Platinum-based Chemotherapy In Advanced Non-small Cell Lung Cancer Research Articles

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study.

8513 Background: A multinational pivotal study WU-KONG1 (NCT03974022) has been conducted to assess sunvozertinib (DZD9008) in pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (exon20ins). Here we report the results of primary analysis. Methods: WU-KONG1 Part B is a phase 2, multinational pivotal study to assess the antitumor efficacy of sunvozertinib at two dose levels, 200 mg and 300 mg, in platinum pre-treated NSCLC patients with EGFR exon20ins. Eligible patients were randomized at the ratio of 1:1 to receive 200 mg or 300 mg sunvozertinib once daily until discontinuation criteria were met. Randomization was stratified by brain metastasis at baseline and number of regimens of prior systemic anti-cancer therapy. The primary endpoint was Independent Review Committee (IRC) assessed objective response rate (ORR) (per RECIST v1.1) and key secondary endpoint included IRC assessed duration of response (DoR). Results: As of January 4, 2024, a total of 184 patients were randomized to receive sunvozertinib treatment at 200 mg or 300 mg. Patients who met the predefined criteria for efficacy analysis were included in the primary analysis. The majority of patients (96.0%) had metastatic diseases, 60.7% had ECOG PS of 1, and 23.7% had baseline brain metastasis. All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. Per IRC assessment, the best ORR was 54.3% (41.0% confirmed and 5.8% pending confirmation). Confirmed complete response (CR) was achieved in 2.9% patients. The disease control rate (including CR, PR and stable disease) was 90.8%. The primary endpoint met its predefined target, with statistical significance. Tumor response was observed in patients with baseline brain metastasis, different demographics and EGFR exon20ins subtypes. With median follow-up time of 5.5 months for responders, the duration of response has not been reached, with 74.6% responders still responding. The PFS data are not mature with approximately 6-month follow-up. Safety findings were similar to previously reported results of sunvozertinib in other clinical studies. The most common drug-related TEAEs included diarrhea, skin rash and CPK increase. The majority of the TEAEs were CTCAE grade 1 or 2 and clinically manageable. Conclusions: In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting. Clinical trial information: NCT03974022 .

Circulating tumor cells dynamics during chemotherapy predict survival and response in advanced non-small-cell lung cancer patients.

Circulating tumor cells (CTCs) are prognostic biomarker in non-small-cell lung cancer (NSCLC). CTCs could also be used as predictor of efficacy of systemic treatments in advanced NSCLC. We described the dynamic changes of CTCs during first-line platinum-based chemotherapy in advanced NSCLC and clarified the correlation between CTC counts and efficacy of chemotherapy. Chemotherapy is administered and blood specimens are collected at four time points from baseline to disease progression for CTC detection. This multicenter prospective study enrolled patients with previously untreated stage III or IV NSCLC fit for standard platinum-based chemotherapy. Bloods were sampled as per standard operating procedures at baseline, cycle 1 and cycle 4 of chemotherapy, and at disease progression for CTC analysis using the CellSearch system. Among 150 patients enrolled, median overall survival (OS) was 13.8, 8.4, and 7.9 months in patients with CTC-, KIT-CTC, and KIT+CTC at baseline (p = 0.002). Patients with persistent negative CTC (46.0%) had longer progression-free survival [5.7 months, 95% confidence interval (CI): 5.0-6.5 versus 3.0 months, 0.6-5.4; hazard ratio (HR): 0.34, 95% CI: 0.18-0.67) and OS (13.1 months, 10.9-15.3 versus 5.6 months, 4.1-7.1; HR: 0.17, 0.08-0.36) compared with patients with persistent positive CTC (10.7%), which was not impacted by chemotherapy. Chemotherapy decreased CTC from 36.0% (54/150) to 13.7% (13/95). CTC persistent presence during treatment represents poor prognosis and resistance to chemotherapy in advanced NSCLC. Chemotherapy could effectively eliminate CTCs. Molecular characterization and the functionalization of CTC will be warranted for further intensive investigation. NCT01740804.

Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.

Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.

Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.

Single or combined immune checkpoint inhibitors compared to first-line platinum-based chemotherapy with or without bevacizumab for people with advanced non-small cell lung cancer.

Evidence of Astragalus injection combined platinum-based chemotherapy in advanced nonsmall cell lung cancer patients: A systematic review and meta-analysis.

Background:Platinum-based chemotherapy is one of the standard treatments for advanced nonsmall cell lung cancer (NSCLC). Despite on an effective treatment for advanced NSCLC patients, its high toxicity and limited clinical effects have raised big concerns. Astragalus injection (AGI) has been commonly employed as an adjutant chemotherapy drug for NSCLC in China. This review was conducted to evaluate the beneficial of AGI in combination with platinum-based chemotherapy in advanced NSCLC.Methods:We collected all studies about AGI plus platinum-based chemotherapy for advanced NSCLC in the PubMed, EMBASE, China National Knowledge Infrastructure Database, the Cochrane Library, Wanfang Database, China Biological Medicine Database, and Chinese Scientific Journal Database established on July 2018 without language restriction. Cochrane handbook was applied to assess the quality of included trials. Stata (version 12.0) and RevMan (version 5.3) were employed for data analysis. The quality of the evidence was assessed with the GRADE approach.Results:Nineteen randomized controlled trials (RCTs) including 1635 patients were included to determine the effectiveness and safety of AGI combined with platinum-based chemotherapy in the treatment of NSCLC. The result of meta-analysis indicated that comparing with chemotherapy alone, AGI combined chemotherapy could significantly improve the objective response rate (relative risk [RR] = 1.19, 95% confidence interval [CI] [1.06, 1.33], P = .002), the Karnofsky performance status (RR = 2.28, 95% CI [1.63, 3.18], P < .00001), and 1-year survival rate (RR = 1.40, 95% CI [1.16, 1.70], P = .0005), meanwhile increase the percentages of CD3+ (weighted mean differences [WMD] = 11.98, 95% CI [8.0, 15.96], P < .00001), CD4+ (WMD = 2.98, 95% CI [0.45, 5.52], P = .02), CD4+/CD8+ (WMD = 0.33, 95% CI [0.20, 0.46], P < .00001), and NK cells (WMD = 9.5, 95% CI [7.25, 11.76], P < .00001), decrease the incidence of leukopenia (RR = 0.52, 95% CI [0.44, 0.61], P < .00001), platelet toxicity (RR = 0.62, 95% CI [0.50, 0.76], P < .00001), and vomiting (RR = 0.72, 95% CI [0.60, 0.87], P = .0006). Based on the system evaluation results, the GRADE system recommendation grading method was adopted to evaluate the evidence quality. The results showed that the level of evidence was low.Conclusions:The AGI apparently has attenuation and synergistic efficacy to platinum-based chemotherapy patients. However, considering the limits of articles included in the present researches, the recommendation is likely to be weak. High-quality RCTs are urgently used to generate conclusive results.

Epigenetic predictive biomarkers for response or outcome to platinum-based chemotherapy in non-small cell lung cancer, current state-of-art

Platinum-based chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC). However, its efficacy is limited and no molecular biomarkers that predict response are available. In this review, we summarize current knowledge concerning potential epigenetic predictive markers for platinum-based chemotherapy response in NSCLC. A systematic search of PubMed and ClinicalTrials.gov using keywords "non-small cell lung cancer" combined with "chemotherapy predictive biomarkers", "chemotherapy epigenetics biomarkers", "chemotherapy microRNA biomarkers", "chemotherapy DNA methylation" and "chemotherapy miRNA biomarkers" revealed 1740 articles from PubMed and 36 clinical trials. Finally, 22 papers and no trials fulfilled the review criteria. Among miRNA, combination of miR-1290, miR-196b and miR-135a in tumor tissue, and miR-21, miR-25, miR27b, and miR-326 in plasma were predictive for response to platinum-based chemotherapy in advanced NSCLC. RASSF1A methylation measured in tumor or blood was predictive for response to neoadjuvant chemotherapy. These biomarkers remain experimental and none have been tested in a prospective trial.

KRAS-specific Amino Acid Substitutions are Associated With Different Responses to Chemotherapy in Advanced Non–small-cell Lung Cancer

BackgroundEmerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non–small-cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy. Patients and MethodsWe retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first-line platinum-based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints. ResultsTaxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82-3.48; P < .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05-4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26-0.38; P < .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22-1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30-0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs. ConclusionKRAS-specific AAS appears to induce different responses to chemotherapy regimens after first-line platinum-based chemotherapy in advanced NSCLC.

Association of Base Excision Repair Gene Polymorphisms with the Response to Chemotherapy in Advanced Non-Small Cell Lung Cancer.

Background:Base excision repair (BER) plays an important role in the maintenance of genome integrity and anticancer drug resistance. This study aimed to explore the role of BER gene polymorphisms in response to chemotherapy for advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.Methods:During the period from November 2009 to January 2016, a total of 152 patients diagnosed with NSCLC Stage IIIB and IV in the First Hospital of Jilin University were admitted into this study. The XRCC1 G28152A, MUTYH G972C, HOGG1 C1245G, and PARP1 T2444C polymorphisms of all the patients were detected by mass spectrometry. The logistic regression was used for statictical analysis. All tests were bilateral test, and a P < 0.05 was considered statistically significant.Results:The logistic regression model showed that the response rate of chemotherapy of the PARP1 T2444C polymorphisms, CC genotype (odds ratio [OR]: 5.216, 95% confidence interval [CI]: 1.568–17.352, P = 0.007), TC genotype (OR: 2.692, 95% CI: 1.007–7.198, P = 0.048), as well as the genotype of TC together with CC (OR: 3.178, 95% CI: 1.229–8.219, P = 0.017) were significantly higher than those of TT wild type. There was no relationship between the MUTYH G972C, XRCC1 G28152A, and HOGG1 C1245G gene polymorphisms and chemosensitivity.Conclusions:The PARP1 2444 mutation allele C might be associated with the decreased sensitivity to platinum-based chemotherapy in advanced NSCLC. These findings may be helpful in designing individualized cancer treatment.

Shenfu Injection Adjunct with Platinum-Based Chemotherapy for the Treatment of Advanced Non-Small-Cell Lung Cancer: A Meta-Analysis and Systematic Review.

Platinum-based chemotherapy is one of the standard treatments for non-small-cell lung cancer (NSCLC), while its high toxicity and limited clinical effects raise big concerns. Shenfu injection (SFI) has been commonly used as an adjutant chemotherapy drug for NSCLC in China. We ascertained the beneficial and adverse effects of SFI in combination with platinum-based chemotherapy for advanced NSCLC by using meta-analysis methods. The randomized controlled trials (RCTs) involving advanced NSCLC treatment with SFI plus platinum-based chemotherapy versus chemotherapy alone were searched on 6 medical databases up to February 2017. Cochrane handbook 5.1.0 was applied to assess the quality of included trials and RevMan 5.3 software was employed for data analysis. 23 RCTs including 1574 patients met our inclusion criteria. We evaluated the following outcome measures: objective tumor response (ORR), disease control rate (DCR), Karnofsky performance score (KPS), adverse effects, and indicators of cellular immune function. The meta-analysis indicated that SFI plus platinum-based chemotherapy may benefit the patients with NSCLC on attenuated synergies of chemotherapy. These findings need to be confirmed by further rigorously designed high-quality and large-scale RCTs.

P2.03b-040 NANOG Predicts Poor Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy: Topic: Biomarkers

NANOG is a master transcription factor that regulates embryonic stem cell pluripotency and cell-fate specification though complex interaction with a myriad of factors in signaling pathways. Cumulating evidence suggests that it has oncogenic potential correlating with cell proliferation, clonogenic growth, tumorigenicity and invasiveness. Increased NANOG expression has been reported to be related with poor survival in several human malignancies including hepatic, breast, ovarian and colorectal cancers. However, clinical significance of NANOG overexpression in lung cancer has been scarcely evaluated, and correlation between NANOG expression and prognosis in advanced non-small cell lung cancer (NSCLC) has not been studied. The aim of this study is to investigate whether NANOG expression is associated with clinical outcomes of patients who were treated with platinum-based chemotherapy for advanced NSCLC. To prove NANOG overexpression in lung cancer, we initially assessed the expression of NANOG using Western blotting in lung cancer tissue from NSCLC patients who underwent surgical resection. Then, NANOG expression was examined by immunohistochemistry and evaluated by a semiquantitative histologic score (H score) in tumor tissues from NSCLC patients treated with platinum-based doublet. We performed survival analyses and evaluated the association between NANOG expression and clinical parameters. NANOG expression in lung cancer tissues was significantly increased compared with non-tumorous tissues (p < 0.001). Survival analyses using 110 tumor specimens showed that, at the cutoff value of H score 200, high NANOG expression was significantly associated with short progression-free survival (hazard ratio [HR] = 2.40, 95% confidence interval [CI]: 1.14 –5.62), and with short overall survival (HR = 2.89, 95% CI: 2.18–4.62). In addition, similar results were shown in the subgroup analyses for adenocarcinoma and squamous cell carcinoma. NANOG expression was not associated with any clinical parameter including age, gender, smoking status, stage, differentiation, or tumor histology. Increased NANOG expression was associated with poor response and short overall survival in advanced NSCLC patients treated with platinum-based chemotherapy. NANOG overexpression could be a potential adverse predictive marker in this setting.

Profile of ramucirumab in the treatment of metastatic non-small-cell lung cancer.

The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.

Treatment on advanced NSCLC: Platinum-based chemotherapy plus erlotinib or platinum-based chemotherapy alone? A systematic review and meta-analysis of randomised controlled trials

We performed a systematic review and meta-analysis to assess the potential of erlotinib plus platinum-based chemotherapy relative to platinum-based chemotherapy alone for advanced non-small-cell lung cancer (NSCLC). Search of PubMed, EMBASE, Web of Science, CBM, CNKI, China Wan Fang databases and the Cochrane library was performed for studies regarding erlotinib plus platinum-based chemotherapy for advanced NSCLC published between 1 January 2000 and 28 August 2014. We identified eight eligible studies including 3,363 patients with advanced NSCLC. For PFS measure, an HR of 0.73 (0.58-0.93) with statistical significance was estimated when erlotinib plus platinum-based chemotherapy compared with platinum-based chemotherapy alone; objective response rate of 32.86 versus 24.85% was obtained for both groups, respectively. HR of 0.93 (0.86-1.00) with P of 0.170 was calculated for OS. We concluded that the erlotinib plus chemotherapy for advanced NSCLC could increase PFS and objective response rate, but not benefit OS.

Wnt signaling pathway pharmacogenetics in non-small cell lung cancer.

Wnt/β-catenin pathway alterations in non-small cell lung cancer (NSCLC) are associated with poor prognosis and resistance. In 598 stage III-IV NSCLC patients receiving platinum-based chemotherapy at MD Anderson Cancer Center (MDACC), we correlated survival with 441 host SNPs in 50 Wnt pathway genes. We then assessed the most significant SNPs in 240 Mayo Clinic patients receiving platinum-based chemotherapy for advanced NSCLC, 127 MDACC patients receiving platinum-based adjuvant chemotherapy and 340 early stage MDACC patients undergoing surgery alone (cohorts 2–4). In multivariate analysis, survival correlates with SNPs for AXIN2 (rs11868547 and rs4541111, of which rs11868547 was assessed in cohorts 2–4), Wnt-5B (rs12819505), CXXC4 (rs4413407) and WIF-1 (rs10878232). Median survival was 19.7, 15.6, and 10.7 months for patients with 1, 2, and 3–5 unfavorable genotypes, respectively (p= 3.8×10−9). Survival tree analysis classified patients into two groups (MST 11.3 vs 17.3 months, p=4.7×10−8). None of the SNPs achieved significance in cohorts 2–4; however, there was a trend in the same direction as cohort 1 for 3 of the SNPs. Using online databases, we found rs10878232 displayed expression quantitative trait loci (eQTL) correlation with the expression of LEMD3, a neighboring gene previously associated with NSCLC survival. In conclusion, results from cohort 1 provide further evidence for an important role for Wnt in NSCLC. Investigation of Wnt inhibitors in advanced NSCLC would be reasonable. Lack of a SNP association with outcome in cohorts 2–4 could be due to low statistical power, impact of patient heterogeneity, or false positive observations in cohort 1.

XRCC3 Thr241Met Polymorphism and Clinical Outcomes of NSCLC Patients Receiving Platinum-Based Chemotherapy: A Systematic Review and Meta-Analysis

IntroductionX-ray repair cross-complementing protein 3 (XRCC3) is an essential gene involved in the double-strand break repair pathway. Published evidence has shown controversial results about the relationship between XRCC3 Thr241Met polymorphism and clinical outcomes of non-small cell lung cancer (NSCLC) patients receiving platinum-based chemotherapy.MethodsA systematic review and meta-analysis was performed to evaluate the predictive value of XRCC3 Thr241Met polymorphism on clinical outcomes of advanced NSCLC receiving platinum-based chemotherapy. Response to chemotherapy, overall survival (OS) and progression-free survival (PFS) were analyzed.ResultsA number of 11 eligible studies were identified according to the inclusion criteria. Carriers of the variant XRCC3 241Met allele were significantly associated with good response to platinum-based chemotherapy (ThrMet/MetMet vs. ThrThr: OR = 1.509, 95% CI: 1.099–2.072, Pheterogeneity = 0.618). The XRCC3 Thr241Met polymorphism was not associated with OS (MetMet vs. ThrThr, HR = 0.939, 95% CI:0.651–1.356, Pheterogeneity = 0.112) or PFS (MetMet vs. ThrThr, HR = 0.960, 95% CI: 0.539–1.710, Pheterogeneity = 0.198). Additionally, no evidence of publication bias was observed.ConclusionsThis systematic review and meta-analysis shows that carriers of the XRCC3 241Met allele are associated with good response to platinum-based chemotherapy in advanced NSCLC, while the XRCC3 Thr241Met polymorphism is not associated with OS or PFS.

Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on the Risk of Lung Cancer and the Clinical Response to Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer: An Updated Meta-Analysis

PurposeMethylenetetrahydrofolate reductase (MTHFR) has been implicated in lung cancer risk and response to platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). However, the results are controversial. We performed meta-analysis to investigate the effect of MTHFR C677T polymorphism on lung cancer risk and response to platinum-based chemotherapy in advanced NSCLC.Materials and MethodsThe databases of PubMed, Ovid, Wanfang and Chinese Biomedicine were searched for eligible studies. Nineteen studies on MTHFR C677T polymorphism and lung cancer risk and three articles on C677T polymorphism and response to platinum-based chemotherapy in advanced NSCLC, were identified.ResultsThe results indicated that the allelic contrast, homozygous contrast and recessive model of the MTHFR C677T polymorphism were associated significantly with increased lung cancer risk. In the subgroup analysis, the C677T polymorphism was significantly correlated with an increased risk of NSCLC, with the exception of the recessive model. The dominant model and the variant T allele showed a significant association with lung cancer susceptibility of ever smokers. Male TT homozygote carriers had a higher susceptibility, but the allelic contrast and homozygote model had a protective effect in females. No relationship was observed for SCLC in any comparison model. In addition, MTHFR 677TT homozygote carriers had a better response to platinum-based chemotherapy in advanced NSCLC in the recessive model.ConclusionThe MTHFR C677T polymorphism might be a genetic marker for lung cancer risk or response to platinum-based chemotherapy in advanced NSCLC. However, our results require further verification.

1245P - A Phase 2 Randomized Open-Label Study of Ramucirumab (IMC 1121b; RAM) in Combination with Platinum-Based Chemotherapy in Patients (PTS) with Recurrent or Advanced Non-Small Cell Lung Cancer (NSCLC): Results From Non-Squamous (NSQ) PTS (NCT01160744)

ABSTRACT Background Vascular endothelial growth factor (VEGF)-mediated angiogenesis plays an important role in NSCLC pathogenesis. RAM is a fully human IgG1 monoclonal antibody that inhibits VEGF receptor-2 (VEGFR-2) binding and signaling. This study investigates RAM in combination with first-line platinum-based chemotherapy in advanced NSCLC. Methods NSQ pts with Stage IV NSCLC, ECOG PS ≤ 2, adequate hematologic, hepatic and renal function were randomized to either Arm A: pemetrexed + carboplatin/cisplatin or Arm B: RAM + pemetrexed + carboplatin/cisplatin, once every 3 weeks. The primary analysis will be when 103 progression-free survival (PFS) events are observed in NSQ pts. This pre-planned interim analysis was performed when 61 NSQ PFS events were observed. Other interim endpoints: objective response rate, disease control rate (DCR), and safety. Results Arm A (n = 71) median (medn) age 64, 63% male (M), 37% female (F), ECOG PS 0-1 / 2 (91.6% / 5.6%). Arm B (n = 69) medn age 64, 52% M, 48% F, ECOG PS 0-1 / 2 (89.9% / 7.2%). Interim efficacy analyses Arm A (N = 71) n (%) Arm B (N = 69) n (%) PFS Events Censored Median (months) 90% CI 37 (52) 34 (48) 4.3 (3.8, 5.7) 24 (35) 45 (65) 6.3 (5.7, -) Best Response PR SD DCR (SD + PR) 26 (37) 25 (35) 51 (72) 30 (44) 30 (44) 60 (88) Nonhematologic adverse events (AEs) were fatigue (61%; 17% Grade[G]3), nausea (55%; 7% G3), vomiting (36%; 4% G3), constipation (30%; 1% G3), hypertension (HTN) (6%; 1% G3), proteinuria (4%; 0 G3), on Arm A; fatigue (63%; 12% G3), nausea (51%; 10% G3), vomiting (33%; 8% G3), constipation (27%; 0 G3), HTN (19%; 10% G3), proteinuria (5%; 0 G3) on Arm B. Hematologic AEs were anemia (A) (55%; 16% G3), neutropenia (N) (23%; 16% G3), thrombocytopenia (T) (23%; 12% G3) on Arm A; A (39%; 8% G3), N (33%; 13% G3), T (31%; 15% G3) on Arm B. Conclusions Based on interim analyses of PFS and acceptable tolerability and safety, RAM may provide clinical benefit in combination with first-line platinum-based chemotherapy in NSQ NSCLC. Enrollment of pts in squamous Arms C and D is ongoing. Disclosure R. Doebele: Research funding: ImClone Systems, Eli Lilly & Co., Pfizer Inc. Honoraria: Boehringer Ingelheim, Abbott Laboratories, Pfizer Inc. Stock: Ariad ( M. Reck: Honoraria for Lectures: Lilly, Hoffmann-La Roche, AstraZeneca, Daiichi-Sankyo Advisory Board (compensated): Lilly, Hoffmann-La Roche, AstraZeneca, Daiichi-Sankyo, Pfizer, Merck, BMS. S. Verma: Advisory Board and honoraria from Eli Lilly. S. Yurasov: I am employed by Eli Lilly and own Lilly stock. D.R. Camidge: Advisory role and honoraria: ImClone Reserach Funding: Eli Lilly. All other authors have declared no conflicts of interest.

Effect of the XRCC1 and XRCC3 genetic polymorphisms on the efficacy of platinum-based chemotherapy in patients with advanced non-small cell lung cancer

背景与目的DNA修复基因多态性预测铂类药物化疗敏感性对非小细胞肺癌(non-small cell lung cancer, NSCLC)个体化治疗具有重要意义。本研究旨在探讨X线修复交错互补基因1(X-ray repair cross complementing gene 1, XRCC1)和X线修复交错互补基因3(X-ray repair cross complementing gene 3, XRCC3)单核苷酸多态性与晚期NSCLC患者对铂类药物化疗疗效的关系。方法采用PCR-RFLP方法检测130例以含铂方案化疗的晚期NSCLC患者外周血DNA中XRCC1 Arg194 Trp、Arg399 Gln和XRCC3 Thr241 Met基因多态性, 分析其基因型与化疗疗效的关系。结果130例晚期NSCLC患者采用含铂方案化疗2个周期后, 化疗总有效率为33.8%。XRCC1 194和399基因多态性与铂类药物化疗敏感性相关, 而XRCC3 241基因多态性与化疗敏感性无关(P=0.145)。携带至少1个XRCC1 194 Trp等位基因者化疗有效率至少是携带Arg/Arg基因型患者的2.5倍(42.1% vs 22.2%, OR=2.545, 95%CI:1.159-5.590, P=0.020)。携带XRCC1 399 Arg/Arg基因型者的化疗有效率为45.5%, 明显高于携带至少1个Gln等位基因者(21.9%)(OR=0.336, 95%CI:0.156-0.722, P=0.005)。XRCC1 194和399基因多态性之间存在联合作用, 同时携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg基因型者的化疗有效率明显高于同时携带194 Arg/Arg和399 Arg/Gln基因型者(44.4% vs 18.8%, OR=3.467, 95%CI:1.223-9.782, P=0.019)。XRCC1和XRCC3基因多态性在化疗敏感性方面存在一定的联合作用, 携带至少1个XRCC1 194 Trp等位基因和399 Arg/Arg野生型基因同时又携带XRCC3 241 Thr/Met基因型者的化疗有效率明显高于其它基因型携带者。结论XRCC1和XRCC3的多态联合可能与晚期NSCLC患者对铂类药物化疗疗效具有相关性。

Influence of Polymorphisms in MTHFR 677 C→T, TYMS 3R→2R and MTR 2756 A→G on NSCLC Risk and Response to Platinum-Based Chemotherapy in Advanced NSCLC

Genetic factors may contribute to individual differences in cancer susceptibility, drug efficacy and toxicity. This study was designed to investigate the effects of the polymorphisms of methylenetetrahydrofolate reductase 677 C→T (MTHFR 677 C→T), thymidylate synthase (TYMS 3R→2R),and methionine synthase 2756 A→G (MTR 2756 A→G) on the risk of lung cancer and response to platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC). We conducted a case-control study involving 438 NSCLC cases (including 101 follow-up cases) and 641 healthy controls in North China. Using a genetic model analysis, the polymorphism MTHFR 677 C→T showed a significantly increased risk for NSCLC in women but not in men, which was observed in the codominant model (CT vs CC adjusted odds ratio [OR] = 2.46; 95% confidence interval [CI]: 1.37-4.42; p = 0.003; TT vs CC adjusted OR: 2.04; 95% CI: 1.09-3.81; p = 0.03) and the dominant model (CT + TT vs CC adjusted OR: 2.30; 95% CI: 1.31-4.05; p = 0.004). In addition, we found that patients with the MTHFR 677 TT genotype showed a better response to platinum-based chemotherapy in the recessive model (TT vs CT + CC adjusted OR: 0.24; 95% CI: 0.09-0.68; p = 0.007), the generalized OR was 0.44 (0.22-0.88; p = 0.04). There were no significant associations of the polymorphisms of TYMS 3R→2R or MTR 2756 A→G with the risk of NSCLC or response to platinum-based chemotherapy in advanced NSCLC in any genetic model. Our results suggest that genetic polymorphisms of MTHFR 677 C→T may contribute to NSCLC development in Chinese women and could also influence treatment response for advanced NSCLC patients with platinum-based chemotherapy. Further studies with larger sample sizes are required to validate this association.

Improving chemotherapy for patients with advanced non‐small cell lung cancer

Lung cancer is the third most common mortal disease in industrialised countries and the prognosis has been slow to improve. The largest subgroup has locally advanced or metastatic non-small cell lung cancer (NSCLC). Unfortunately, these patients can usually not be cured and the main treatment option is palliative chemotherapy. Given the palliative intention of the chemotherapy, it is clinically highly relevant to establish the optimal treatment duration. While chemotherapy prolongs survival and improves quality of life (QoL), it also has side effects and only a minority of patients achieve an objective treatment response. Clinicians need guidance on treatment duration from controlled trials to balance these aspects. Improvements of the conditions under which chemotherapy is given can increase patient and staff satisfaction and increase system performance. This is especially relevant to incurable patients who spend a lot of their limited time at oncology outpatient clinics. Staffing, infrastructure and organisation of these units are often suboptimal to serve patients with palliative needs and reports of improvement projects can inspire and guide clinicians in improving their microsystems of care. Clinicians, health care administrators and the public need knowledge about the outcomes of palliative chemotherapy in unselected patient populations. The efficacy of palliative chemotherapy for advanced NSCLC has been amply documented in controlled clinical trials. Meanwhile, the elderly and patients with higher performance status have usually been under-represented in these trials and population studies of the effectiveness of chemotherapy are needed. (i) To establish the optimal duration of platinum-based first line chemotherapy for advanced NSCLC; (ii) To improve the care processes at an oncology outpatient clinical microsystem; (iii) To describe the use of chemotherapy in a national population and investigate associations between chemotherapy use and survival; and (iv) To explore approaches to improve the system of chemotherapy from the macro perspective of a whole country. The thesis combines methods from different knowledge domains. In a randomised trial, we compared three with six courses of platinum-based chemotherapy for advanced NSCLC. In a quality improvement study, we used logistic improvement tools, qualitative and quantitative patient and staff satisfaction measurements. Finally using data from the Norwegian cancer and chemotherapy registries, we investigated temporary and geographical variations of chemotherapy use and correlations with the survival of patients with advanced NSCLC. Methods and findings from the three studies were explored to inform a national improvement strategy for the chemotherapy of advanced NSCLC. Survival and QoL were equal with three or six courses of chemotherapy for advanced NSCLC. Systematic process changes at the outpatient clinic led to increased patient and staff satisfaction. Furthermore, the study illustrates the application of established process improvement and evaluation tools in a clinical microsystem. In the registry study, we found delays of the introduction of palliative chemotherapy in Norway and significant associations between the use of chemotherapy and the survival of patients with advanced NSCLC. The general section of the thesis describes approaches to system-wide improvements and introduces a quality improvement matrix. We conclude from our randomised trial and related research that chemotherapy beyond three courses is not beneficial for patients with advanced NSCLC. The report from the oncology outpatient clinic illustrates the value of the clinical microsystem approach for quality improvement at the front line of care. Patient feedback through a focus group, simple methods of assessing and simplifying processes of care, as well as measuring results over time were effective tools in our project. The description of the experiences can serve as an example for the improvement of microsystems in settings with similar problems. Finally, in the registry study of Norwegian patients with lung cancer, we found significant geographical and temporal variations of the utilisation of chemotherapy that were related to survival. Potential areas of improvement in the system of care for lung cancer are recruitment of patients in clinical studies, standardisation of the processes of care in outpatient clinics, definition of strategic aims of quality, development of balanced quality indicators, as well as measuring and reporting of outcomes by means of a quality registry.

Shenqi fuzheng, an injection concocted from Chinese medicinal herbs, combined with platinum-based chemotherapy for advanced non-small cell lung cancer: a systematic review.

BackgroundPlatinum-based chemotherapy has been a standard therapy for advanced non-small cell lung cancer (NSCLC), but it has high toxicity. In China, Shenqi Fuzheng, a newly developed injection concocted from Chinese medicinal herbs has been reported that may increase efficacy and reduce toxicity when combined with platinum-based chemotherapy, but little is known about it outside of China. The aim of this study was to systematically review the existing clinical evidence on Shenqi Fuzheng Injection(SFI) combined with platinum-based chemotherapy for advanced NSCLC.MethodsPubmed, Cochrane Library, EMBASE, CNKI, and CBM search were organized for all documents published, in English and Chinese, until April 2010. The randomized controlled clinical trials were selected based on specific criteria, in which a SFI plus platinum-based chemotherapy treatment group was compared with a platinum-based chemotherapy control group for patients with advanced NSCLC. The quality of studies was assessed by modified Jadad's scale, and Revman 4.2 software was used for data syntheses and analyses.ResultsTwenty nine studies were included in this review based on our selection criteria. Of them, ten studies were of high quality and the rest were of low quality, according to the modified Jadad scale. The meta-analysis showed there was a statistically significant higher tumor response (RR, 1.19; 95% CI, 1.07 to 1.32; P = 0.001) and performance status ((RR, 1.57; 95% CI, 1.45 to 1.70; P < 0.00001); but lower severe toxicity for WBC (RR, 0.37; 95% CI, 0.29 to 0.47; P < 0.00001), PLT (RR, 0.33; 95% CI, 0.21 to 0.52; P < 0.00001), HB (RR, 0.44; 95% CI, 0.30 to 0.66; P < 0.0001) and nausea and vomiting (RR, 0.32; 95% CI, 0.22 to 0.47; P < 0.00001), when the SFI plus platinum-based chemotherapy treatment group was compared with the platinum-based chemotherapy control group. Sensitivity analysis was restricted to studies with the high quality, and the result was similar when the studies with low quality were excluded. Asymmetry was observed in a funnel plot analysis, and Egger's test also indicated an evidence of publication bias (P = 0.016).ConclusionsSFI intervention appears to be useful to increase efficacy and reduce toxicity when combined with platinum-based chemotherapy for advanced NSCLC, although this result needs to be further verified by more high-quality trials.