Chemotherapy In Advanced Non-small Cell Lung Cancer Research Articles

Maintenance gemcitabine versus best supportive care following platinum-paclitaxel chemotherapy for patients with advanced nonsmall cell lung cancer

Background: Approximately two-thirds of all patients with newly diagnosed nonsmall cell lung cancer (NSCLC) have advanced disease (Stage IIIB or IV) that is only amenable to palliative chemotherapy. Switch maintenance therapy with a different active agent aims to hit clonal variants resistant to the first-line therapy before they have had time to increase in number. Based on this, we conducted a randomized Phase III study to compare gemcitabine (Gem) versus best supportive care (BSC) as maintenance therapy. Methods: Between July 2011 and January 2012, chemo-naive patients with Stage IIIB/IV NSCLC were initially treated with six cycles of cisplatin (40 mg/m2 day 1, 2) and paclitaxel (175 mg/m2 day 1) every 3 weeks. Subsequently, nonprogressors were randomized 1:1 to receive maintenance G (1000 mg/m2 on days 1 and 8 every 3 weeks) or BSC alone till disease progression. The primary endpoint was a comparison of overall survival (OS) between two arms, and the secondary endpoint was progression-free survival (PFS). Results: Exactly 134 patients were enrolled (median age: 50 years, males 76.8%, Stage IV disease 50.7%, Eastern Cooperative Oncology Group performance status 0/1: 67.9%). Following 6 cycles of initial therapy, the Response Rate (RR) was 35.1% (Complete Response (CR) 3%, Partial Response (PR) 32.1%), and 38.8% had stable disease. Ninety-nine nonprogressors were randomized to receive Gem (n = 50) or BSC (n = 49). The median OS for Gem was 10 months (95% confidence interval [CI]: 9.2–10.7) and 8 months (95% CI: 6.7–9.2) for BSC, with a hazard ratio (HR) 0.64 (95% CI: 0.51–0.77, P = 0.002). The median PFS was 9 months (95% CI: 8.1–9.9) for G versus 7 months (95% CI: 6.3–7.7) for BSC, with a HR 0.67 (95% CI: 0.50–0.84, P = 0.009). Maintenance therapy was tolerated well despite a higher incidence of grade 3/4 toxicity (anemia 12% vs. 8.1%; neutropenia 18% vs. 4.1%; thrombocytopenia 14% vs. 2%; and fatigue 8% vs. 2%). Conclusion: Switch maintenance therapy with gemcitabine, following initial platinum-based doublet chemotherapy in advanced NSCLC can produce significantly longer PFS and OS compared to BSC alone at the cost of higher grade 3/4 hematological toxicities.

Role of RRM1 in the Treatment and Prognosis of Advanced Non-small Cell Lung Cancer

肺癌是最常见和死亡率最高的恶性肿瘤之一，75%-80%为非小细胞肺癌（non-small cell lung cancer, NSCLC）。且绝大部分患者就诊时已处晚期，失去了根治性手术或放疗的机会，化疗是主要的治疗手段。但由于肿瘤生物学行为的多样性和对化疗药物的耐药等，使得晚期NSCLC的化疗不容乐观。近年来，分子标志物的个体化化疗在晚期NSCLC的应用，使得这些患者生存期有所延长，生活质量有所提高。针对晚期NSCLC，根据分子标志物选择合适的药物，达到个体化化疗是临床中所要面对和解决的问题。本文就核苷酸还原酶M1（ribonucleotide reductase subunit 1, RRM1）在晚期NSCLC治疗和预后中的作用做一简要综述。由RRM1指导的个体化化疗并不能作为晚期NSCLC的常规决策，还需进一步研究。

Palliative chemotherapy (CT) for advanced non-small cell lung cancer (NSCLC): Investigating disparities between patients who are treated versus those who are not.

e17681 Background: Palliative CT in advanced NSCLC is associated with improved overall survival (OS) and quality of life, yet many patients remain untreated. In this study, we explored the differen...

100PD - A Prospective Randomized Open Label Phase III Study of Maintenance Gemcitabine Versus Best Supportive Care Following Platinum-Paclitaxel Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer

Aim: Approximately two-thirds of all patients with newly diagnosed non-small-cell lung cancer (NSCLC) have advanced disease (stage IIIB or IV) that is only amenable to palliative chemotherapy. Switch maintenance therapy with a different active agent aims to hit clonal variants resistant to the first-line therapy before they have had time to increase in number. Based on this, we conducted a randomized phase III study to compare Gemcitabine (G) versus Best Supportive Care (BSC) as maintenance therapy for patients with advanced NSCLC. Methods: Between July 2011 and January 2012, chemo-naive patients with stage IIIB/IV NSCLC were initially treated with six cycles of cisplatin (40 mg/m2 day 1, 2) and paclitaxel (175 mg/m2 day 1) every 3 weeks. Subsequently, non-progressors were randomized 1:1 to receive maintenance G (1000 mg/m2 on days 1 and 8 every 3 weeks) or BSC alone till disease progression. The primary endpoint was the comparison of overall survival (OS) between the two arms and the secondary endpoint was progression free survival (PFS). The survival analyses were performed by using SPSS version 20.0. Results: 134 patients were enrolled (median age: 50 years, males 76.8%, stage IV disease 50.7%, ECOG performance status 0/1: 67.9%). Following 6 cycles of initial therapy, the RR was 35.1% (CR-3%, PR-32.1%), and 38.8% had SD. 99 non-progressors were randomized to receive G (n = 50) or BSC (n = 49). The median OS for G was 10 months (95% CI: 9.2-10.7) and 8 months (95% CI: 6.7-9.2) for BSC, with a hazard ratio (HR) 0.64 (95% CI: 0.51-0.77, P = 0.002). The median PFS was 9 months (95% CI: 8.1-9.9) for G versus 7 months (95% CI: 6.3-7.7) for BSC, with a HR 0.67 (95% CI: 0.50-0.84, P = 0.009). Maintenance therapy was tolerated well despite a higher incidence of grade 3/4 toxicity (anemia 12% vs. 8.1%; neutropenia 18% vs. 4.1%; thrombocytopenia 14% vs. 2%; and fatigue 8% vs. 2%). Conclusions: Switch maintenance therapy with gemcitabine, following initial platinum-based doublet chemotherapy in advanced NSCLC can produce significantly longer PFS and OS compared to BSC alone at the cost of higher grade 3/4 hematological toxicities. Disclosure: All authors have declared no conflicts of interest.

Nivolumab (Anti-PD-1; BMS-936558, ONO-4538) Maintenance as Monotherapy or in Combination With Bevacizumab (BEV) for Non-Small Cell Lung Cancer (NSCLC) Previously Treated With Chemotherapy: Metastatic Non-Small Cell Lung Cancer

an AESI reported in 2% of pts in the N single-agent treatment to progression phase were rash (Any Gr: 25.5%; Gr 3: 4.0%, hypomagnesemia (Any Gr: 16.0%; Gr 3: 2.5%), conjunctivitis (Any Gr: 4.7%; Gr 3: 0.7%), venous thromboembolic events (Any Gr: 2.5%; Gr 3 1.8%), and arterial thromboembolic events (Any Gr: 2.2%; Gr 3: 1.8%). Conclusions: OS and PFS were statistically significantly improved when N was added to GC. Pts who continued on N single-agent to progression had substantially better outcomes than the general population, and long-term use of N did not result in any unexpected increases in AESIs. Author Disclosure: M.A. Socinski: None. N. Thatcher: F. Honoraria; Eli Lilly and others. H. Speakers Bureau; Eli Lilly and others. K. Advisory Board; Eli Lilly and others. A.V. Luft: None. A. Szczesna: None. T. Ciuleanu: None. W. Szafra nski: None. R. Ramlau: None. B. Balint: None. A. Kazarnowicz: None. O. Molinier: G. Consultant; Eli Lilly. K. Advisory Board; Roche. H. Depenbrock: A. Employee; Eli Lilly. M. Stock; Eli Lilly. S. Nanda: A. Employee; Eli Lilly. M. Stock; Eli Lilly. C. Obasaju: A. Employee; Eli Lilly. M. Stock; Eli Lilly. N. Stock Options; Eli Lilly. L. Paz-Ares: F. Honoraria; Eli Lilly.

Baseline Urinary PGE-M Is a Prognostic and Predictive Marker for Cox-2 Inhibition in Addition to Standard Chemotherapy for Advanced Non-Small Cell Lung Cancer (NSCLC): CALGB 30801 (Alliance): Metastatic Non-Small Cell Lung Cancer

Overexpression of COX-2 has been associated with worse outcome in NSCLC. In C30203, we found that administration of the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved outcome (progression-free and overall survival, PFS, OS) in pts with moderate to high COX-2 expression by immunohistochemistry (IHC). C30801 was designed to confirm that finding. Analysis of the stable urinary metabolite of PGE-2, PGE-M, a marker of COX-2 pathway activation, was prospectively defined as a correlative study.

Ramucirumab: a promising development in advanced non-small cell lung cancer

The VEGF pathway is a critical target for anti-angiogenic therapy in advanced non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeting VEGF-A, is the only anti-angiogenic agent approved for first-line use in combination with platinum-based chemotherapy. Ramucirumab is another monoclonal antibody that specifically binds to the extracellular domain of the main angiogenic receptor VEGFR-2 on endothelial cells. Clinical development of ramucirumab demonstrated promising activity and a tolerable safety profile in combination with first-line chemotherapy in advanced NSCLC. Recently, the REVEL Phase III trial, including both squamous and nonsquamous carcinoma, demonstrated that the addition of ramucirumab to standard second-line docetaxel provided a significant improvement of overall survival, providing an evidence for VEGFR-targeted antiangiogenic therapy in advanced NSCLC.

Abstract CT238: Phase III randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance)

Abstract Background: Overexpression of COX-2 has been associated with worse outcome in NSCLC. In C30203, we found that administration of the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved outcome (progression free and overall survival, PFS, OS) in pts with moderate to high COX-2 expression by immunohistochemistry (IHC). C30801 was designed to prospectively confirm that finding. Patients and Methods: Pts with NSCLC (stage IIIb with pleural effusion, IV 6th ed) were pre-registered and biopsy specimens analyzed for COX-2 by IHC. Pts with COX-2 expression > or = 2, PS 0-2 and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin (AUC = 6), pemetrexed (500 mg/m2) d 1, q21 days for pts with non-squamous NSCLC; carboplatin(AUC=5.5) d1, gemcitabine (1000 mg/m2) d 1,8 for pts with squamous histology. Randomization was to celecoxib (400 mg bid) (Arm A) or placebo (Arm B). The primary endpoint was to demonstrate improvement in PFS in patients with COX-2 index >=4 with hazard ratio of 0.645. Results: The study was halted by the DSMB for futility after 312 of the planned 322 pts were randomized. The current analysis is based upon the first 300 pts. There were no significant differences between the groups (Table). There was a possible harmful effect for COX-2 inhibition in the COX-2 2-3 subset (OS HR = 1.75, p =.0977). Toxicity was similar for both arms. Subset analyses evaluating histology, chemotherapy regimen, incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Conclusions: 1. COX-2 expression by IHC failed to select pts who could benefit from selective COX-2 inhibition. 2. COX-2 inhibition did not significantly increase toxicity associated with chemotherapy or increase cardiovascular morbidity. 3. We will evaluate other possible determinants of toxicity and response to COX-2 inhibition. OutcomeArm AArm BCOX-2 2-3 (n=37)COX-2 > or = 4 (n=111)COX-2 2-3 (n=46)COX-2 > or = 4 (n=106)PFS (months)4.404.934.606.11OS (months)9.0310.5814.8512.68 Citation Format: Martin J. Edelman, Xiaofei Wang, Lydia Hodgson, Richard T. Cheney, Maria Baggstrom, Thomas Sachdev, Ajeet Gajra, Erin Bertino, Karen Reckamp, Julian Molina, Joan Schiller, Kisha Mitchell-Richards, Paula Friedman, Jon Ritter, Everett Vokes, Alliance for Clinical Trials in Oncology. Phase III randomized, placebo controlled trial of COX-2 inhibition in addition to standard chemotherapy for advanced non-small cell lung cancer (NSCLC):CALGB 30801 (Alliance). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT238. doi:10.1158/1538-7445.AM2014-CT238

Azithromycin enhances the favorable results of paclitaxel and cisplatin in patients with advanced non-small cell lung cancer.

Although new chemotherapeutic drugs have been applied constantly, their efficacy for non-small cell lung cancer (NSCLC) is still not satisfactory. In recent years, epidemiological investigations have shown that lung cancer may be induced by chronic Chlamydia pneumoniae (Cpn) infection, since stable high titers of Cpn antibodies, especially IgA, are a hallmark of chronic infections. Azithromycin is commonly used for the treatment of Cpn infections; however, there are only few reports regarding the application of azithromycin (A) combined with paclitaxel and cisplatin (TP) for advanced NSCLC. Considering that patients with NSCLC have a higher rate of Cpn infection, we proposed to employ azithromycin for Cpn infection in chemotherapy for advanced NSCLC. The aim of this study was to explore the effects of azithromycin on chemotherapy for NSCLC. A total of 86 patients with stage III-IV NSCLC were randomly divided into TP and ATP groups; the characteristics of patients in the two groups showed no significant differences. The TP group was treated with paclitaxel and cisplatin, and the ATP group was treated with azithromycin combined with TP for at least 4 weeks, followed by evaluation and comparison of efficacy, side effects and patients' quality of life before and after chemotherapy between the two groups. Testing for Cpn infection revealed a significant difference in the case number before and after therapy in the ATP group (P < 0.01) compared with the TP group (P > 0.05), and a statistical difference was observed (P < 0.01) between the ATP and TP groups after treatment. The changes in quality of life of patients after two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only cognitive function after treatment. The changes in symptom scores of patients after the two different chemotherapy regimens were statistically significant (P < 0.05), but there was a significant difference in only shortness of breath and cough after treatment. Kaplan-Meier estimate was utilized to describe the survival function of patients in the two groups. The median survival time was 12.0 months for the TP group and 13.0 months for the ATP group. One-year survival rates of the TP and ATP groups were 45.0 and 75.0%, respectively, which were significantly different (P < 0.05). Our study of azithromycin+paclitaxe l+cisplatin on stage III-IV NSCLC patients achieved favorable results in terms of side effects and overall survival.

Cytotoxic Chemotherapy for Non-small Cell Lung Cancer

Non-small-cell lung cancer is one of the leading causes of deaths from cancer worldwide. There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. Even as new chemotherapeutic agents are proving effective, a pivotal role for platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but determining which patients will most benefit from it remains controversial in the real-world setting. Ongoing efforts to overcome resistance to targeted agents utilizing combination regimens of chemotherapy plus targeted agents, are currently being explored and optimized. This review highlights recent developments in novel chemotherapeutics. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.

The possibility of traditional chinese medicine as maintenance therapy for advanced nonsmall cell lung cancer.

Lung cancer has become the leading cause of cancer deaths, with nonsmall cell lung cancer (NSCLC) accounting for around 80% of lung cancer cases. Chemotherapy is the main conventional therapy for advanced NSCLC. However, the disease control achieved with classical chemotherapy in advanced NSCLC is usually restricted to only a few months. Thus, sustaining the therapeutic effect of first-line chemotherapy is an important problem that requires study. Maintenance therapy is given for patients with advanced NSCLC if three is no tumor progression after four to six cycles of first-line platinum-based chemotherapy. However, selection of appropriate maintenance therapy depends on several factors, while traditional Chinese medicine (TCM) as maintenance therapy is recommended for all kinds of patients. It has been demonstrated that TCM can prolong the survival time, improve the quality of life (QOL), and reduce the side effects for advanced NSCLC. Although the trials we searched about TCM serving as maintenance therapy is only 9 studies, the results indicate TCM can prolong the progression free survival (PFS) and improve the QOL. So it is possible for TCM to be as maintenance therapy for advanced NSCLC. More rigorous trials are required to further verify its efficacy.

A Method for Biomarker Directed Survival Prediction in Advanced Non-Small-Cell Lung Cancer Patients Treated with Carboplatin-Based Therapy

Platinum-based chemotherapy is a primary treatment of choice for advanced non-small-cell lung cancer (NSCLC). Analytical methods to specifically evaluate biomarkers predictive of therapeutic efficacy have not been developed. Two randomized phase III trials of carboplatin-based chemotherapy in advanced NSCLC were used for learning and validating the predictive value of ERCC1 in situ protein levels, as measured by accurate quantitative analysis (AQUA). A novel Bayesian method was applied to identify the outcome-based threshold in the learning trial only. Overall survival (OS) was assessed by Kaplan-Meier analysis with log rank testing to determine statistical significance in the validating trial. For patients treated with gemcitabine and carboplatin, the median OS was 9.5 months (95% CI 6.7 to 11.8) for the high ERCC1 group compared to 15.6 months (95% CI 11.6 to 24.8) for the low ERCC1 group in the validation trial (log rank p-value = 0.007). The hazard ratio for low ERCC1 was 0.598 (95% CI, 0.394 to 0.908; p = 0.016) relative to high ERCC1 adjusted for age, sex, and histology. Conclusions: Patients with advanced NSCLC could be stratified into high and low ERCC1 expression groups. Patients with low levels benefited from platinum-based chemotherapy, whereas those with high levels did not.

Association between TYMS Expression and Efficacy of Pemetrexed–Based Chemotherapy in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

BackgroundThe predictive value of thymidylate synthase (TYMS) to sensitivity to pemetrexed-based chemotherapy in advanced non-small cell lung cancer (NSCLC) patients is controversial. We conducted a meta-analysis of all relevant published data to assess the association of TYMS expression with the clinical outcomes of pemetrexed-based regimen in advanced NSCLC.Patients and MethodsWe conducted an electronic search using using PubMed, Embase, OVID and Cochrane Library databases and manual search. Pooled odds ratio (OR) for the response rate and hazard ratio (HR) for the overall survival and progression free survival were calculated using the software Revman 5.0.ResultsThere were 11 studies (n=798) met our criteria for evaluation. Response rate to pemetrexed-based regimen was significantly higher in patients with low/negative TYMS (OR=2.96, 95%CI [1.81, 4.86] P<0.0001). Patients with low/negative TYMS who were treated with pemetrexed-based regimen had longer progression free survival (HR 0.50, 95%CI [0.41, 0.61] P <0.00001) and overall survival (HR 0.41, 95%CI [0.22, 0.78] P=0.007) than those with high/positive TYMS.ConclusionsLow/negative TYMS expression was significantly associated with higher response rate, longer median survival and longer progression free survival for advanced NSCLC patients receiving pemtrexed-based chemotherapy. Hence, TYMS may be a potential predictor of sensitivity to pemtrexed-based chemotherapy in advanced NSCLC. Large scale prospective clinical trials are still warranted.

The continuing role of chemotherapy for advanced non-small cell lung cancer in the targeted therapy era.

There have been remarkable advances in the targeted treatment of advanced non-small cell lung cancer (NSCLC) over the past several years. Survival outcomes are steadily improving as management paradigms shift in the diagnosis and treatment of advanced NSCLC. Customizing treatment based on histology and molecular typing has become a standard of care in this era of targeted therapy. While new chemotherapeutic agents have proven effective, the pivotal role of platinum-based chemotherapy doublets has been confirmed. Maintenance chemotherapy has become an option, but who to employ it in remains unclear in the real-world setting. Efforts to overcome resistance to targeted agents are ongoing utilizing combination regimens of chemotherapy plus targeted agents, but optimizing combination strategies needs further exploration. This review highlights recent developments in novel chemotherapeutics and in chemotherapy strategies over the past two years. Despite advances in molecular medicine, there remains an essential role for chemotherapy in advanced NSCLC, even in the recent targeted therapy era.

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.

Toward a Science of Research Prioritization? The Use of Value of Information by Multidisciplinary Stakeholder Groups

In this issue of Medical Decision Making, Carlson and others describe the process of convening an external group of diverse stakeholders to identify 3 high-priority cancer genomics tests for further research and to rank these in order of priority for conducting further research. The external multidisciplinary stakeholder advisory group involved 13 members, including patient advocates, payers, test developers, a regulator, policy makers, and practicing oncologists. This group committed to meet over 2 years to help the South West Oncology Group (SWOG) leadership and investigators identify and prioritize future research areas and to help assess where scarce research funds would be best spent. The stakeholder group began by identifying 3 topics for research from a larger number of possible options in the area of cancer genomic tests. They were provided with a landscape review, and they developed priority-setting criteria in collaboration with the SWOG investigators to undertake this process. They identified 3 genomic tests for which further research would be useful: 1) ERCC1 expression testing for platinum-based adjuvant therapy in fully resected earlystage non–small cell lung cancer (NSCLC); 2) epidermal growth factor receptor (EGFR) mutation testing for erlotinib maintenance therapy after firstline chemotherapy in advanced NSCLC, and 3) breast cancer tumor markers (BC markers) for detection of recurrence after primary breast cancer therapy. The stakeholder group was subsequently provided with value of information (VOI) analyses to quantify the value of conducting further research on each of these genomic tests. More specifically, they were provided with expected value of perfect information (EVPI) analyses, which estimate the upper level dollar value of reducing the uncertainty about which strategy is the optimal intervention. Providing the stakeholder group with these analyses involved a number of complex steps: developing simulation models for each genomic test, calculating the EVPI, training the external group of stakeholders in understanding what these results mean and how to use them, and discussing the results and reranking their choices based on what they may have learned from the VOI analyses. Indeed, Carlson and colleagues describe how the stakeholder group ranking of the tests changed from 1) ERCC1, 2) EGFR, 3) BC markers to 1) ERCC1, 2) BC markers, 3) EGFR. The BC markers ranked higher relative to EGFR compared with the initial prioritization vote in part because the VOI analyses helped the stakeholders appreciate the benefits of studying a technology associated with high uncertainty. Of the stakeholders, 69% reported finding these analyses helpful and 53% reported that they changed their priority ranking because of the information provided by the VOI results. The science of research prioritization has made important advances over the past 20 years. Research prioritization has moved from an approach largely based on convening groups of experts for unstructured discussions to a scientific process that studies who and how to engage in priority-setting decisions and provides measurements of the value provided Received 11 March 2013 from Patient Centered Outcomes Research Institute (RLF); Department of Medicine, Department of Economics, and the Harris School of Public Policy Studies at the University of Chicago (DOM). Accepted for publication 20 March 2013.

Toxicity of Bevacizumab in Combination with Chemotherapy in Older Patients

Bevacizumab leads to improved survival for patients with metastatic colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) when added to chemotherapy. Little is known about factors associated with receipt of bevacizumab, or whether bevacizamab is associated with increased toxicity when added to chemotherapy. We conducted a prospective study of patients aged ≥65 years, which evaluated the association between geriatric assessment (GA) metrics and chemotherapy toxicity. We examined differences in characteristics and outcomes of patients with CRC and NSCLC cancers who received bevacizumab with chemotherapy versus chemotherapy alone. From a total of 207 patients, 27 (13%) received bevacizumab plus chemotherapy and 180 (87%) received chemotherapy alone. Groups were similar in sociodemographic and cancer characteristics. There were no baseline differences in GA domains except that patients with heart disease were less likely to receive bevacizumab (4% vs. 26%, p = .01). Seventy-eight percent of patients who had bevacizumab had grade 3-5 toxicity compared to only 57% who received chemotherapy alone (p = .06). Patients receiving bevacizumab were more likely to develop grade 3 hypertension than those who received chemotherapy alone (15% vs. 2%, p < .01). In multivariable analysis, factors associated with grade 3 or more toxicity included: bevacizumab (OR: 2.86, p = .04), CRC (OR: 2.54, p < .01), and baseline anemia (OR: 2.58, p = .03). Heart disease was more common in those who did not receive bevacizumab. Older patients who receive bevacizumab with chemotherapy have a higher odds of developing a grade 3-5 toxicity compared with those who receive chemotherapy alone.

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.

Chemotherapy plus Vandetanib or Chemotherapy Alone in Advanced Non-small Cell Lung Cancer: A Meta-analysis of Four Randomised Controlled Trials

AimsMost patients with advanced non-small cell lung cancer (NSCLC) require systemic chemotherapy. Vandetanib, targeting epidermal growth factor receptor and vascular endothelial growth factor receptor signalling in NSCLC, has recently been evaluated in combination chemotherapy in advanced NSCLC. However, the advantage of chemotherapy plus vandetanib over chemotherapy alone in advanced NSCLC remains largely unknown. A meta-analysis of randomised controlled trials was carried out to compare the efficacy and toxicity of chemotherapy plus vandetanib with chemotherapy alone in advanced NSCLC. Materials and methodsThe PubMed database, American Society of Clinical Oncology, European Society for Medical Oncology and the Cochrane Library and references of published trials were searched. Two reviewers independently assessed the quality of the trials. Data were extracted and the overall response rate, pooled progression-free survival, overall survival with 95% confidence intervals and main toxicity were analysed. ResultsFour randomised controlled trials involving 2160 patients with advanced NSCLC were ultimately analysed. Compared with chemotherapy alone, chemotherapy plus vandetanib significantly increased the overall response rate (relative risk = 1.96, 95% confidence interval = 1.53––2.52) and progression-free survival (hazard ratio = 0.79, 95% confidence interval = 0.71–0.87), but there was no significant difference in overall survival (hazard ratio = 0.91, 95% confidence interval = 0.79–1.03). Patients who received chemotherapy plus vandetanib had more rash, diarrhoea, hypertension and QTc prolongation (odds ratio = 2.32, 95% confidence interval = 1.93–2.79; odds ratio = 1.64, 95% confidence interval = 1.37–1.97; odds ratio = 4.08, 95% confidence interval = 2.51–6.01, odds ratio = 17.77, 95% confidence interval = 3.54–61.66, respectively), and less nausea and vomiting (odds ratio = 0.70, 95% confidence interval = 0.58–0.85; odds ratio = 0.69, 95% confidence interval = 0.55–0.86, respectively). The incidences of haemorrhage, fatigue and cough were comparable between the two groups. ConclusionsAlthough similar in overall survival, chemotherapy plus vandetanib showed particular advantages over chemotherapy alone in terms of progression-free survival and overall response rate. The toxicity was comparable between the two groups. Therefore, chemotherapy plus vandetanib might be a safe and valid therapeutic option for advanced NSCLC patients.

MIS4-12 - Tumor Response and Survival in Patients with Advanced Non-Small-Cell Lung Cancer: The Predictive Value of Chemotherapy-Induced Changes in Fibrinogen

ABSTRACT Background Hyperfibrinogenemia is a common problem associated with various carcinomas. In advanced non-small-cell lung cancer (NSCLC), whether chemotherapy-induced changes in fibrinogen level relate to chemotherapeutic response and prognosis remains unclear. The purposes of this study were: (i) to analyze the correlation between the chemotherapy-induced changes of plasma fibrinogen level and the chemotherapeutic response after the first two courses of standard first-line platinum-based chemotherapy; and (ii) to evaluate the prognostic significance of the basal plasma fibrinogen level in patients with advanced NSCLC. Methods In this retrospective study, the data of 160 patients with advanced NSCLC in the First Hospital of China Medical University were collected and analyzed using SPSS software. Results The median pre-chemotherapy plasma fibrinogen level was 4.4 g/l.Pre-chemotherapy plasma fibrinogen levels correlated significantly with gender (P = 0.041) and age (P = 0.007). Post-chemotherapy plasma fibrinogen levels correlated with gender (P = 0.023), age (P = 0.004), ECOG (P = 0.002) and tumor response (P = 0.049). Plasma fibrinogen levels markedly decreased after chemotherapy in 98 (61.25%) patients with pre-chemotherapy hyperfibrinogenemia (P = 0.008); and in this population, there was a significant link between the decrease in fibrinogen level, and initial partial response (PR; P = 0.017) and stable disease (SD; P = 0.031). Univariate and multivariate analysis revealed that higher values of fibrinogen (more than 4.4 g/l) and ECOG 1 were positively associated with shorter overall survival (OS). Conclusions This study showed that a reduction in plasma fibrinogen levels induced by chemotherapy might be a promising biomarker for evaluating the efficacy of chemotherapy in advanced NSCLC. In addition, basal plasma fibrinogen levels could be used as an independent prognostic parameter for the overall survival of patients with advanced NSCLC.