Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer

Welsh, James W.; Komaki, Ritsuko; Amini, Arya; Munsell, Mark F.; Unger, Wyatt; Allen, Pamela K.; Chang, Joe Y.; Wefel, Jeffrey S.; McGovern, Susan L.; Garland, Linda; Chen, Su S.; Holt, Jamie; Liao, Zhongxing; Brown, Paul D.; Sulman, Erik P.; Heymach, John V.; Kim, Edward S.; Stea, Baldassarre

doi:10.1200/jco.2011.40.1174

Cited by 357 publications

(273 citation statements)

References 28 publications

(5 reference statements)

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“…Although RTOG 0320 found a potentially deleterious effect to combination SRS and erlotinib, Welsh et al found no significant additional neurotoxicity in a phase II study that added erlotinib to whole brain RT.The overall response rate was 86%. Compared with historic controls, patients had longer overall survival with combination therapy and patients with EGFR-mutant disease had particularly longer survival than those with EGFR wild-type disease [47,56]. Other agents of interest in lung cancer include the ALK mutation-targeted crizotinib, also approved for first-line treatment of ALK-positive lung cancer.…”

Section: Targeted Therapies For Breast Cancer Lung Cancer and Renalmentioning

confidence: 99%

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

et al. 2016

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Brain metastases are the most common intracranial malignancy. Many approaches, including radiation therapy, surgery, and cytotoxic chemotherapy, have been used to treat patients with brain metastases depending on the patient's disease burden and symptoms. However, stereotactic surgery (SRS) has revolutionized local treatment of brain metastases. Likewise, targeted therapies, including small-molecule inhibitors and monoclonal antibodies that target cancer cell metabolism or angiogenesis, have transformed managing systemic disease. Prospective data on combining these treatments for synergistic effect are limited, but early data show favorable safety and efficacy profiles.The combination of SRS and targeted therapy will further individualize treatment, potentially obviating the need for cytotoxic chemotherapy or whole-brain radiation.There is a great need to pursue research into these exciting modalities and novel combinations to further improve the treatment of patients with brain metastases.This article discusses reported and ongoing clinical trials assessing the safety and efficacy of targeted therapy during SRS. The Oncologist 2016;21:244-251 Implications for Practice: Treatment of patients with brain metastases requires a multidisciplinary approach. Stereotactic radiosurgery is increasingly used in the upfront setting to treat new brain metastasis. Targeted therapies have revolutionized systemic treatment of many malignancies and may sometimes be used as initial treatment in metastatic patients. There is sparse literature regarding safety and efficacy of combining these two treatment modalities. This article summarizes the supporting literature and highlights ongoing clinical trials in combining radiosurgery with targeted therapy.

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Section: Targeted Therapies For Breast Cancer Lung Cancer and Renalmentioning

confidence: 99%

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

et al. 2016

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“…Interestingly, patients negative for EGFR mutations had a median overall survival of 9.3 months, whereas patients who were positive for EGFR mutations had a median overall survival of 19.1 months. [89] The clinical benefit and feasibility of targeting ALK was demonstrated first with the multitargeted tyrosine kinase inhibitor crizotinib that competitively binds to the ATPbinding pocket of the ALK and MET tyrosine kinases and inhibits phosphorylation of activated ALK. This was subsequently confirmed in phase II and III trials.…”

Section: Breast Cancermentioning

confidence: 99%

“…Examples include PETbased approaches for noninvasive measuring of drug uptake with 89 Zr-trastuzumab and 89 Zr-bevacizumab. [106,107] Recent studies using magnetic resonance-guided focused ultrasound suggest a role for this noninvasive, radiationfree alternative for treatment of small deep-seated brain metastases.…”

Section: Future Perspectivesmentioning

confidence: 99%

Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

Tabatabai¹,

Koch²,

Roggia³

et al. 2016

JCMT

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The incidence of metastatic disease in the central nervous system (CNS) is rising. According to current estimates, up to a third of adult cancer patients will suffer from CNS metastasis. Clinical evidence-based data from prospective randomized trials are rare, however, because CNS metastasis patients were often excluded from clinical trial participation. The management of CNS metastasis patients is therefore rather ill-defined and an interdisciplinary challenge. Recent basic and translational science data have begun contributing to a more profound understanding of the molecular mechanisms leading to invasion of tumor cells into the CNS. This report reviews advances, challenges, and perspectives in this field.

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“…Pre-clinical data showed a synergistic effect between EGFR-inhibition and radiotherapy (23), likely due to the radio-sensitizing effect of TKIs and to the damage of BBB caused by radiation. Different phase II studies demonstrated a tolerable safety profile and encouraging activity of WBRT and EGFR-TKI combination in EGFRpositive NSCLC patients with BM (24,25). The prospective randomized TRACTS study (NCT01763385) is currently investigating WBRT plus erlotinib combination vs. erlotinib alone in this subset of patients, and results are eagerly awaited.…”

mentioning

confidence: 99%

Upfront radiation versus EGFR-TKI: which is the best approach for EGFR-mutated NSCLC patients with brain metastasis?

Passiglia¹,

Rolfo²

2017

Transl. Cancer Res

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and colleagues have recently reported the results of a multicenter retrospective analysis comparing the impact of three different treatment strategies on survival outcomes of 351 patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) and brain metastases (BM). Treatment options included stereotactic radiosurgery (SRS) followed by EGFR-TKI (n=100), whole-brain radiotherapy (WBRT) followed by EGFR-TKI (n=120), or EGFR-TKI followed by SRS or WBRT at the time of intracranial progression (n=131). Results showed a significantly longer median overall survival (OS) in patients who received upfront SRS (46 months) as compared to WBRT (30 months) or upfront TKI (25 months) (P<0.001), suggesting SRS followed by EGFR-TKI as the best treatment approach for these patients. The significant survival improvement was independent from significant prognostic covariables such as age, ECOG performance status, number of BM, EGFR mutation, and extracranial metastases, which were included in the multivariable analysis. The upfront use of radiotherapy resulted also in a significantly longer median time to intracranial progression (23 vs. 18 months; P=0.025) and 2-year OS rate (78% vs. 51%; P<0.001), and it was maintained regardless of patients' prognosis.The results of several randomized phase III (2-9) studies convincingly and consistently demonstrated a significant superiority of upfront EGFR-TKI over platinum-based chemotherapy for the subgroup of patients whose tumors harbor an EGFR activating mutation, leading to a paradigm shift in the first-line treatment of these patients, to whom the current gold standard is starting with an EGFR-TKI, gefitinib, erlotinib, or afatinib. However, several years later the approval of the first EGFR-TKI in the clinical setting the specific role of these agents in the therapeutic strategy of patients with BM remains still debated. Brain metastasis are a common event in EGFR-mutated NSCLC, with major negative impact on patients' quality of life (QoL) and survival, ranging from 4.5 to 11.0 months after the diagnosis (10,11). Despite the recent innovations in the treatments of EGFR positive NSCLC, current options available for EGFR-mutated patients with BM are very limited, also because of their historical low accrual in prospective clinical trials. Surgical resection, SRS or WBRT concomitantly or followed by EGFR-TKIs remain the most common approaches to treat these patients (12). However the optimal treatment sequences and combinations have not been clarified yet. Activity of upfront firstgeneration EGFR-TKIs has been reported in retrospective series including low number of East-Asian patients (13-16), overall showing encouraging intracranial response rates (RR) despite to the low penetration of such agents Editorial Upfront radiation versus EGFR-TKI: which is the best approach for EGFR-mutated NSCLC patients with brain metastasis?

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Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer

Cited by 357 publications

References 28 publications

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

The Rationale for Targeted Therapies and Stereotactic Radiosurgery in the Treatment of Brain Metastases

Interdisciplinary management of central nervous system metastasis and neoplastic meningitis: recent developments and future perspectives

Upfront radiation versus EGFR-TKI: which is the best approach for EGFR-mutated NSCLC patients with brain metastasis?

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