Toxic epidermal necrolysis related to AP (pemetrexed plus cisplatin) and gefitinib combination therapy in a patient with metastatic non-small cell lung cancer.

Toxic epidermal necrolysis (TEN) is a rare acute life-threatening mucocutaneous disorder that is mostly drug-related (80%-95%). It is clinically characterized as a widespread sloughing of the skin and mucosa. AP regimen (pemetrexed plus cisplatin) has been the preferred first-line chemotherapy for metastatic non-squamous non-small cell lung cancer (NSCLC). Gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has already been recommended as a first-line treatment in EGFR-mutant metastatic NSCLC. We report rare presentation of TEN involving adverse effects of AP and gefitinib combination treatment in a 42-year-old woman diagnosed with metastatic NSCLC harboring an EGFR mutation. On the 21st day after administration of the first cycle of AP regimen and the 8th day after the initiation of gefitinib treatment, she developed an acne-like rash, oral ulcer, and conjunctivitis, which later became blisters and ultimately denuded. The characteristic clinical courses were decisive for the diagnosis of TEN. Treatment with systemic steroids and immunoglobulin as well as supportive treatment led to an improvement of her general condition and a remarkable recovery.

Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial.

Pemetrexed-based chemotherapy presented about 40 % response rate (RR) on brain lesions of non-small cell lung cancer (NSCLC). But whole brain radiotherapy (WBRT) is still the standard treatment when surgery or radio-surgery is not feasible. This trial evaluated the efficacy and safety and efficacy of pemetrexed-cisplatin plus concurrent WBRT in this population. Forty-two patients were enrolled this study. Patients with newly diagnosed NSCLC with brain metastasis (BM) and performance status (PS) 0-2 were eligible for WBRT. Patients received up to six cycles of cisplatin and pemetrexed (75 and 500 mg/m(2), respectively) every 3 weeks. On day 1-12 during the first cycle of chemotherapy, patients received WBRT 30 Gy/10 fx/12 days. Primary end point was objective RR and progression free survival (PFS) on BM. Secondary end points included extracerebral and overall RR, survival and safety profile. Forty-one were evaluable for response. The histology was all adenocarcinoma. The objective cerebral RR (complete and partial response) in the intent-to-treat population was 68.3 % (28 of 41 patients). Extracerebral and overall RR was 34.1 and 36.6 %, respectively. Progression free survival of BM was 10.6 months, and median overall survival was 12.6 months. The combined treatment with pemetrexed-cisplatin and concurrent WBRT are effective in patients with NSCLC with newly diagnosed BM. This modality of treatment appears to be particularly favorable in RR and progression free survival of BM. Further clinical studies are warranted.

Treatment Patterns and Survival Outcomes of Non-Small Cell Lung Cancer Patients Initially Diagnosed With Brain Metastases in Real-World Clinical Practice.

BACKGROUND: This study aimed to comprehensively analyze the characteristics, treatment patterns, and survival outcomes of non-small-cell lung cancer (NSCLC) patients initially diagnosed with brain metastases (BMs) in real-world practice. METHODS: We enrolled NSCLC patients initially diagnosed with BMs between Jan 2004 and Jan 2018 in our institution. Patient demographics, treatment modalities, and survival outcomes were then analyzed. Brain localized treatment (BLT) included early brain radiotherapy (EBR), deferred brain radiotherapy (DBR), and surgery. RESULTS: A total of 954 patients were identified. Concerning initial treatment, 525 patients (55.0%) received systemic medication (SM)+BLT, 400 patients (41.9%) received SM only, and 29 patients received BLT only (3.0%). SM+BLT cohort was associated with longer median overall survival (mOS) than the SM only and the BLT only cohorts both in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative/unknown patients (15.3 months, 95% confidence interval [CI], 14.2-16.4; 11.1 months, 9.0-13.2; 7.0 months, 5.4-8.6; p<0.001) and in EGFR/ALK-positive patients (33.7 months, 28.5-38.9; 22.1 months, 17.8-26.4; 4.0 months, 3.6-4.4; p < 0.001). As for timing of radiotherapy, SM+EBR (14.1 months, 12.7-15.5) was associated with inferior mOS than SM+DBR (19.4 months, 14.2-24.6) in EGFR/ALK-negative/unknown patients. No significant difference was found in EGFR/ALK-positive patients (28.3 months, 19.1-37.5; 33.3 months, 28.1-38.5). Patients in the EGFR/ALK-negative/unknown cohort treated with first-line pemetrexed with platinum (PP) (15.8 months, 14.0-17.6, p<0.001) had longer mOS than those received non-PP regimens (13.1 months, 11.6-14.6). However, no difference was observed among EGFR/ALK-positive patients who were treated with tyrosine kinase inhibitors (TKIs) (29.5 months, 21.1-37.9; p = 0.140), PP (27.2 months, 21.6-32.8) and non-PP regimens (25.0 months, 16.0-34.0). CONCLUSIONS: Our study confirmed that the use of SM+BLT is associated with superior mOS than those treated with SM only and BLT only. SM+DBR might be a better radiotherapeutic strategy for this patient population. EGFR/ALK-negative/unknown patients showed a survival benefit with PP treatment.

Nomogram Model of LNR Predicts Survival in Premenopausal Patients with Node-positive Luminal Breast Cancer.

AIM: The aim of this study was to assess the prognostic value of lymph node ratio (LNR) in premenopausal patients with luminal breast carcinoma. MATERIALS AND METHODS: A total of 885 female patients who presented with axillary lymph node-positive luminal breast cancer between 2000 and 2009 were investigated. Using X-tile, we classified patients into low-, intermediate- and high-risk groups based on LNR. The Kaplan-Meier method was used to determine cumulative survival curves. Cox proportional hazards analyses were used to identify the factors that contributed to disease-free (DFS) and overall (OS) survival. RESULTS: The median age of patients was 42 years (range=21-58 years). A training set of 295 patients and a validation set of 590 patients were used to determine the optimal LNR cut-off points (0.20 and 0.63). DFS was 87.7%, 77.4% and 53.9% (p<0.001) and OS was 91.5%, 76.7% and 50.9% (p<0.0001) for the low- (≤0.20), intermediate- (0.21-0.63) and high-risk (>0.63) groups, respectively. The 10-year DFS and OS rates were significantly longer in the low-risk group than in the high-risk group. Nomogram analysis demonstrated that LNR contributed more compared to nodal stage in predicting both DFS and OS. CONCLUSION: We conclude that LNR strongly predicts prognosis in premenopausal patients with lymph node-positive luminal breast cancer.

Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center.

BACKGROUND: The current published prognosis models for brain metastases (BMs) from cancer have not addressed the issue of either newly diagnosed non-small-cell lung cancer (NSCLC) with BMs or the lung cancer genotype. We sought to build an adjusted prognosis analysis (APA) model, a new prognosis model specifically for NSCLC patients with BMs at the initial diagnosis using adjusted prognosis analysis (APA). PATIENTS AND METHODS: The model was derived using data from 1158 consecutive patients, with 837 in the derivation cohort and 321 in the validation cohort. The patients had initially received a diagnosis of BMs from NSCLC at Sun Yat-Sen University Cancer Center from 1994 to 2015. The prognostic factors analyzed included patient characteristics, disease characteristics, and treatments. The APA model was built according to the numerical score derived from the hazard ratio of each independent prognostic variable. The predictive accuracy of the APA model was determined using a concordance index and was compared with current prognosis models. The results were validated using bootstrap resampling and a validation cohort. RESULTS: We established 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively. Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < .001). The results were further confirmed in the validation cohort. CONCLUSION: Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

Benefit from thoracic radiotherapy in patients with extensive-disease small-cell lung cancer with elevated lactate dehydrogenase.

BACKGROUND: High lactate dehydrogenase (LDH) is associated with a large tumor burden in extensive-disease small-cell lung cancer (ED-SCLC). This study evaluated the benefit of additional thoracic radiotherapy (TRT) in patients with ED-SCLC with elevated LDH. METHODS: We analyzed 94 patients with ED-SCLC and evaluated LDH at Sun Yat-sen University Cancer Center during the period between January 2000 and March 2010. Patients were divided into two groups according to whether TRT was received. Survival was evaluated by the Kaplan-Meier method and Cox's regression analysis. RESULTS: The median age of the 94 patients with ED-SCLC was 58.5 years. The main metastatic sites included the liver, bone, brain, and adrenal glands. The response rate in the TRT group was 46.9%. There were 32 patients (34.04%) receiving TRT and 5.3% receiving prophylactic cranial irradiation. The median survival time reached 10 months (95% confidence interval: 8.22, 11.78 months), and the 1-, 2-, and 5-year survival rates were 43.6%, 11.7%, and 2.1%, respectively. There was a significant difference in the median progression-free survival (PFS) and overall survival (OS) between the TRT group and the no TRT group (PFS: 9.0 months vs 6.0 months, P=0.018; OS: 13.0 months vs 9.0 months, P=0.006). CONCLUSION: The use of TRT improves the survival of patients with ED-SCLC. Future studies should use the LDH level for categorizing patients for treatment.

Clinicopathologic characteristics and prognostic factors for HER2-positive patients with metastatic breast cancer in southern China.

INTRODUCTION: The aim of the study was to analyze clinicopathologic characteristics and survival and to identify prognostic factors for Chinese patients with HER2-positive metastatic breast cancer. MATERIAL AND METHODS: A total of 243 patients with HER2-positive metastatic breast cancer, treated during the period 2002 to 2009, were followed up from initial disease diagnosis to death or date of last follow-up (December 2011). Cumulative survival curves were created using Kaplan-Meier analysis with the log-rank test. Prognostic factors were analyzed by univariate and multivariate Cox proportional hazards regression analysis. RESULTS: During follow-up, 205 patients died, with a median OS of 27 months (95% CI: 23.5, 30.5 months), and the 1-, 3-, and 5-year survival rates were 84.4%, 38.6%, and 18.1%, respectively. The median OS of HR+ patients was significantly higher than that of HR- patients (p < 0.001). Surgery (hazard ratio = 0.60, p = 0.002), endocrine therapy (hazard ratio = 0.53, p < 0.01), and anti-HER2 therapy (hazard ratio = 0.63, p = 0.003) were favorable independent prognostic factors for patients with HER2-positive metastatic breast cancer. CONCLUSIONS: These results indicated that surgical intervention, endocrine therapy, and anti-HER2 therapy were good for these HER2 positive patients with metastatic breast cancer, but ECOG performance status < 1 and metastasis to brain were unfavorable independent prognostic factors. HR status was not an independent prognostic factor.

Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy.

INTRODUCTION: To explore the ability of gefitinib to penetrate blood brain barrier (BBB) during whole brain radiation therapy (WBRT). PATIENTS AND METHODS: Enrolled in this study were eligible patients who were diagnosed with BM from NSCLC. Gefitinib was given at 250 mg/day for 30 days, then concurrently with WBRT (40 Gy/20 F/4 w), followed by maintenance. Serial CSF and blood samples were collected on 30 day after gefitinib administration, and at the time of 10, 20, 30 and 40 Gy following WBRT. CSF and plasma samples of 13 patients without BM who were treated with gefitinib were collected as control. CSF and plasma gefitinib levels were measured by LC-MS/MS. RESULTS: Fifteen BM patients completed gefitinib plus WBRT. The CSF-to-plasma ratio of gefitinib in patients with BM was higher than that in patients without BM (1.34% vs. 0.36%, P < 0.001). The CSF-to-plasma ratio of gefitinib increased with the increased dose of WBRT and reached the peak (1.87 ± 0.72%) at 30 Gy, which was significantly higher than that 1.34 ± 0.49% at 0 Gy (P = 0.01). The median time to progression of brain lesions and the median overall survival were 7.07 and 15.4 months, respectively. CONCLUSION: The BBB permeability of gefitinib increased in accordance with escalated dose of WBRT.

High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer.

BACKGROUND: To investigate the role of PD-L1 expression in tumor recurrence and metastasis in Chinese patients with breast cancer. METHODS: Suitable tissue samples were available from 870 patients with breast cancer. Paraffin-embedded tumor sections were stained with PD-L1 antibody. The correlations between PD-L1 expression and clinical characteristics, ER/PR/HER2 status and survival parameters were analyzed. Kaplan-Meier and univariate Cox proportional hazards model analyses were used to compare the survival of patients with high PD-L1 expression and patients with no PD-L1 expression. RESULTS: The median follow-up time was 98 months(range, 17-265 months).The positive rate of PD-L1 expression in breast cancer was 21.7% (189/870). PD-L1 high expression was inversely associated with larger tumor size, higher tumor grade, more positive lymph node number, as well as negative ER and PR status. PD-L1 expression was particularly higher in TNBC compared with non-TNBC, although no statistical significance was observed. Nomogram logistic regression results based on clinical and pathological features showed that the following factors were more likely associated with high PD-L1 expression: patient age younger than 35 years, larger tumor size, lymphovascular invasion and advanced stage. Our data indicated that patients with high PD-L1 expression had poor DFS, DMFS and overall survival compared with those with no PD-L1 expression. Univariate Cox proportional hazards model analysis showed that PD-L1 was an independent prognostic factor for tumor prognosis. CONCLUSIONS: PD-L1 expression is an important indicator of unfavorable prognosis in breast cancer patients.

Clinical analysis of 50 Eastern Asian patients with primary pulmonary large-cell neuroendocrine carcinoma.

BACKGROUND: To understand the clinicopathological features of patients with primary pulmonary large-cell neuroendocrine carcinoma (LCNEC), including the frequency of epidermal growth factor receptor (EGFR) mutation, and to explore prognostic factors. METHODS: We investigated a cohort of 50 individuals from our center database who were diagnosed with operable pulmonary LCNEC and treated in Sun Yat-sen University Cancer Center. Serum albumin (ALB) and neuron-specific enolase (NSE) were also collected. Survival curves were obtained with the Kaplan-Meier method, and the differences between groups in survival were tested by the log-rank test. RESULTS: The median age was 59 years (range, 40-80 years). Fourteen patients underwent mutational analysis of EGFR; of these, 12 had wild-type EGFR and the remaining two had EGFR mutations in exons. The median disease-free survival (DFS) of pulmonary LCNEC was 49.3 months and that of overall survival (OS) was not reached. DFS and OS were shorter for patients with decreased serum ALB than for patients with normal serum ALB (P=0.003 and P=0.004, respectively). Meanwhile, a high level of NSE was also significantly associated with short DFS and OS (P=0.005 and P=0.000, respectively). Multivariate analysis showed that decrease in serum ALB was an independent prognostic factor for OS (P=0.046). CONCLUSION: The frequency of EGFR mutation in LCNEC patients is low. Serum ALB and NSE levels are valuable prognostic factors for LCNEC patients.

Chemotherapy with concurrent brain and thoracic radiotherapy in brain-only metastases of treatment naive small-cell lung cancer: a phase II study.

To study the treatment outcomes of brain-only metastases from small-cell lung cancer (SCLC) at initial diagnose treated by chemotherapy with concurrent brain and thoracic radiotherapy (RT). From Jan 2004 to Jan 2009, 36 treatment-naïve SCLC patients with brain-only metastases in Sun yat-sen University were enrolled. Treatment contained initial EP chemotherapy with concurrent whole-brain radiotherapy (WBRT). EP regimen consisted of etoposide 100 mg/m(2) IV d1-3, cisplatin 80 mg/m(2) IV d1, repeated every 3 weeks. WBRT with total dose of 30 Gy in 10 fractions was started within 1 week from the beginning of chemotherapy followed by thoracic RT including 2 Gy once daily to a total dose of 60 Gy. Treatment responses were evaluated after 3 cycles of chemotherapy. EP regimen was given totally 6 cycles for no tumor progression. Thirty-four patients were evaluable. All of the 20 CNS symptomatic patients experienced symptoms relief. Objective responses in the brain and primary thoracic lesions were observed in 26 (76.5%, 16CR + 10PR) and 29 (85.3%, 23CR + 6PR) patients, respectively. The median survival time (MST) was 19.2 months, and the 1-and 2-year overall survival rates (OS) were 70.6 and 29.4%, respectively, in all patients. Patients with CR response had the longest MST of 21.9 months and 1-and 2-year OS of 93.8 and 43.8%, respectively. Treatment toxicity profiles were acceptable. The treatment strategy of concurrent chemotherapy with brain and thoracic RT might achieve promising survival outcomes comparable to limited-stage SCLC in initially diagnosed SCLC with brain-only metastases.

Gefitinib alone or with concomitant whole brain radiotherapy for patients with brain metastasis from non-small-cell lung cancer: a retrospective study.

BACKGROUND: Gefitinib, a tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), is used both as a single drug and concurrently with whole brain radiotherapy (WBRT) the standard treatment for brain metastases (BM), and is reported to be effective in a few small studies of patients with BM from non-small-cell lung cancer (NSCLC). However, no study has compared the two treatment modalities. This retrospective analysis was conducted to compare the efficacy of gefitinib alone with gefitinib plus concomitant WBRT in treatment of BM from NSCLC. METHODS: We retrospectively reviewed 90 patients with BM from NSCLC who received gefitinib alone (250 mg/day, gefitinib group) or with concomitant WBRT (40 Gy/20 f/4 w, gefitinib-WBRT group) between September 2005 and September 2009 at Sun Yat-Sen University Cancer Center. Forty-five patients were in each group. RESULTS: The objective response rate of BM was significantly higher in gefitinib-WBRT group (64.4%) compared with gefitinib group (26.7%, P<0.001). The disease control rate of BM was 71.1% in gefitinib- WBRT group and 42.2% in gefitinib group (P=0.006). The median time to progression of BM was 10.6 months in gefitinib-WBRT group and 6.57 months in gefitinib group (P<0.001). The median overall survival (OS) of gefitinib-WBRT and gefitinib alone group was 23.40 months and 14.83 months, respectively (HR, 0.432, P=0.002). CONCLUSION: Gefitinib plus concomitant WBRT had higher response rate of BM and significant improvement in OS compared with gefitinib alone in treatment of BM from NSCLC.