Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with ...EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC.
We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.
Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months 95% CI 24·9–32·5) than with vinorelbine plus cisplatin (18·0 months 13·6–22·3; hazard ratio HR 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two 2% patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 34% patients vs none with gefitinib), leucopenia (14 16% vs none), and vomiting (eight 9% vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.
Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.
Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.
ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus ...vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor (
) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.
From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and
-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat ITT population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.
Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio HR, 0.92; 95% CI, 0.62 to 1.36;
= .674); respective 5-year OS rates were 53.2% and 51.2% (
= .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP (
= .316) and 5y DFS rates were 22. 6% and 23.2% (
= .928), respectively.
Adjuvant therapy with gefitinib in patients with early-stage NSCLC and
mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
The ADJUVANT study reported the comparative superiority of adjuvant gefitinib over chemotherapy in disease-free survival of resected EGFR-mutant stage II-IIIA non-small cell lung cancer (NSCLC). ...However, not all patients experienced favorable clinical outcomes with tyrosine kinase inhibitors (TKI), raising the necessity for further biomarker assessment. In this work, by comprehensive genomic profiling of 171 tumor tissues from the ADJUVANT trial, five predictive biomarkers are identified (TP53 exon4/5 mutations, RB1 alterations, and copy number gains of NKX2-1, CDK4, and MYC). Then we integrate them into the Multiple-gene INdex to Evaluate the Relative benefit of Various Adjuvant therapies (MINERVA) score, which categorizes patients into three subgroups with relative disease-free survival and overall survival benefits from either adjuvant gefitinib or chemotherapy (Highly TKI-Preferable, TKI-Preferable, and Chemotherapy-Preferable groups). This study demonstrates that predictive genomic signatures could potentially stratify resected EGFR-mutant NSCLC patients and provide precise guidance towards future personalized adjuvant therapy.
Background
Controversy still exists in which subtype of non-small-cell lung cancer squamous cell carcinoma (SCC) or adenocarcinoma is more likely to have lymph node (LN) metastasis. The aim of this ...study is to compare the pattern of LN metastasis in two cohorts of matched patients surgically treated for SCC or adenocarcinoma.
Methods
A retrospective analysis of patients undergoing lobectomy or segmentectomy with systematic lymphadenectomy without preoperative treatment for lung SCC or adenocarcinoma was conducted in this study. Data for analysis consisted of age, gender, tumor size, lobe-specific tumor location, tumor location (peripheral or central), and pathologic findings. We conducted the propensity score-matched (PSM) analysis to eliminate potential bias effects of possible confounding factors.
Results
From January 2015 to December 2016 in our department, we finally included a total of 387 patients (including 63 patients with SCC and 324 patients with adenocarcinoma) for analysis. For the unmatched cohort, there was no sufficient evidence of significantly different number of positive LNs (
P
= 0.90) and rate of LN metastasis (
P
= 0.23) between SCC patients and adenocarcinoma patients. However, potential confounding factors, for example gender, tumor size, tumor location, tumor differentiation, and total number of dissected LNs, were significantly different between patients with SCC and those with adenocarcinoma. In the analysis of matched cohort after PSM analysis, those above confounding factors were comparable between the two groups. However, patients with adenocarcinoma had significantly more mean positive LNs (2.2 and 0.7;
P
= 0.008) and a higher rate of LN metastasis (53% and 29%;
P
= 0.016) than those with SCC.
Conclusions
Lung adenocarcinoma had a higher risk of LN metastasis than SCC, suggesting that different therapeutic modalities may be indicated for the two different subtypes of lung cancer.
Adjuvant gefitinib therapy prolonged disease-free survival in patients with resected early-stage EGFR-mutation positive NSCLC in the ADJUVANT study (CTONG 1104). However, treatment failure patterns ...after gefitinib therapy are less well characterized.
Overall, 222 stage N1–N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure; sites and data of first treatment failure were recorded. A post hoc analysis of treatment failure patterns which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat patients was conducted.
There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the central nervous system in the gefitinib group (29 of 106 27.4%), extracranial metastases were most frequent in the VP group (32 of 87 36.8%). Temporal distribution analysis showed lower tumor recurrence with gefitinib than with VP 0 to 21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9 to 15 months with VP and 24 to 30 months with gefitinib. The highest peak for central nervous system metastases post-surgery occurred after 12 to 18 months with VP and 24 to 36 months with gefitinib.
Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant tyrosine kinas inhibitors may be considered as a treatment option in resected stage N1–N2 EGFR-mutant NSCLC but longer duration should be explored.
Abstract
Hydroalkylation, the direct addition of a C(sp
3
)–H bond across an olefin, is a desirable strategy to produce valuable, complex structural motifs in functional materials, pharmaceuticals, ...and natural products. Herein, we report a reliable method for accessing α-branched amines via nickel-catalyzed hydroalkylation reactions. Specifically, by using bis(cyclooctadiene)nickel (Ni(cod)
2
) together with a phosphine ligand, we achieved a formal C(sp
3
)–H bond insertion reaction between olefins and N-sulfonyl amines without the need for an external hydride source. The amine not only provides the alkyl motif but also delivers hydride to the olefin by means of a nickel-engaged β–hydride elimination/reductive elimination process. This method provides a platform for constructing chiral α-branched amines by using a P-chiral ligand, demonstrating its potential utility in organic synthesis. Notably, a sulfonamidyl boronate complex formed in situ under basic conditions promotes ring-opening of the azanickellacycle reaction intermediate, leading to a significant improvement of the catalytic efficiency.
Background
Approximately 8.3–15.9% of patients with clinical stage I non‐small cell lung cancer are subsequently shown to have lymph node metastasis. However, the clinical characteristics of patients ...with lymph node metastasis in China are not fully understood.
Methods
This is a multicenter retrospective analysis of pathological T1 non‐small cell lung cancer patients who underwent surgical resection from 2 January 2014 to 27 December 2017. Clinical and pathological information was collected with the assistance of the Large‐scale Data Analysis Center of Cancer Precision Medicine‐LinkDoc database. The clinical and pathological factors associated with lymph node metastasis were analyzed by univariate and multivariate logistic regression.
Results
A total of 10 885 participants (51.6% women; 15.3% squamous cell carcinoma) were included in the analysis. The median age was 60.0 years (range 12.9–86.6 years). A total of 1159 patients (10.6%) had metastases in mediastinal nodes (N2), and 640 patients (5.9%) had metastasis in pulmonary lymph nodes (N1). Most patients had T1b lung cancer (4766, 43.8%). Of the patients, 3260 (29.9%) were current or former smokers. The univariate and multivariate analyses showed that younger age, squamous cell carcinoma, poor differentiation, larger tumor size, carcinoembryonic antigen level ≥5 ng/mL, and vascular invasion (+) were significantly associated with higher percentages of lymph node metastases (P < 0.001 for all).
Conclusion
This real‐world study showed the significant association of lymph node metastasis with age, tumor size, histology and differentiation, carcinoembryonic antigen levels, and status of vascular invasion. Female patients with T1a adenocarcinoma in the right upper lobe barely had lymph node metastasis.
Background
Due to their rarity, the clinicopathological characteristics and prognostic factors of spinal cord gliomas are still unclear. Here, we aimed to clarify these issues in a cohort of 108 ...spinal cord astrocytomas.
Methods
We characterized the clinicopathological characteristics, including 2016 World Health Organization (WHO) grade, age, sex, location, segment length, resection, pre‐ and postsurgery, Modified McCormick Scale (MMS), radio‐ and chemotherapy, and Ki‐67 and H3 K27M mutations, in 108 spinal cord astrocytomas through heatmaps. The Cox regression analysis and Kaplan‐Meier curves were used to study the prognostic value of these clinicopathological features.
Results
There are a total 38 H3 K27M‐mutant tumors, including 31 cases with histological grade II/III tumors. The age of low‐grade astrocytoma patients (WHO grade I/II, n = 54) was significantly younger (27.0 vs 35.5 years, P = .001) than those with high‐grade tumors (WHO grade III/IV, n = 54). All patients underwent surgical resection with neurophysiological monitoring, and the surgery did not result in significant changes in MMS. The presurgery MMS was associated with overall survival in the high‐grade subgroup (P = .008) but not in the low‐grade subgroup (P = .312). While, the high content of resection improved the survival of only patients with low‐grade astrocytomas (P = .016) but not those with high‐grade astrocytomas (P = .475). Both the low‐grade and high‐grade astrocytomas had no obvious benefit from neither adjuvant chemotherapy nor radiotherapy (all P > .05).
Conclusions
We characterized the clinicopathological characteristics and their prognostic values in 108 spinal cord astrocytomas, which could help with evidence‐based management of spinal cord astrocytomas.
We characterized the clinicopathological characteristics and their prognostic values in 108 spinal cord astrocytomas, which could help with evidence‐based management of spinal cord astrocytomas.
Abstract
BACKGROUND
“Diffuse midline glioma, H3 K27M-mutant” (DMG) mainly arises within the pontine, thalamic, and spinal cord regions. Because of the rarity of spinal cord gliomas, the general ...knowledge surrounding DMGs is mainly based on pontine and thalamic gliomas, whereas tumor location tends to influence the clinicopathological features and prognosis.
OBJECTIVE
To determine the clinicopathological characteristics and molecular profiles of DMGs located in the spinal cord.
METHODS
The clinical and molecular pathologic features and prognosis were comprehensively analyzed in a series of 44 patients with spinal cord DMGs.
RESULTS
The median age was 36 yr, and 88.7% of patients (39/44) were adults (≥18 yr). Histopathologically, malignant grades included grade II (16 cases), grade III (20 cases), and grade IV (8 cases). Compared with patients with histological grade IV, patients with lower histological grade (grade II/III) were older (37 vs 24 yr, P = .020) and were associated with longer overall survival (24.1 vs 8.6 mo, P = .007). All 30 tested tumors were isocitrate dehydrogenase (IDH) wild type, and 96% of cases (22/23) presented with unmethylated O6-methylguanine-DNA methyltransferase. Univariate and multivariate analyses showed that histological grade and presurgery McCormick Scale scores were independent prognostic factors for overall survival, whereas extensive surgical resection and chemoradiotherapy were not significantly associated with improved survival. The most frequent anatomic locations were the cervical enlargement (C4-T1, n = 16) and conus medullaris (T12-L1, n = 13), which exhibited distinctive clinical characteristics and molecular features.
CONCLUSION
The findings provide guidelines for the evidence-based practice of the specialized management of spinal cord DMGs.
To evaluate prognostic significance of albumin-to-alkaline phosphatase ratio (AAPR) for patients undergoing video-assisted thoracoscopic surgery (VATS) lobectomy for non-small-cell lung cancer ...(NSCLC) by a propensity score-matching (PSM) analysis.
This PSM study was conducted on the prospectively-maintained database in our institution between December 2013 and March 2015. Overall survival analyses and further subgroup analyses were both performed to distinguish the differences in postoperative survival between patients stratified by an optimal cutoff of AAPR. Multivariable Cox proportional hazards regression models were established to determine the independent prognostic factors.
There were 390 patients with operable NSCLCs included. An AAPR of 0.57 was identified as the optimal cutoff regarding to postoperative survival. Both overall survival (OS) and disease-free survival (DFS) in patients with AAPR≤0.57 were significantly shortened compared to those in patient with AAPR>0.57 (Log-rank P < 0.001). Patients with AAPR≤0.57 had significantly lower rates of OS and DFS than those of patients with AAPR>0.57 (P < 0.001). These differences still remained significant after subgroup analyses and PSM analyses. Multivariate analyses on the entire cohort and the PSM cohort commonly indicated that low preoperative AAPR could be an independent prognostic factor for unfavorable OS and DFS of resected NSCLCs.
AAPR can serve as a novel risk stratification tool to refine prognostic prediction for surgical NSCLC. It may help surgeons to screen high-surgical-risk patients and further formulate individualized treatment schemes.
•Propensity-score matching analysis to study prognostic roles of basic albumin-to-alkaline phosphatase ratio in operable NSCLC.•Lower albumin-to-alkaline phosphatase ratio is significantly associated with worse prognosis of operable NSCLC.•Albumin-to-alkaline phosphatase ratio serves as an excellent prognostic indicator in minimally invasive lung cancer surgery.
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