Unusual Toxicities and Clinical Outcomes in Extracranial Tumor Sites With Concurrent Whole-Brain Radiation Therapy and Erlotinib Treatment in Patients With Non–Small-Cell Lung Cancer With Brain Metastasis

Abstract

Introduction: Twenty-five to thirty percent of patients with newly diagnosed NSCLC present with synchronous brain metastases. Radiation Therapy Oncology Group (RTOG) is conducting a phase III trial evaluating the synergistic effect of erlotinib in combination with wholebrain radiation therapy (WBRT), and an interim analysis has not shown any severe toxicities. However, in patients with extensive extracranial disease, the benefits on the extracranial disease with such an approach have not been fully evaluated. We report our institutional experience with this combination treatment, with particular attention to some severe, unusual toxicities. Study Design and Methods: Medical records of all patients presenting with newly diagnosed NSCLC and brain metastasis who received concurrent WBRT and erlotinib treatment were retrospectively reviewed. All patients received erlotinib 150 mg daily, which overlapped with WBRT for a minimum of 3 days and a maximum of 30 days. Erlotinib was continued after WBRT until disease progression or toxicity. Result: Ten patients were treated; 3 were men and 7 were women, aged 35 to 82 years with a median age of 56 years. Four patients were nonsmokers, and 6 were smokers. Six patients had lung and brain disease, while 4 patients had lung, brain, and other systemic metastases. Eight patients had multiple brain metastasis, and 5 had at least 1 brain tumor larger than 2 cm. Seven patients had a Karnofsky performance score (KPS) of > 70. The overall follow-up ranged from 1.5 to 24 months (median, 3.5 months). Among 9 patients evaluable for response in the extracranial sites, 4 (40%, intent-totreat) showed partial response (PR), 3 (30%) had stable disease (SD), and 2 (20%) had progression (PD). The 4 responding patients were continued on the treatment for 4, 10, 12, and 13 months, respectively. Among the 4 responders, 1 was a male smoker, another was a female smoker, and 2 others were female nonsmokers. Nine patients had restaging magnetic resonance imaging (MRI) of the brain after completion of radiation; of these, 7 had regression and 2 had SD. The most frequent toxicities were rash (90%), fatigue (80%), and thrombocytopenia (60%). Two deaths occurred both on day 38. One patient developed grade 4 neutropenia with sepsis, grade 3 hyponatremia and mental status changes; the other had grade 3 hyponatremia, rapid respiratory distress, and mental status changes. In addition, another patient developed hyponatremia with persistent grade 3 mental status changes requiring home hospice. There was no evidence of tumor progression in the brain in the above 3 patients. Conclusion: Our study demonstrated that 50% of the patients benefited from combination treatment with PR or SD of the systemic lesions, lasting from 3 to 13 months. Responding patients included female and male smokers. On the other hand, there were also severe toxicities not previously reported, including grade 4 neutropenia with sepsis, grade 3 hyponatremia, and mental status changes leading to 2 deaths. As this is a small retrospective study without randomization, it is unclear whether the combination treatment is the cause of the above unusual toxicities. However, we recommend caution to be exercised on routine treatment of erlotinib with WBRT, pending data from further large-scale clinical trials.