Yun Fan

Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-small-cell lung cancer: survival analysis in 210 patients

Background Chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors are controversial in the treatment of patients with brain metastases from non-small-cell lung cancer (NSCLC). Methods We retrospectively studied the effects of solely localized treatment or localized treatment in combination with chemotherapy and/or EGFR tyrosine kinase inhibitors on outcomes in 210 NSCLC patients with brain metastases. The effects of treatment modality, Karnofsky performance status, age, primary tumor histology, number of brain metastases, and other factors on survival time were analyzed, and the robustness of two prognostic indices, ie, recursive partitioning analysis and graded prognostic assessment, was evaluated. Results The median survival time in patients with systemic medication and localized treatments was higher than in those with localized treatments alone (11 versus 3 months, P=0.000). Within the systemic medication group, median survival time was significantly longer for EGFR tyrosine kinase inhibitors than for other types of chemotherapy (12 versus 9 months, P=0.002). In the EGFR tyrosine kinase inhibitor group, median survival time for patients with EGFR gene mutation was 20 months versus 8 months for those with the wild-type EGFR gene. The median survival time with pemetrexed was significantly higher than with other chemotherapies (13 versus 7 months, P=0.006). In multivariate analysis, the prognosis was significantly correlated with treatment modality (P=0.000), Karnofsky performance status (P=0.000), number of brain metastases (P=0.001), and histologic tumor type (P=0.007). In the graded prognostic assessment model, survival curves for the subgroups showed clear separations. Conclusion NSCLC patients with brain metastasis benefited from pemetrexed and/or tyrosine kinase inhibitors along with localized treatments, and the graded prognostic assessment index is a robust model for prognostic evaluation.

A phase II study of icotinib and whole-brain radiotherapy in Chinese patients with brain metastases from non-small cell lung cancer

AbstractPurposenIcotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. A phase II study was conducted to evaluate the efficacy and safety of icotinib in combination with whole-brain radiotherapy (WBRT) in Chinese NSCLC patients with brain metastases (BMs); the cerebrospinal fluid (CSF)/plasma concentrations of icotinib were also investigated.MethodsEligible patients had BMs from NSCLC, regardless of the EGFR status. Icotinib was administered at 125xa0mg orally 3 times/day until tumor progression or unacceptable toxicity, concurrently with WBRT (3.0xa0Gy per day, 5xa0days per week, to 30xa0Gy). CSF and plasma samples were collected simultaneously from 10 patients. Icotinib concentrations in the CSF and plasma were measured by high-performance liquid chromatography coupled with tandem mass spectrometry.ResultsTwenty patients were enrolled. The median follow-up time was 20.0xa0months. The overall response rate was 80.0xa0%. The median progression-free survival time was 7.0xa0months (95xa0% CI 1.2–13.2xa0months), and the median survival time (MST) was 14.6xa0months (95xa0% CI 12.5–16.7xa0months). Of the 18 patients with known EGFR status, the MST was 22.0xa0months for those with an EGFR mutation and was 7.5xa0months for those with wild-type EGFR (Pxa0=xa00.0001). The CSF concentration and penetration rate of icotinib were 11.6xa0±xa09.1xa0ng/mL and 1.4xa0±xa01.1xa0%, respectively. No patient experienced ≥grade 4 toxicity.ConclusionsIcotinib was well tolerated in combination with WBRT and showed efficacy in patients with BMs from NSCLC. This clinical benefit was related to the presence of activating EGFR mutations.

PD-L1 and c-MET expression and survival in patients with small cell lung cancer

Background Blocking the binding between the PD-1 and PD-L1 has been reported to produce antitumor responses. The MET/HGF axis appears to be another signaling pathway frequently altered in small cell lung cancer (SCLC). Our study was aimed to investigate the expression and prognostic roles of PD-L1 and c-MET in SCLC. Methods The expression levels of PD-L1 and c-MET were evaluated by immunohistochemical analysis in 83 SCLC specimens. Survival analysis was performed using the Kaplan-Meier method. Results Of the SCLC specimens, 51.8% and 25.3% exhibited positivity for PD-L1 and c-MET, respectively. Higher PD-L1 expression in tumor specimens was significantly correlated with a limited disease (LD) stage, normal levels of serum lactate dehydrogenase (LDH) and neuron-specific enolase (NSE). No association was found between the levels of c-MET and PD-L1 expression or between c-MET expression and other clinical characteristics. SCLC patients with PD-L1-positive tumors showed significantly longer overall survival (OS) than patients with PD-L1-negative tumors (17.0 vs 9.0, p=0.018). Conversely, those with positive c-MET expression exhibited a shorter OS trend (12.0 vs 15.0, p=0.186). However, sub-analysis of LD-stage patients revealed longer OS among the c-MET-negative group (25.0 vs 14.0; p=0.011). The OS of patients with positivity for both PD-L1 and c-MET showed no significant difference compared with other patients (p=0.17). According to multivariate analyses, neither PD-L1 nor c-MET immunoreactivity was a prognostic factor. Conclusion Expression of PD-L1 was correlated with LD stage and might serve as a prognostic for better OS in SCLC patients. In LD-stage patients, high c-MET expression might be predictive of a poor outcome.

Phase II trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer

AbstractAim:To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC).Methods:In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m2 as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m2 as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU.Results:A total of 28 patients was enrolled in the study. The median age was 54 years (range 27–75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729±0.637 μg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present.Conclusion:The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.

Dual-negative expression of Nrf2 and NQO1 predicts superior outcomes in patients with non-small cell lung cancer

Functional studies in non-small cell lung cancer (NSCLC) patients revealed that hyperactivation of the NF-E2-related factor 2 (Nrf2) pathway facilitates tumor growth. We examined the usefulness of Nrf2 and NQO1 as indicators of prognosis in NSCLC. Tumor and adjacent non-tumor tissue samples were collected from 215 NSCLC patients who had tumor resections between 2006 and 2011. Immunohistochemistry was performed to detect Nrf2 or NQO1 expression. The correlation between Nrf2 or NQO1 expression and survival outcomes was evaluated using the Kaplan-Meier method and Cox proportional hazards regression model. Levels of Nrf2 and NQO1 were elevated in tumor tissues. In particular, Nrf2 was elevated in nearly all tumor cells. NQO1 expression positively correlated with Nrf2 expression (P = 0.039). Nrf2 expression positively correlated with lymph node metastasis (P = 0.001) and negatively correlated with tumor differentiation (P = 0.032). As compared with either Nrf2 or NQO1 alone, dual-negative expression of Nrf2 and NQO1 was more predictive of superior overall survival (P = 0.020) and disease free survival (P = 0.037). Subgroup analyses showed that females, nonsmokers, and patients with advanced-stage NSCLC were suitable populations in which to evaluate prognosis based on Nrf2 and NQO1 co-expression. These results indicate that dual-negative expression of Nrf2 and NQO1 is predictive of a better prognosis in NSCLC patients.

Pharmacodynamic and pharmacokinetic study of pegylated liposomal doxorubicin combination (CCOP) chemotherapy in patients with peripheral T-cell lymphomas.

AbstractAim:To investigate the pharmacodynamic and pharmacokinetic parameters of pegylated liposomal doxorubicin (PLD) combined with cyclophosphamide, vincristine, and prednisolone in patients with peripheral T-cell lymphomas (PTCL).Methods:Seven chemonaive patients and four patients with relapsed peripheral T-cell lymphomas were treated with a CCOP regimen consisting of an intravenous administration of cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2), and PLD (30 mg/m2) on d 1, as well as an oral administration of prednisolone (60 mg/m2) on d 1–5. This regimen was repeated every 3 weeks for six cycles, and the clinical response and toxicity of the regimen were monitored. In addition, the plasma concentration of PLD at different time points was determined before and after treatment. The pharmacokinetics (PKs) software was used to estimate the pharmacokinetic parameters of PLD.Results:The 11 PTCL patients received 35 treatment cycles. Three of them achieved complete response (CR), two partial response (PR), four stable disease (SD), and two progressive disease (PD). The overall response rate (ORR) was 45.5%, and the CR rate was 27.3%. In the 7 chemonaive patients, three achieved CR, two PR, one SD, and one PD. The ORR was 71.4%, and CR rate was 42.9%. The median follow-up time was 15 months, but 6 out of 11 patients were dead at the time of data analysis. The 1-year overall survival rate was 45.5%, and the median progression-free survival (PFS) rate was 6.5 [95% confidence interval (95% CI) 3.17–19.02] with a survival rate of 11.5 months (95% CI 6.65–16.36). The main toxicity was myelosuppression. Oral mucositis and hand-foot syndrome seldom occurred. The PLD plasma concentration from nine patients ranged from 1.7036 to 9.2207 mg·L−1 after administration of the CCOP regimen (0–168 h). The pharmacokinetic parameters AUC0–∞, CL, t1/2, and Vd were 910.76 mg/L·h, 0.043 L·h−1·m−2, 68.40 h, and 3.56 L/m2, respectively.Conclusion:The CCOP regimen was effective and well tolerated in patients with peripheral T-cell lymphomas. The results of the pharmacokinetic parameters showed that PLD had long retention time in blood circulation.

Bevacizumab treatment for advanced non-small cell lung cancer: A case report.

The safety of Avastin in lung cancer (SAiL) study is a multi-center, open-source, stand-alone study. Patients with untreated, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) were administered up to six cycles of chemotherapy combined with bevacizumab-humanized monoclonal antibodies, followed by maintenance therapy with bevacizumab until further progression of the disease. From August, 2006 to July, 2008 there were a total of 2,172 patients enrolled in the study, with a median progression-free survival time of 7.8 months and an overall survival time of 14.6 months. The present study describes the case of a 54-year-old male with lung cancer and T3N0M1 subcutaneous metastasis, which was initially treated with bevacizumab-combined carboplatin/paclitaxel (C/P) therapy and then maintained solely with bevacizumab for five years. Following six cycles of C/P bevacizumab treatment, the therapeutic evaluation revealed a stable disease (SD). The patient was kept on bevacizumab maintenance therapy for 50 months without disease progression until a persistent 3+ proteinuria was diagnosed in a follow-up review, which led to bevacizumab withdrawal and concomitant tumor growth. The present study concluded that the long-term application of bevacizumab monoclonal antibodies (mABs) was safe in a late-stage non-small cell lung cancer patient. The major adverse reaction that was exhibited was proteinuria, which was associated with the cumulative dose of bevacizumab and was able to be reversed by withdrawal. Patients with a prolonged SD may benefit from bevacizumab maintenance therapy.

Uncommon mutation types of epidermal growth factor receptor and response to EGFR tyrosine kinase inhibitors in Chinese non-small cell lung cancer patients

PurposeEpidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.MethodsSeven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. We categorised EGFR uncommon mutations as: sensitizing rare mutations (group 1: G719X, L861Q, S768I); Ex20 ins (group 2), or complex mutations (G719Xu2009+u2009L861Q, G719Xu2009+u2009S768I, 19 delu2009+u2009T790M, 19 delu2009+u2009L858R, L858Ru2009+u2009S768I, and L858Ru2009+u2009T790M; group 3).ResultsOf 66 patients given EGFR-TKI treatment, rare sensitive mutations, Ex20 ins, and complex mutations were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) cases, respectively. TKI efficacy in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8xa0months. Additionally, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins cases (8.6 vs. 4.1 vs. 3.1xa0months; pu2009=u20090.041). Importantly, complex EGFR mutations were independent predictors of increased overall survival (Hazard Ratiosu2009=u20090.31; 95% confidence intervals: 0.11–0.90; pu2009=u20090.031). Among them, patients harboring Del-19 combined with L858R mutations showed a tendency to have higher response rate (RR) and improved PFS than those with other complex mutation patterns (RR: 66.7 vs. 14.3%, pu2009=u20090.021; PFS: 10.1 vs. 8.6xa0months, pu2009=u20090.232).ConclusionsPersonalized treatment should be evolving in different types of uncommon EGFR mutations. Clinical benefit from EGFR-TKIs was higher in NSCLC patients with complex EGFR mutations than those with other uncommon EGFR mutation types.

Multiple treatment modalities for brain metastasis in patients with EGFR-mutant non-small-cell lung cancer

Background There are many controversies concerning the best management of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients with brain metastases (BMs). The use of upfront EGFR tyrosine kinase inhibitors (TKIs) and the withholding of local therapies or upfront radiation therapies (RTs) remain controversial. Available treatment options include local therapies such as whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and surgery, EGFR-TKIs, and chemotherapy. However, the optimal management of combination therapies is still under consideration. Patients and methods A total of 45 EGFR-mutated NSCLC patients with BMs were included. All patients successively received EGFR-TKIs, RT (WBRT or SRS), and chemotherapy between 2010 and 2015 at Zhejiang Cancer Hospital. Patient follow-up was conducted by telephone until February 2017. The treatment response was evaluated, and survival data were collected and analyzed by Kaplan–Meier analysis and the Cox regression method. Results The median overall survival (OS) was 28 months. Patients with the exon 19 deletion showed the strongest trend toward a longer median OS compared to patients with the exon 21 L858R mutation (not reached vs 26.5 months, P=0.0969). There was no difference in OS between the upfront RT group and the deferral group (26.5 vs 28 months, P=0.57), and similar results were found between the first-line chemotherapy group and the EGFR-TKI group (28 vs 23.2 months, P=0.499). In multivariate analysis, the prognosis correlated with EGFR mutation type (P=0.017). Conclusion EGFR-mutant NSCLC patients with BM benefited from the combination and sequential therapies of EGFR-TKIs, chemotherapy, and RTs. Patients with the EGFR exon 19 deletion may have a better OS. However, the optimal timing of RT interval remains to be explored.

Applicability of the lung-molGPA index in non-small cell lung cancer patients with different gene alterations and brain metastases

OBJECTIVESnThe Lung-molGPA index is based on the original diagnosis-specific graded prognostic assessment (DS-GPA) and incorporates recently reported gene alteration data, predicting the outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases (BM). However, the prognostic values of both DS-GPA and Lung-molGPA remain undetermined, especially for patients with different molecular types.nnnMATERIALS AND METHODSnA total of 1184 NSCLC patients with BM were analyzed for clinical factors and outcomes at Zhejiang Cancer Hospital, China. All prognostic factors were weighted for significance by hazard ratios. The applicability of DS-GPA and Lung-molGPA were reappraised in NSCLC patients with BM and various genetic profiles. Additionally, a modified Lung-molGPA was newly developed for NSCLC patients with gene variations.nnnRESULTSnNSCLC patients in the present study had a median survival time of 14.0 months from BM diagnosis. Both the DS-GPA and Lung-molGPA models could effectively predict the outcomes of NSCLC patients with BM (Pu2009<u20090.001), and the Lung-molGPA model appeared to deliver more accurate predictions. Furthermore, Lung-molGPA scores demonstrated discriminatory capability in patients with gene variations (Pu2009<u20090.001), and no significant difference was reached in wild-type patients (Pu2009=u20090.133). Regarding oncogene-positive NSCLC patients with BM, a modified Lung-molGPA index was established based on the prognostic factors with a C-index of 0.73 (95% CI: 0.68-0.80) to accurately calculate survival probability (Pu2009<u20090.001).nnnCONCLUSIONSnIn the era of precision medicine, Lung-molGPA accurately predicted the prognosis of NSCLC patients with mutant genotypes and BM, although it did not perform well in wild-type patients. Thus, it is worthwhile to explore the prognostic model for patients with positive driving genes.