Non-small cell lung cancer intracranial metastases treatment

Non-small cell lung cancer intracranial metastases treatment

Brain metastases are common in patients with non-small cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients 1).


EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression free survival compared to standard chemotherapy in the molecularly defined Non-small cell lung cancer (NSCLC) subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies 2).

The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPKAKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway stimulates the proliferation of tumor cells and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases 3).


KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non-small cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 4).


A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 5).


PUBMEDEMBASE, the Cochrane LibraryWeb of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastasis (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).

A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.

There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis 6).

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 7).


Response rates after platinum based antineoplastics, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10-25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown 8).

see Non small cell lung cancer intracranial metastases whole brain radiotherapy

see Non small cell lung cancer intracranial metastases radiosurgery

see Non small cell lung cancer intracranial metastases surgery.


1)

Bulbul A, Forde PM, Murtuza A, Woodward B, Yang H, Bastian I, Ferguson PK, Lopez-Diaz F, Ettinger DS, Husain H. Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer. Oncology (Williston Park). 2018 Apr 15;32(4):156-63. Review. PubMed PMID: 29684234.
2)

Wrona A, Dziadziuszko R, Jassem J. Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors. Cancer Treat Rev. 2018 Dec;71:59-67. doi: 10.1016/j.ctrv.2018.10.011. Epub 2018 Oct 21. Review. PubMed PMID: 30366200.
3)

Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K. Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma. Int J Mol Sci. 2021 Jan 8;22(2):593. doi: 10.3390/ijms22020593. PMID: 33435596; PMCID: PMC7826874.
4)

She C, Wang R, Lu C, Sun Z, Li P, Yin Q, Liu Q, Wang P, Li W. Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. Thorac Cancer. 2018 Nov 28. doi: 10.1111/1759-7714.12913. [Epub ahead of print] PubMed PMID: 30485664.
5)

Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO Open. 2018 Jan 26;3(1):e000262. doi: 10.1136/esmoopen-2017-000262. eCollection 2018. Review. PubMed PMID: 29387475; PubMed Central PMCID: PMC5786916.
6)

Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review. Med Sci Monit. 2015 Jan 12;21:144-52. doi: 10.12659/MSM.892405. PubMed PMID: 25579245.
7)

Kim SY, Hong CK, Kim TH, Hong JB, Park CH, Chang YS, Kim HJ, Ahn CM, Byun MK. Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. Yonsei Med J. 2015 Jan 1;56(1):103-11. doi: 10.3349/ymj.2015.56.1.103. PubMed PMID: 25510753; PubMed Central PMCID: PMC4276743.
8)

Cedrych I, Kruczała MA, Walasek T, Jakubowicz J, Blecharz P, Reinfuss M. Systemic treatment of non-small cell lung cancer brain metastases. Contemp Oncol (Pozn). 2016;20(5):352-357. doi: 10.5114/wo.2016.64593. Epub 2016 Dec 20. Review. PubMed PMID: 28373815; PubMed Central PMCID: PMC5371701.

Brain metastases from Head and Neck Cancer

Brain metastases from Head and Neck Cancer

Limited data is available on head and neck cancer (HNC) patients presenting with brain metastases (BM) at initial diagnosis.

Survival was significantly influenced by Eastern Cooperative Oncology Group (ECOG) performance score, number of cerebral lesions and extracranial metastatic disease. These characteristics were included in a score.

Scoring was based on 6-month survival data: ECOG 0-1=1 point, ECOG 2-3=0 points, 1-3 cerebral lesions=1 point, ≥4 cerebral lesions=0 points, lack of extracranial metastases=1 point, and presence of extracranial metastases=0 points. Addition of these points for each patient resulted in 0-3 points. Three groups were built comprising 0-1, 2 and 3 points. Six-month survival rates for these groups were 0%, 50% and 100%, respectively.

This instrument guides physicians in choosing optimal irradiation programs for patients with cerebral metastases from head-and-neck cancer 1),


Messing et al. sought to evaluate the incidencemanagement, and treatment outcomes of these patients using the National Cancer Database (NCDB).

They identified 465,925 patients diagnosed with HNC between 2010 and 2015 in the NCDB. 14,583 of these patients presented with metastatic disease to any site. 440 of these patients had BM at the time of initial diagnosis. Overall survival was compared using the Kaplan-Meier estimatorCox Proportional hazards modelpropensity score matching, and subgroup analyses were performed.

The median age overall was 62.0 years. Nasopharynx NOS (13.2%) and Parotid Gland (10.9%) were the most common anatomical sites with the highest frequency of BM. The overall median survival time was 7.1 months. Predictors for the presence of BM included distant metastasis to the bone, liver, or lung on univariate analysis, and bone or lung on multivariate analysis. High-risk Human Papilloma Virus status was associated with a lower chance of BM. No pattern was determined when comparing lymph node level involvement and BM. The median survival for patients receiving radiation therapy and multi-agent chemotherapy was 8.4 and 11.7 months, respectively. Immunotherapy administered as first course therapy did not influence median survival. Most patients received radiation (62.7%) therapy and chemotherapy (50.2%).

The data extracted and analyzed from the NCDB should work to aid in the surveillance and management of BM in patients with HNC 2).


Out of 9432 HNC patients, 88 patients developed BM (0.9%, median follow-up 3.4 years). On average, the BM were diagnosed 18.5 months after the primary diagnosis and tended to arise after distant metastases to extracranial sites (85%) such as the lungs (78%). At BM presentation, 84% were symptomatic and two thirds had a poor performance status (ECOG ≥ 2, 68%). The median post-BM survival was 2.5 months (95% CI 2.1-3.3 months). On multivariable analysis, management of BM with radiotherapy (RT) alone (3.3 months, 95% CI 2.3-4.6, p = 0.005) and RT with surgery (4.4 months, 95% CI 2.8-6.9, p < 0.001) was associated with longer survival compared to best supportive care alone (1.4 months, 95% CI 1.0-2.0 months). Age, sex, performance status, sub-localization of the primary HNC, presence of extracranial metastases, and number of intracranial metastases were not associated with post-BM survival (all p ≥ 0.05).

BM occur late in the course of HNC and carry a poor prognosis. Treatment with intracranial radiotherapy both with and without surgery was associated with improved survival 3).

see Brain metastases from Head and Neck squamous cell carcinoma.


1)

Rades D, Dziggel L, Hakim SG, Rudat V, Janssen S, Trang NT, Khoa MT, Bartscht T. Predicting Survival After Irradiation for Brain Metastases from Head and Neck Cancer. In Vivo. 2015 Sep-Oct;29(5):525-8. PMID: 26359409.
2)

Messing I, Goyal S, Sherman JH, Thakkar P, Siegel R, Joshi A, Goodman J, Ojong-Ntui M, Rao YJ. Incidence and Prognosis of Brain Metastases in Head and Neck Cancer Patients at Diagnosis. Laryngoscope. 2021 Feb 18. doi: 10.1002/lary.29448. Epub ahead of print. PMID: 33599979.
3)

Liu AK, Wu J, Berthelet E, Lalani N, Chau N, Tran E, Hamilton SN. Clinical features of head and neck cancer patients with brain metastases: A retrospective study of 88 cases. Oral Oncol. 2021 Jan;112:105086. doi: 10.1016/j.oraloncology.2020.105086. Epub 2020 Nov 10. PMID: 33186892.

Brain metastases recurrence diagnosis

Brain metastases recurrence diagnosis

It is difficult to differentiate local brain metastases recurrence from radiation induced-changes in case of suspicious contrast enhancement. New advanced MRI techniques (perfusion and spectrometry) and Amino Acid Positron Emission tomography allow to be more accurate and could avoid a stereotactic biopsy for histological assessment, the only reliable but invasive method.

Whereas positron emission tomography (PET) with the widely used 18F-2-deoxy-2-fluoro-D-glucose (18F-FDG) has low diagnostic accuracy after SRS, the use of radiolabelled amino acids or amino acid analogues such as L-methyl-11C-methionine (11C-MET) and O-(2-18F-Fluoroethyl)-L-Tyrosine (18F-FET) reaches sensitivity and specificity values in the range of 78 and 100 % rendering especially 18F-FET a highly reliable tracer in glioma imaging.


In patients with MRI-suspected tumor recurrence after focused high dose radiotherapy, 18F-FET PET has a high sensitivity and specificity for the differentiation of vital tumor tissue and radiation-induced lesions 1).


Tran et al. performed a feasibility study to prospectively evaluate 11C methionine positron emission tomography and11C PBR28 positron emission tomography in 5 patients with 7 previously SRS-treated brain metastases demonstrating regrowth to differentiate tumor regrowth (TR) from radiation necrosis (RN).

Sequential imaging with dual tracers was well-tolerated. [11C]methionine was accurate for detecting pathologically confirmed TR in 7/7 lesions, whereas [11C]PBR28 was only accurate in 3/7 lesions. Tumor PBRTSPO expression was elevated in both melanoma and lung cancer cells, contributing to lack of specificity of [11C]PBR28-PET.

Sequential use of PET tracers is safe and effective. [11C]Methionine was a reliable TR marker, but [11C]PBR28 was not a reliable marker of RN. Studies are needed to determine the causes of post-radiation inflammation and identify specific markers of RN to improve diagnostic imaging 2).

The multimodal MRI has greatly contributed to refine the differential diagnosis between tumour recurrence and radionecrosis, which remains difficult. The FDG PET is helpful, in favour of the diagnosis of local tumour recurrence when a hypermetabolic lesion is found. Others tracers (such as carbon 11 or a fluoride isotope) deserve interest but are not available in all centres. Stereotactic biopsy should be discussed if any doubt remains 3).

An increase in FLAIR signal of the fluid within the resection cavity might be a highly specific and early sign of local tumor recurrence/tumor progression also for brain metastases. 4).


1)

Romagna A, Unterrainer M, Schmid-Tannwald C, Brendel M, Tonn JC, Nachbichler SB, Muacevic A, Bartenstein P, Kreth FW, Albert NL. Suspected recurrence of brain metastases after focused high dose radiotherapy: can [18F]FET- PET overcome diagnostic uncertainties? Radiat Oncol. 2016 Oct 21;11(1):139. doi: 10.1186/s13014-016-0713-8. PMID: 27769279; PMCID: PMC5073742.
2)

Tran TT, Gallezot JD, Jilaveanu LB, Zito C, Turcu G, Lim K, Nabulsi N, Huang H, Huttner A, Kluger HM, Chiang VL, Carson R. [11C]Methionine and [11C]PBR28 as PET Imaging Tracers to Differentiate Metastatic Tumor Recurrence or Radiation Necrosis. Mol Imaging. 2020 Jan-Dec;19:1536012120968669. doi: 10.1177/1536012120968669. PMID: 33147119.
3)

Patsouris A, Augereau P, Tanguy JY, Morel O, Menei P, Rousseau A, Paumier A. [Differentiation from local tumour recurrence and radionecrosis after stereotactic radiosurgery for treatment of brain metastasis.]. Cancer Radiother. 2014 Jan 13. pii: S1278-3218(13)00444-7. doi: 10.1016/j.canrad.2013.10.013. [Epub ahead of print] French. PubMed PMID: 24433952.
4)

Bette S, Gempt J, Wiestler B, Huber T, Specht H, Meyer B, Zimmer C, Kirschke JS, Boeckh-Behrens T. Increase in FLAIR Signal of the Fluid Within the Resection Cavity as Early Recurrence Marker: Also Valid for Brain Metastases? Rofo. 2017 Jan;189(1):63-70. doi: 10.1055/s-0042-119686. PubMed PMID: 28002859.
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