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Journal of Thoracic Oncology : Official... Nov 2006This clinical practice guideline, based on a systematic review, evaluates second-line or subsequent therapy for patients with recurrent or progressive non-small cell... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
This clinical practice guideline, based on a systematic review, evaluates second-line or subsequent therapy for patients with recurrent or progressive non-small cell lung cancer.
METHODS
Relevant randomized trials and meta-analyses were identified through a systematic search of the literature. External feedback was obtained from practitioners in Ontario, and the guideline was approved by the provincial Lung Cancer Disease Site Group.
RESULTS
Twenty-four randomized trials met the eligibility criteria. Two phase III trials demonstrated a significant benefit in overall survival and quality of life (QOL) for single-agent docetaxel. A pooled analysis comparing docetaxel administered weekly versus three-weekly found similar survival between the schedules and a non-significant reduction in febrile neutropenia for the weekly regimen. One phase III trial found that single-agent pemetrexed provided similar survival and QOL, compared to docetaxel. Another phase III trial demonstrated that oral topotecan was non-inferior to docetaxel for one-year survival rate, although QOL significantly favored docetaxel over topotecan. Docetaxel-based and other combination chemotherapy regimens have not been shown to be superior to single-agent docetaxel. One phase III trial revealed a statistically significant survival and QOL benefit for erlotinib over placebo for patients who were not eligible for further chemotherapy. Modest tumor response rates and symptom control have been demonstrated for gefitinib; however, a statistically significant survival benefit has not been established for gefitinib over placebo.
CONCLUSION
Second-line or subsequent therapy with single-agent docetaxel, pemetrexed, or erlotinib offers patients a significant survival and QOL advantage.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials, Phase III as Topic; Docetaxel; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Maximum Tolerated Dose; Neoplasm Recurrence, Local; Neoplasm Staging; Ontario; Palliative Care; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Taxoids; Time Factors
PubMed: 17409993
DOI: No ID Found -
Radiation Oncology (London, England) Mar 2019It remains unknown which is the most preferable regimen used concurrently with thoracic radiation for locally advanced non-small cell lung cancer (NSCLC). We performed a... (Comparative Study)
Comparative Study Meta-Analysis
Comparative efficacy and safety for different chemotherapy regimens used concurrently with thoracic radiation for locally advanced non-small cell lung cancer: a systematic review and network meta-analysis.
BACKGROUND
It remains unknown which is the most preferable regimen used concurrently with thoracic radiation for locally advanced non-small cell lung cancer (NSCLC). We performed a network meta-analysis to address this important issue.
METHODS
PubMed, Embase, Cochrane Library, Web of Science and major international scientific meetings were searched for relevant randomized controlled trials (RCTs). Overall survival (OS) data was the primary outcome of interest, and progression-free survival (PFS), and serious adverse events (SAEs) were the secondary outcomes of interests, reported as hazard ratio (HR) or odds ratio (OR) and 95% confidence intervals (CIs).
RESULTS
14 RCTs with a total of 2975 patients randomized to receive twelve categories of treatments were included in the meta-analysis. Direct comparison meta-analysis showed that etoposide-cisplatin (EP) was more effective than paclitaxel-cisplatin/carboplatin (PC) in terms of OS (HR = 0.85, 95% CI: 0.77-0.94) and PFS (HR = 0.66, 95% CI: 0.47-0.95). In network meta-analysis, all regimen comparisons did not produce statistically significant differences in survival. Based on treatment ranking of OS and the benefit-risk ratio, S-1-cisplatin (SP) was likely to be the most preferable regimen for its best efficacy and low risk of causing SAEs. Uracil/tegafur-cisplatin (UP) and pemetrexed-cisplatin/carboplatin (PP) were ranked the second and third respectively. Gemcitabine-cisplatin (GP) and PC + Cetuximab (PC-Cet) appeared to be the worst and second-worst regimens for their poor efficacy and poor tolerability.
CONCLUSIONS
Based on efficacy and tolerability, SP is likely to be the most preferable regimen used concurrently with thoracic radiation for locally advanced NSCLC, followed by UP and PP. Further direct head-to-head studies are needed to confirm these findings.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Humans; Lung Neoplasms; Network Meta-Analysis; Prognosis; Thoracic Neoplasms
PubMed: 30925881
DOI: 10.1186/s13014-019-1239-7 -
Lung Cancer (Amsterdam, Netherlands) Sep 2013The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
The sole agents pemetrexed (PEM), docetaxel and anti-EGFR agents are approved second-line therapies for non-small cell lung cancer (NSCLC) after failure with cisplatin-based doublets. The potential usefulness of platinum-based doublets as rechallenge for second-line chemotherapy has not yet been established.
METHODS
Studies that enrolled NSCLC platinum pre-treated patients were identified using electronic databases (MEDLINE and EMBASE). Pemetrexed and taxanes (TAXs)-based platinum combinations were considered. A systematic review was conducted using Comprehensive Meta-Analysis (version 2.2.064) software to calculate the event rate of response and 95% confidence interval. Median weighted progression-free survival (PFS) and overall survival (OS) time for PEM and TAXs-based doublets were compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I(2) index.
RESULTS
Eleven studies published between 1999 and 2012 were included in this analysis with a total of 607 patients enrolled; 468 were treated with PEM-doublets and 139 with TAXs-doublets. The overall response rate was 27.5% with a higher response rate of 37.8% (range, 29.7-46.7%) for TAXs-based treatment vs. 22% (range, 13.4-34.1%) for PEM-based combinations; (p < 0.0001). Median PFS and OS were 3.9 and 8.7 months with weighted PFS of 3.9 vs. 5.3 months (p < 0.0001) and similar OS for PEM vs. TAXs-based doublets.
CONCLUSIONS
With the limitations of small and not randomised trials included, this pooled analysis shows that NSCLC patients who relapsed after a first-line platinum-based chemotherapy obtain a tumour response of 27% from a platinum rechallenge containing PEM or TAXs. Response rate and median PFS appear better with TAXs-than with PEM-doublets.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Neoplasm Staging; Odds Ratio; Platinum; Publication Bias; Retreatment; Treatment Outcome
PubMed: 23891507
DOI: 10.1016/j.lungcan.2013.06.022 -
World Journal of Clinical Oncology Aug 2016To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer.
AIM
To evaluate the current role of sorafenib, an oral multikinase inhibitor in the treatment of breast cancer.
METHODS
An extensive search of the literature until March 2016 was carried out in Medline and clinicaltrials.gov, by using the search terms "sorafenib" and "breast cancer". Papers found were checked for further relevant publications. Overall, 21 relevant studies were found, 18 in advanced breast cancer (16 in stage IV and two in stages III-IV) and three in early breast cancer.
RESULTS
Among studies in advanced breast cancer, there were two trials with sorafenib as monotherapy, four trials of sorafenib in combination with taxanes, two in combination with capecitabine, one with gemcitabine and/or capecitabine, one with vinorelbine, one with bevacizumab, one with pemetrexed and one with ixabepilone, three trials of sorafenib in combination with endocrine therapy and two trials in women with brain metastases undergoing whole brain radiotherapy. In addition, there was one trial of sorafenib added to standard chemotherapy in the adjuvant setting, and two trials in the neoadjuvant setting. In general, sorafenib was well tolerated in breast cancer patients, though its dosage had to be adjusted in some trials, and discontinuation rates were high, particularly for the combination of sorafenib with anastrozole. Sorafenib monotherapy and combinations with taxanes, bevacizumab and ixabepilone showed inadequate efficacy, while efficacy results from combinations with gemcitabine and/or capecitabine and possibly tamoxifen were more promising.
CONCLUSION
At present, sorafenib should not be used for the treatment of breast cancer outside of clinical trials and more clinical data are needed in order to support its standard use in breast cancer therapy.
PubMed: 27579253
DOI: 10.5306/wjco.v7.i4.331 -
Oral Surgery, Oral Medicine, Oral... Oct 2011The aim of this study was to conduct a quantitative systematic review, including published data, comparing the efficacy of mineral trioxide aggregate and calcium... (Comparative Study)
Comparative Study Meta-Analysis Review
OBJECTIVE
The aim of this study was to conduct a quantitative systematic review, including published data, comparing the efficacy of mineral trioxide aggregate and calcium hydroxide as material used for the endodontic management of immature teeth.
STUDY DESIGN
Relevant studies published through November 2009 were identified through literature searches using Pubmed (Medline) and Scopus databases. Controlled trials in which calcium hydroxide versus mineral trioxide aggregate were used for the apexification of immature permanent teeth were selected for this study. The evaluation included clinical outcome and apical barrier formation. The principal measure of treatment effect was risk difference. The overall effect was tested by using Z score. Heterogeneity was tested by using the χ(2) statistic and I square (I(2)). A fixed-effect model was used when the studies in the subgroup were sufficiently similar. A random-effects model was used in the summary analysis when there was heterogeneity between the subgroups.
RESULTS
Based on reduction of relative risk with 95% confidence intervals we found that the rate of clinical success (P = .29) and apical barrier formation (P = .76) of the 2 interventions had no perceivable discrepancy. Regarding success and apical barrier formation, either calcium hydroxide or mineral trioxide aggregate may be used for the apexification of immature teeth.
Topics: Apexification; Calcium Hydroxide; Dentin, Secondary; Glutamates; Guanine; Humans; Pemetrexed; Root Canal Filling Materials; Tooth Apex; Tooth Root; Treatment Outcome
PubMed: 21778090
DOI: 10.1016/j.tripleo.2011.03.047 -
Journal of Comparative Effectiveness... Feb 2023In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was... (Meta-Analysis)
Meta-Analysis Review
In the absence of head-to-head trials comparing immunotherapies for advanced nonsquamous non-small-cell lung cancer (NsqNSCLC), a network meta-analysis (NMA) was conducted to compare the relative efficacy of these treatments. A systematic literature review of randomized controlled trials evaluating first-line-to-progression and second-line treatments for advanced NsqNSCLC informed Bayesian NMAs for overall survival (OS) and progression-free survival (PFS) end points. Among first-line-to-progression treatments, pembrolizumab + pemetrexed + platinum showed the greatest OS benefit versus other regimens and a PFS benefit versus all but three regimens. Among second-line treatments, an OS benefit was seen for atezolizumab, nivolumab and pembrolizumab versus docetaxel. Pembrolizumab + pemetrexed + platinum showed the maximum OS benefit in the first-line setting. In the second-line setting, anti-PD-1/anti-PD-L1 monotherapies were better than docetaxel.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Docetaxel; Pemetrexed; Network Meta-Analysis; Platinum; Bayes Theorem; Immunotherapy; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36621905
DOI: 10.2217/cer-2022-0016 -
Medicine Jul 2012Symptomatic choroidal metastasis is a rare presenting manifestation of lung cancer. We describe here 3 patients with non-squamous non-small cell lung cancer who... (Review)
Review
Symptomatic choroidal metastasis is a rare presenting manifestation of lung cancer. We describe here 3 patients with non-squamous non-small cell lung cancer who presented with choroidal metastasis and who were diagnosed and treated by the authors. We performed a systematic literature review of the previously reported patients with choroidal metastasis from lung cancer in the English-language literature. We excluded case series lacking individual patient data and identified 75 patients. In 23 of these patients, choroidal metastasis was not the presenting manifestation of lung cancer. Therefore, we included 55 patients (3 index and 52 previously reported) in the analysis. We present the demographic profile, histology, disease stage, ocular and lung lesions, diagnostic and treatment (systemic and ocular) modalities, and treatment outcomes. The majority of patients were male (67.3%) and were current or ex-smokers (78.3%); the mean age was 55.1 (standard deviation 11.2) years. Adenocarcinoma (n = 23) was the most common histologic type followed by squamous (n = 11) and small cell (n = 8). Left eye (n = 32) involvement was more common than right eye (n = 19) or bilateral (n = 4). Among patients for whom the location of primary lesion was specified, the left upper lobe (n = 13) was the most common site. The most common diagnostic modalities were bronchoscopic lung biopsy (n = 15) and enucleation (n = 13), while the liver (30.9%) was the most common extraocular metastatic site identified. Systemic chemotherapy was given in 56.4% of cases, and disease progression was the most common outcome among evaluable patients. Ocular treatment modalities included radiation (n = 23), enucleation (n = 14), and systemic steroids (n = 8). Regression of choroidal metastases with treatment was observed in 66.7% of patients who did not undergo enucleation as the primary treatment modality. Of the 3 index patients, 2 each received pemetrexed-cisplatin (as first-line therapy), gefitinib or erlotinib (as second- or third-line therapy), and intravitreal bevacizumab; and 1 patient received systemic bevacizumab. Two patients had partial response radiologically with systemic treatment, and all 3 patients had regression of choroidal metastases with ocular treatment. Recommendations regarding systemic and local (ocular) management of patients with choroidal metastasis as the presenting manifestation of lung cancer are provided.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Carcinoma, Non-Small-Cell Lung; Choroid Neoplasms; Combined Modality Therapy; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Risk Assessment; Survival Rate; Treatment Outcome; Vision Disorders; Vision, Low
PubMed: 22732948
DOI: 10.1097/MD.0b013e3182574a0b -
Respirology (Carlton, Vic.) Nov 2011We conducted a systematic review of prospective, randomized, controlled trials (RCT) to examine whether histology had a treatment modifying effect (TME) on the efficacy... (Review)
Review
BACKGROUND AND OBJECTIVE
We conducted a systematic review of prospective, randomized, controlled trials (RCT) to examine whether histology had a treatment modifying effect (TME) on the efficacy outcomes of chemotherapeutic agents in patients with advanced (stage IIIB-IV) non-small cell lung cancer (NSCLC).
METHODS
Potentially pertinent publications were reviewed in full to determine if there was any TME by histology for overall survival (OS), progression-free survival (PFS) or treatment response rate (TRR).
RESULTS
Data from three pemetrexed RCT, comparing (i) pemetrexed versus docetaxel, (ii) pemetrexed and cisplatin versus gemcitabine and cisplatin, and (iii) pemetrexed versus placebo, showed a statistically significant TME by histology for OS and PFS. One trial comparing pemetrexed and carboplatin versus gemcitabine and carboplatin found no significant associations between histology and OS. The results of this systematic review indicate that pemetrexed appears to have the most consistent treatment-by-histology interaction effect on the efficacy outcomes of chemotherapeutic agents in patients with advanced or metastatic NSCLC. Patients with non-squamous histology gain the greatest benefit from treatment with pemetrexed. Conversely, patients with squamous cell disease appeared to experience poorer OS when pemetrexed was compared with other active treatments, and similar OS when compared with placebo. Reproducible patterns of TME effect by histology with other chemotherapeutic agents are less clear.
CONCLUSIONS
We consider that the historical approach to treating all NSCLC patients with the same chemotherapy regimen is now no longer acceptable.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials, Phase III as Topic; Deoxycytidine; Docetaxel; Evidence-Based Medicine; Female; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Pemetrexed; Randomized Controlled Trials as Topic; Reproducibility of Results; Taxoids; Gemcitabine
PubMed: 21801275
DOI: 10.1111/j.1440-1843.2011.02025.x -
The Cochrane Database of Systematic... Jan 2007Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy whose incidence is expected to increase in the United Kingdom, Western Europe, and Australia over... (Review)
Review
BACKGROUND
Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy whose incidence is expected to increase in the United Kingdom, Western Europe, and Australia over the next 20 years as a result of occupational exposure to asbestos fibres. Surgery is feasible in only a small proportion of cases, and radiotherapy and cytotoxic chemotherapy are used in palliation. Pemetrexed is the first and only chemotherapy agent that has been granted a marketing approval for use in combination with cisplatin for the treatment of chemo-naïve patients with unresectable MPM.
OBJECTIVES
To examine evidence on the clinical effectiveness of pemetrexed disodium used in combination with cisplatin for the treatment of unresectable malignant pleural mesothelioma in chemotherapy naïve patients compared with other cytotoxic agents used alone or in combination, or supportive care.
SEARCH STRATEGY
CENTRAL (Issue 2, 2005), EMBASE (1980-2005), MEDLINE (1980-2005), HTA database (1990-2005), Web of Knowledge (1990-2005) and handsearching (including reference lists of retrieved articles and the pharmaceutical company submission to to NICE), up to October 2005.
SELECTION CRITERIA
Randomised Controlled Trials (RCTs) where the use of pemetrexed disodium in combination with cisplatin is compared with other cytotoxic agents, or supportive care for the treatment of malignant pleural mesothelioma (or non-RCTs, in the absence of RCT data ).
DATA COLLECTION AND ANALYSIS
Outcomes included overall survival, tumour response, progression-free survival, toxicity and quality of life. Data extraction and quality assessment of included trials was completed independently. Trial data and quality assessment were tabulated and presented narratively.
MAIN RESULTS
One RCT involving 448 patients and comparing pemetrexed plus cisplatin versus cisplatin alone for the treatment of unresectable malignant mesothelioma was included in the review. In the intention-to-treat study population, the median survival was statistically significantly longer in the combination arm of pemetrexed plus cisplatin when compared with the cisplatin alone arm. (12.1 and 9.3 months, respectively, p=0.002). The incidence of grade 3/4 toxicities was higher in the combination arm compared with the cisplatin alone arm.
AUTHORS' CONCLUSIONS
Pemetrexed disodium in combination with cisplatin and with folic acid and vitamin B(12 )supplementation may improve survival when used in combination with cisplatin in good performance status patients. Further studies including patients with poor performance status are needed in order to generalise the treatment findings. Further studies are also needed into the optimum chemotherapy, and a clear definition of what constitutes best supportive care.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Glutamates; Guanine; Humans; Mesothelioma; Pemetrexed; Pleural Neoplasms
PubMed: 17253564
DOI: 10.1002/14651858.CD005574.pub2 -
Chinese Medical Journal Nov 2023The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The brain is a common metastatic site in patients with non-small cell lung cancer (NSCLC), resulting in a relatively poor prognosis. Systemic therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is recommended as the first-line treatment for EGFR -mutated, advanced NSCLC patients. However, intracranial activity varies in different drugs. Thus, brain metastasis (BM) should be considered when choosing the treatment regimens. We conducted this network meta-analysis to explore the optimal first-line therapeutic schedule for advanced EGFR -mutated NSCLC patients with different BM statuses.
METHODS
Randomized controlled trials focusing on EGFR-TKIs (alone or in combination) in advanced and EGFR -mutant NSCLC patients, who have not received systematic treatment, were systematically searched up to December 2021. We extracted and analyzed progression-free survival (PFS) and overall survival (OS). A network meta-analysis was performed with the Bayesian statistical model to determine the survival outcomes of all included therapy regimens using the R software. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare intervention measures, and overall rankings of therapies were estimated under the Bayesian framework.
RESULTS
This analysis included 17 RCTs with 5077 patients and 12 therapies, including osimertinib + bevacizumab, aumolertinib, osimertinib, afatinib, dacomitinib, standards of care (SoC, including gefitinib, erlotinib, or icotinib), SoC + apatinib, SoC + bevacizumab, SoC + ramucirumab, SoC + pemetrexed based chemotherapy (PbCT), PbCT, and pemetrexed free chemotherapy (PfCT). For patients with BM, SoC + PbCT improved PFS compared with SoC (HR = 0.40, 95% CI: 0.17-0.95), and osimertinib + bevacizumab was most likely to rank first in PFS, with a cumulative probability of 34.5%, followed by aumolertinib, with a cumulative probability of 28.3%. For patients without BM, osimertinib + bevacizumab, osimertinib, aumolertinib, SoC + PbCT, dacomitinib, SoC + ramucirumab, SoC + bevacizumab, and afatinib showed superior efficacy compared with SoC (HR = 0.43, 95% CI: 0.20-0.90; HR = 0.46, 95% CI: 0.31-0.68; HR = 0.51, 95% CI: 0.34-0.77; HR = 0.50, 95% CI: 0.38-0.66; HR = 0.62, 95% CI: 0.43-0.89; HR = 0.64, 95% CI: 0.44-0.94; HR = 0.61, 95% CI: 0.48-0.76; HR = 0.71, 95% CI: 0.50-1.00), PbCT (HR = 0.29, 95% CI: 0.11-0.74; HR = 0.31, 95% CI: 0.15-0.62; HR = 0.34, 95% CI: 0.17-0.69; HR = 0.34, 95% CI: 0.18-0.64; HR = 0.42, 95% CI: 0.21-0.82; HR = 0.43, 95% CI: 0.22-0.87; HR = 0.41, 95% CI: 0.22-0.74; HR = 0.48, 95% CI: 0.31-0.75), and PfCT (HR = 0.14, 95% CI: 0.06-0.32; HR = 0.15, 95% CI: 0.09-0.26; HR = 0.17, 95% CI: 0.09-0.29; HR = 0.16, 95% CI: 0.10-0.26; HR = 0.20, 95% CI: 0.12-0.35; HR = 0.21, 95% CI: 0.12-0.39; HR = 0.20, 95% CI: 0.12-0.31; HR = 0.23, 95% CI: 0.16-0.34) in terms of PFS. And, SoC + apatinib showed relatively superior PFS when compared with PbCT (HR = 0.44, 95% CI: 0.22-0.92) and PfCT (HR = 0.21, 95% CI: 0.12-0.39), but similar PFS to SoC (HR = 0.65, 95% CI: 0.42-1.03). No statistical differences were observed for PFS in patients without BM between PbCT and SoC (HR = 1.49, 95% CI: 0.84-2.64), but both showed favorable PFS when compared with PfCT (PfCT vs. SoC, HR = 3.09, 95% CI: 2.06-4.55; PbCT vs. PfCT, HR = 0.14, 95% CI: 0.06-0.32). For patients without BM, osimertinib + bevacizumab was most likely to rank the first, with cumulative probabilities of 47.1%. For OS, SoC + PbCT was most likely to rank first in patients with and without BM, with cumulative probabilities of 46.8%, and 37.3%, respectively.
CONCLUSION
Osimertinib + bevacizumab is most likely to rank first in PFS in advanced EGFR -mutated NSCLC patients with or without BM, and SoC + PbCT is most likely to rank first in OS.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Afatinib; Lung Neoplasms; Bevacizumab; Bayes Theorem; Network Meta-Analysis; Protein Kinase Inhibitors; Pemetrexed; ErbB Receptors; Brain Neoplasms; Mutation
PubMed: 37160733
DOI: 10.1097/CM9.0000000000002468