cell lung cancer (NSCLC). However in a study by Zhao et al, majority of patients presented with brain metastasis following lung cancer followed by breast cancer.[17]
Karnofsky performance status (KPS) and graded prognostic assessment (GPA) are important indicators helpful in assessing the prognosis of patients with brain metastasis. The Radiation Therapy Oncology Group (RTOG) recently recommended disease specific graded prognostic assessment (GPA) for patients with brain metastasis.[18] The GPA has been divided into 4 groups i.e. 0-1 (median survival- 2.6 months), GPA 1.5-2.5 (3.8 months), ; GPA 3 (6.9 months) and GPA 3.5-4.0 (11 months). In present study, majority of cases i.e. 47.1% and controls (52.9%) belonged to KPS grade of 80 and about 23.5% cases had GPA 0 whereas majority (76.5%) of controls had GPA of 2. Thus, WBRT with TMZ was given to significantly higher proportions of patients with lower GPA whereas WBRT alone was given in significantly higher proportions of controls (p<0.01). However, the two groups were comparable with respect to KPS (p>0.05).
Toxicity following management is particularly relevant in the treatment of brain metastases, as they further deteriorate the morbidity and quality of life of patient. In present study, though nausea was observed in almost equal proportions of cases and controls during week 1 and week 2, but severity of nausea higher in controls but the difference was statistically insignificant (p>0.05). Similarly, no significant difference was observed between cases and controls for vomiting, diarrhea (p>0.05). Hematological effect were adverse in significantly higher proportions of cases as compared to controls at week 2 (p<0.05). Hepatic, renal involvement and radiation dermatitis was neither observed in cases nor in controls. The findings of present study were concordant with the findings of Liu et al in which hematological and gastrointestinal adverse effects were observed in higher proportions of cases and controls but the difference was statistically significant (P > 0.05).[19] Zhao et al in however observed contrasting findings as compared to present study. They documented that RT plus TMZ arm was associated with significantly more grade 3 to 4 nausea and thrombocytopenia.[17] Yong et al[20] and Deng et al[21] concluded that though TMZ in combination with WBRT is associated with higher incidence of adverse events particularly nausea and thrombocytopenia but patients can tolerate these effects and can be managed using medications.
The present study documented no statistically significant difference symptomatic response between cases and controls for headache and blurring of vision (p>0.05). However, vomiting was observed in significantly higher proportions in cases as compared to controls (p<0.05) whereas seizures were documented in significantly higher proportions of controls (p<0.05) during fourth week follow up. These findings were concordant with the findings of Liu et al in which the authors observed symptomatic improvement during and 4–6 weeks after treatment in significantly higher proportions of patients in observation group (94.4%) as compared to control groups (63.89%) (P = 0.0014).[20] As TMZ is itself associated with nausea and vomiting, and hence the symptomatic response for GI symptoms was significantly lower among cases as compared to controls (p<0.05) in our study.
Though, overall response was better in cases as compared to controls, but the difference was statistically insignificant (p>0.05) in present study. Complete response was observed in one patient in case group whereas partial response was observed in 70.6% cases and controls each. Stable disease was observed in 23.5% cases whereas disease was progressive in 23.5% controls. These findings were concordant with the findings of Zhu et al in which the authors observed significantly better improvement in TMZ + WBRT arm as compared to WBRT alone in ORR (P = 0.0108).[22] Similarly, Xin et al observed statistically significant better overall response rate in WBRT with TMZ group as compared to WBRT alone group (p<0.05).[15]