The Unique Spatial-Temporal Treatment Failure Patterns of Adjuvant Gefitinib Therapy: A Post Hoc Analysis of the ADJUVANT Trial (CTONG 1104).

INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A surveillance method-oriented detection of post-operative spatial-temporal recurrence for non-small cell lung cancer.

BACKGROUND: This study evaluated spatial-temporal recurrence patterns after curative resection for non-small cell lung cancer (NSCLC) to clarify and recommend appropriate post-operative surveillance. METHODS: A total of 2,486 consecutive patients between January 2005 and December 2012 with NSCLC (stage I-IIIA) who underwent definitive surgical resection were retrospectively analyzed. We used a hazard rate curve to evaluate event dynamics. Disease-free survival (DFS) was evaluated by the Kaplan-Meier method. Univariate and multivariate analyses with Cox proportional hazards regression identified risk factors that predicted DFS. RESULTS: The median follow-up was 50.1 months. Recurrences were diagnosed in 852 (34.3%) patients. Four hundred eighty-nine events first occurred in the chest, 177 in the brain, 117 in the bone, and 71 in the abdomen. Of all recurrences, 78.5% occurred in the first 3 years. Univariate and multivariate analyses identified the age at diagnosis (P<0.001), histology (P=0.023), tumor size (P<0.001), pathologic N stage (P<0.001), and grade (P=0.043) as independent risk factors for intra-thoracic recurrences. Histology (P<0.001), tumor size (P<0.001), surgical method (P=0.021), pathologic N stage (P<0.001), and grade (P=0.005) were independent to predict extra-thoracic recurrences. The hazard rate curve displayed an initial surge of time to any treatment failure during 12 months after surgery. Based on sub-group analysis, both intra- and extra-recurrences increased with stage and brain recurrences in stage IIIA occurred earlier than stage II. Hazard rate curve of brain recurrences in squamous cell carcinoma showed a moderate peak during 9-15 months. Hazard rate curves of brain and bone recurrences in adenocarcinoma displayed clear peaks at 9-27 and 15-30 months, respectively. CONCLUSIONS: Intra- and extra-thoracic recurrences correlate with different clinicopathological factors. Brain MRI and bone ECT were recommended for selected patients in particular time to early detect extra-thoracic recurrences.

Primary pulmonary mucoepidermoid carcinoma: an analysis of 21 cases.

BACKGROUND: The optimal treatment for pulmonary mucoepidermoid carcinoma (MEC), a rare type of tumor, has not been established yet. This study analyzed the survival of pulmonary MEC patients and attempted to find clues for optimal treatment. METHODS: A total of 21 patients with pulmonary MEC from November 2004 to January 2011 were included in the investigation. Immunohistochemistry, epidermal growth factor receptor (EGFR) mutation, and survival were retrospectively studied. RESULTS: Among the 21 pulmonary MEC patients, 17 were diagnosed with low-grade malignancy and 4 with high-grade malignancy through pathological examination. The prognosis was found to be poor in the presence of lymph nodes. The expression rates of EGFR and HER2 were 28.6% and 0%, respectively, which correlated with neither grade nor prognosis. The mutation rate of EGFR was 0. Log-rank test results indicated that age, grade, lymph node metastasis, and tumor-node-metastasis stage were prognostic factors. CONCLUSION: Age, grade, lymph node metastasis and tumor-node-metastasis stage correlate with the survival of pulmonary MEC patients. TRIAL REGISTRATION: This study was approved and registered by the Ethics Committee of Zhongshan Hospital. Written informed consent was obtained from all participants prior to treatment.

Prognostic role of Twist, Slug, and Foxc2 expression in stage I non-small-cell lung cancer after curative resection.

UNLABELLED: By using immunohistochemistry in tissue microarrays of 137 cases, we evaluated the prognostic power of a 3-marker epithelial-mesenchymal transition­related model in patients with stage I non-small-cell lung cancer who underwent radical surgical resection. The Twist/Slug/Foxc2 coexpression model accurately prognosticated these patients and may be helpful in refining current treatment strategy for stage I non-small-cell lung cancer. BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. Only about 60% of patients with stage I non-small-cell lung cancer (NSCLC) can be cured by surgery alone. Current clinical and molecular markers are inadequate prognosticators. We developed a 3-marker model that closely approximates survival probability of patients with stage I NSCLC. METHODS: Expression of Twist, Slug, and Foxc2 was assessed by immunohistochemistry in tissue microarrays that contained paired tumor and peritumoral lung tissue from 137 patients who underwent surgical resection for stage I NSCLC. The prognostic value of Twist, Slug, and Foxc2, and the cumulative effects of the 3 markers on survival were evaluated. RESULTS: Increased expression of Twist, Slug, and Foxc2 was observed in 38.0%, 18.2%, and 27.7% of primary tumors, respectively. Overexpression of Twist, Slug, and Foxc2 in stage I NSCLC was associated with a worse overall survival (P = .001, P = .002, P < .001, respectively) and correlated with a shorter recurrence-free survival (P < .001, P = .001, P < .001 respectively). The cumulative influence of these markers on outcome was analyzed; a combination of more than 2 positive markers was an independent predictor of recurrence-free and overall survival (P = .002 and P = .009, respectively). CONCLUSIONS: The Twist/Slug/Foxc2 model is useful in predicting survival of stage I NSCLC and may be helpful in refining current treatment strategy.