Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

Economopoulou, Panagiota; Mountzios, Giannis

doi:10.21037/tlcr.2016.12.06

Cited by 33 publications

(29 citation statements)

References 85 publications

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“…There is no recommendation in the current guidelines and no evidence regarding the concurrent administration of cranial radiotherapy and ALK-TKI (20). In our study, both of the patients who concurrently underwent WBRT with ALK-TKI suffered from grade 3 otitis media as a consequence of the concurrent treatment.…”

Section: Discussionmentioning

confidence: 66%

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Nakashima

Nonoshita

Hirata

et al. 2019

In Vivo

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Background: We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. Patients and Methods: Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both wholebrain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. Results: Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wildtype cases (p=0.013), respectively. Conclusion: Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC. Anaplastic lymphoma kinase gene rearrangement (ALKr) is a significant driver of gene mutation for novel moleculartargeted therapy in lung cancer, and is identified in about 2-7% of non-small cell lung cancer (NSCLC) cases (1). The predominant histological subtype in ALKr NSCLC is adenocarcinoma, and ALKr is rarely seen in other histological subtypes, including small-cell lung cancer. In addition, unlike mutation of epidermal growth factor receptor (EGFR), which differs in humans according to race, there is no race-related difference in the frequency of ALKr. With regard to the prognostic significance of ALKr, some investigations have reported ALKr itself to be a favorable prognostic factor (2). The existence of brain metastases (BMs) is a major factor leading to poor survival outcome in NSCLC, with the median survival of patients with BMs ranging from 3 to 14.8 months according to diagnosis-specific graded prognostic assessment (3). The incidence of BMs from ALKr NSCLC ranges from approximately 25% to 35%; it is greater than that for those with wild-type NSCLC, and slightly higher or equivalent to that of NSCLC with EGFR mutation (4). BMs seem to be more commonly detected at initial diagnosis in those with ALKr NSCLC compared with those with wildtype NSCLC. Many previous clinical trials reported that multi-targeted receptor tyrosine kinase inhibitors (TKIs) of ALK, such as crizotinib, alectinib and ceritinib, achieved better local control of BMs and intracranial progression-free survival (IPFS) in ALKr NSCLC (5-7). Crizotinib, a first-generation ALK-TKI, was associated with a median IPFS of 7 months in patients with BMs that was previously untreated in the analysis of PROFILE 1005 and 1007 (8). After the experience of progression with a single ALK-TKI, it is promising to consider sequential therapy with multiple ALK-TKI (9-12). Regardless of the efficacy of ALK-TKI for BMs, it is concerning that many patients invariably develop progression of intracranial disease. Therefore, radiotherapy such as whole-brain radioth...

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Section: Discussionmentioning

confidence: 66%

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Nakashima

Nonoshita

Hirata

et al. 2019

In Vivo

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“…Regarding benefits, a combination of EGFR-TKIs and radiotherapy has been hypothesised to result in radiosensitisation and increased permeability of the BBB to EGFR-TKIs [16,17]. Many meta-analyses and retrospective studies regarding the combination of EGFR-TKIs with radiotherapy have yielded conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…However, others have reported no survival benefit [23][24][25][26]. Thus, the optimal treatment combination or sequence for brain metastasis remains controversial [16]. Besides, these studies had many limitations, owing to the retrospective analyses, such that the majority did not examine the late effects of radiotherapy on neurocognitive function.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment options other than EGFR-TKIs are surgical resection or stereotactic radiosurgery (SRS) for limited numbers of brain metastases and whole-brain radiotherapy (WBRT) for multiple brain metastases. However, the optimal treatment combination or sequence of radiotherapy with EGFR-TKIs of all generations has not been clearly studied [16].…”

Section: Introductionmentioning

confidence: 99%

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Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

Ameku¹,

Higa

2020

Case Reports in Oncological Medicine

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Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.

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“…Therefore, whole brain radiotherapy is controversial at present. Especially for those patients with poor general medical condition, best support care has similar efficacy as whole brain radiotherapy [5,[28][29][30]. It was revealed that radiotherapy times are negatively related with the prognosis.…”

Section: It Is Recommended By National Comprehensive Cancermentioning

confidence: 99%

Clinical study of the treatment of multiple brain metastases from adenocarcinoma of the lung by simultaneous integrated boost intensity-modulated radiotherapy

Shao¹,

S²,

Wang³

et al. 2018

J Cancer Res Ther.

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Objective: To investigate the effects of simultaneous integrated boost intensity-modulated radiotherapy (SIB) and sequential boost conformal radiotherapy (CRT) in treatment of multiple brain metastases from lung adenocarcinoma. Methods: Forty-two patients with multiple brain metastases from lung adenocarcinoma were analyzed. The epidermal growth factor (EGFR) mutations were negative, ECOG (Eastern Cooperative Oncology Group) were not more than two, the diameters of brain metastases were from 0.5cm to 3.0cm and the numbers of brain metastases were from three to five. The target volume of radiotherapy included whole brain and brain metastatic tumor. The radiation models were divided into SIB in 26 cases and CRT in 16 cases. The median radiation dose of whole brains in SIB and CRT groups were 40Gy, and the brain metastases tumor were 55Gy, 60Gy respectively, and the median number of radiotherapy for 22 times, 30 times. Thirty one patients followed by pemetrexed maintenance chemotherapy (PMC) or docetaxel maintenance chemotherapy (DMC) and 11 patients received no maintenance chemotherapy (NMC). Results: The 1-, 3-, and 5-year survival rates of whole group were 92.8%, 23.8%, and 4.8%, respectively. The median survival time of SIB and CRT groups were 36 months, 29 months, respectively. The SIB group was better than CRT group, and PMC was better than DMC or NMC. Multiple factors analyses showed ECOG, dose and times of brain metastatic tumor radiotherapy, and cycles of PMC were independent risk factors for survival time. The late main adverse reaction was hypomnesia. Conclusion: SIB was superior to CRT, and PMC could improve survival time.

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Non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases: role of tyrosine kinase inhibitors (TKIs) and evidence in favor or against their use with concurrent cranial radiotherapy

Cited by 33 publications

References 85 publications

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Complete Remission of Multiple Brain Metastases in a Patient with EGFR-Mutated Non-Small-Cell Lung Cancer Treated with First-Line Osimertinib without Radiotherapy

Clinical study of the treatment of multiple brain metastases from adenocarcinoma of the lung by simultaneous integrated boost intensity-modulated radiotherapy

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