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An editorial is presented on metastatic non-small-cell lung cancer (NSCLC) treatment. Topics mentioned include the importance of cisplatin-based chemotherapy to NSCLC treatment, the importance of the identification of mutations that causes the progression of lung cancer, and the immunohistochemical testing of tumor cells. Also mentioned are the cost of chemotherapy-immunotherapy and the effectiveness of carboplatin-pemetrexed-pembrolizumab therapy for NSCLC.

Abstract: Introduction: Estrogen receptor beta (ERβ) has been detected in non-small cell lung cancer (NSCLC) cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the epidermal growth factor receptor (EGFR) inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored. Methods: Post-menopausal women with advanced NSCLC received gefitinib 250mgpo daily and fulvestrant 250mgIM monthly. Results: Twenty-two patients were enrolled. Eight patients had adenocarcinoma, six NSCLC-NOS, four squamous cell, and four BAC. Seven patients were never-smokers. Eight patients received ≥2 lines of prior chemotherapy, six received one prior chemotherapy, and eight were treatment-naïve. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (response rate of 15%, 95% CI: 5–36%). The median progression-free survival (PFS), overall survival (OS), and estimated 1-year OS were 12 weeks (3–112 weeks), 38.5 weeks (7–135 weeks), and 41% (95% CI: 20–62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the eight patients whose tumors exhibited at least 60% ERβ nuclear IHC staining measured 65.5 weeks, while that of the five patients with ERβ staining of less than 60% was 21 weeks. One patient with bronchioalveolar carcinoma (BAC) and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERβ IHC expression and histology or smoking history. Conclusions: Combination therapy with gefitinib and fulvestrant in this population was well tolerated and demonstrated disease activity. [Copyright &y& Elsevier]

Expression of epidermal growth factor and its transmembrane receptor (EGFR) stimulates tumor growth. Matuzumab is a humanized anti-EGFR monoclonal antibody that blocks EGFR activation and downstream signaling, inhibits tumor growth, and provides a clinical benefit for some patients. The plasma half-life (6-10 days) and pharmacodynamic activity allow flexible dosing on weekly, every-2-week, and every-3-week schedules. Matuzumab has shown single-agent antitumor activity in heavily pretreated patients with a variety of tumors, with a favorable safety profile. Skin rash is the most common toxicity, but is severe (Grade 3) in < 1 percent. This article describes preclinical and clinical development of matuzumab. [ABSTRACT FROM AUTHOR]

Although most lung cancers are a result of smoking, approximately 25% of lung cancer cases worldwide are not attributable to tobacco use, accounting for over 300,000 deaths each year. Striking differences in the epidemiological, clinical and molecular characteristics of lung cancers arising in never smokers versus smokers have been identified, suggesting that they are separate entities. This Review summarizes our current knowledge of this unique and poorly understood disease. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer death worldwide. The disease is particularly difficult to detect, and patients often present at an advanced stage. Current treatments have limited effectiveness, and unfortunately, the prognosis remains poor. Recent insights into the molecular pathogenesis and biologic behavior of lung cancer have led to the development of rationally designed methods of early detection, prevention, and treatment of this disease. This article will review the important clinical implications of these advances, with a focus on new molecularly targeted therapies currently in development. [ABSTRACT FROM AUTHOR]

Abstract: Despite improvements in cytotoxic chemotherapy and combined modality therapies for lung cancer, the prognosis for patients remains poor, and the majority of patients die from the disease. Angiogenesis, i.e. the formation of new blood vessels, is important for tumor growth, invasion and metastasis and represents a rational target in the development of more effective treatments. The vascular endothelial growth factor (VEGF) signaling pathway plays a crucial role in the angiogenic process and consequently, inhibitors of this system are currently under development. The most studied anti-angiogenic agents include anti-VEGF monoclonal antibodies and VEGF receptor tyrosine kinase inhibitors. Recent clinical trials have yielded promising results. This article will review angiogenesis inhibitors targeting the VEGF pathway which are currently being developed for the treatment of lung cancer. [Copyright &y& Elsevier]

Small cell lung cancer (SCLC) is characterized by early dissemination and a rapid, aggressive clinical course. It has, however, marked susceptibility to both chemotherapy and radiotherapy, although treatment is complicated by the fact that SCLC tumors invariably develop resistance to multiple chemotherapeutic agents. Local therapy is rarely of benefit in SCLC because three-quarters of patients present with metastatic disease and many of the remaining patients are thought to have micrometastatic disease. Chemotherapy is, therefore, the cornerstone of treatment. Of the many combination regimens used, etoposide/cisplatin or etoposide/carboplatin have emerged as the regimens of choice because they offer a good therapeutic index and can be combined with radiotherapy. Response to second-line therapy remains consistently poor. As the prototype platinum compound, cisplatin has played a major role in the management of SCLC. Although its exact contribution to the treatment of SCLC has been difficult to ascertain, a recent meta-analysis reported a significant 1-year survival advantage of approximately 4% with cisplatin-containing regimens versus regimens without. However, cisplatin is characterized by several serious adverse events and, like other chemotherapeutic agents, is eventually rendered ineffective against SCLC because of acquired resistance. Several new platinum formulations or compounds are showing promising activity in SCLC. The impetus for their development has been to circumvent cisplatin resistance or to improve upon the toxicity profile of cisplatin. If the early promise shown by these compounds is confirmed in the clinic, they may offer a new approach to the treatment of SCLC, including recurrent disease for which limited treatment options are currently available.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related death in the United States, accounting for over 30% of cancer deaths in men and 25% in women. Small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) are uniformly aggressive tumors, with rates of regional or distant metastases at diagnosis as high as 70%. Because the majority of these tumors are unresectable, patients with relatively good performance status receive platinum-based chemotherapy. Although no treatment consensus exists, currently recommended regimens for SCLC include PE (cisplatin and etoposide), CAV (cyclophosphamide, doxorubicin, and vincristine), CAE (cyclophosphamide, doxorubicin, and etoposide), and CAVE (cyclophosphamide, doxorubicin, vincristine, and etoposide). Of these, the PE regimen has been widely accepted in the United States, although CE (carboplatin and etoposide) provides better tolerability. For NSCLC, standard chemotherapy regimens have included platinum-based therapy (cisplatin and a vinca alkaloid or PE). Data from recent studies suggest that the addition of paclitaxel to platinum modestly improves tumor response and survival in NSCLC. Although SCLC and NSCLC are both responsive to first-line chemotherapy, most patients relapse and die from their disease, with 5-year survival rates of approximately 15%. Given the disappointing survival rates associated with SCLC and NSCLC, the introduction of new cytotoxic agents has been eagerly anticipated. Evidence of improved response and extended survival is mounting for various combinations of established regimens (e.g., PE) with newer drugs exhibiting novel mechanisms of action and single-agent antitumor activity, such as gemcitabine, paclitaxel, docetaxel, vinorelbine, and topotecan. This article reviews the current standards of care in SCLC and NSCLC, and introduces the potential role of newer agents given in combination with standard chemotherapy.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Topotecan (HYCAMTIN[sup ®] ; GlaxoSmithKline, Brentford, Middlesex, UK) is a novel topoisomerase I inhibitor with potentially broad applicability in the treatment of solid and hematologic malignancies. In addition to its use in relapsed small-cell lung cancer (SCLC), topotecan is under investigation in numerous studies for first-line therapy in SCLC and for first- and second-line treatment of non-small-cell lung cancer (NSCLC). Preliminary evidence presented in this supplement demonstrates that single-agent topotecan and topotecan-based combination regimens are active in these settings. In addition to its potential use in SCLC and NSCLC, the feasibility and antitumor activity of topotecan as single-agent therapy and in combination therapy are under active investigation in a variety of other solid and hematologic tumors. Other important avenues of investigation include the feasibility and tumor activity of a more convenient oral formulation, as well as the investigation of alternate regimens (e.g., 3-day, weekly), with high priority given to regimen toxicity, patient convenience, and quality of life. Preliminary results of some of these trials are presented in this summary. The results of other clinical experience trials are eagerly anticipated.Copyright © 2001 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Plain language summary Lung cancer in women is a modern epidemic and represents a global health crisis. Cigarette smoking remains the most important risk factor for lung cancer in all patients and, among women globally, rates of smoking continue to increase. Although some data exist supporting sex‐based differences across the continuum of lung cancer, there is currently a dearth of research exploring the differences in risk, biology, and treatment outcomes in women. Consequently, the American Cancer Society National Lung Cancer Roundtable recognizes the urgent need to promote awareness and future research that will close the knowledge gaps regarding lung cancer in women. To this end, the American Cancer Society National Lung Cancer Roundtable Task Group on Lung Cancer in Women convened a summit undertaking the following to: (1) summarize existing evidence and identify knowledge gaps surrounding the epidemiology, risk factors, biologic differences, and outcomes of lung cancer in women; (2) develop and prioritize research topics and questions that address research gaps and advance knowledge to improve quality of care of lung cancer in women; and (3) propose strategies for future research. Lung cancer is the leading cause of cancer mortality in women, and, despite comparatively lower exposures to occupational and environmental carcinogens compared with men, disproportionately higher lung cancer rates in women who ever smoked and women who never smoked call for increased awareness and research that will close the knowledge gaps regarding lung cancer in women. Lung cancer is the leading cause of cancer mortality in women, and, despite comparatively lower exposures to occupational and environmental carcinogens compared with men, disproportionately higher lung cancer rates in women who ever smoked and women who never smoked call for increased awareness and research that will close the knowledge gaps regarding lung cancer in women. [ABSTRACT FROM AUTHOR]

The author reflects on the noninvasive monitoring of tumors. She suggests that despite results achieved with conventional chemotherapeutic agents, decades worth of cancer research has yielded therapeutic results based on an understanding of cancer biology. She argues that it is important to monitor tumors to determine whether cancer treatment is effective and that the ability to detect genetic markers that guide treatment is essential to identifying appropriate treatment for cancer patients.

An introduction is presented in which the editor discusses various reports within the issue on topics including gene expression signature, personalized medicine applications and prognostic factor for breast cancer.

Discusses treatments for advanced non-small-cell lung cancer (NSCLC). Randomized trials that evaluated the addition of an additional cytotoxic drug to a single agent or a double-agent regimen in advanced, incurable NSCLC; Methodologic deficiencies identified in this study.

Provides information on several therapeutic options for lung cancer.

Presents a question-and-answer advisory on issues in medicine. Prognosis with asymptomatic pulmonary nodules; Allergic rhinitis in an allergy clinic nurse; Adult respiratory distress syndrome after smoke inhalation from burning poison ivy; Combination drug therapy for benign prostatic hyperplasia.

The article presents a study which examines the role of DNA biomarkers to assess therapy and chemoprevention for non-small cell lung cancer. It is mentioned that methylation of multiple gene promoters in sputum is strongly associated with lung cancer risk and reinforces the use of gene methylation as a biomarker in the prevention trial. The study also revealed that sputum can be used as a surrogate for tumor tissue to predict the methylation status of advanced lung cancer in cases where biopsy is not feasible. Additionally, a bar graph which shows the frequency of methylation of multiple genes in sputum obtained from lung cancer survivors and smokers is presented.

Background: We conducted a randomized study to determine whether any of three chemotherapy regimens was superior to cisplatin and paclitaxel in patients with advanced non–small-cell lung cancer. Methods: A total of 1207 patients with advanced non–small-cell lung cancer were randomly assigned to a reference regimen of cisplatin and paclitaxel or to one of three experimental regimens: cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel. Results: The response rate for all 1155 eligible patients was 19 percent, with a median survival of 7.9 months (95 percent confidence interval, 7.3 to 8.5), a 1-year survival rate of 33 percent (95 percent confidence interval, 30 to 36 percent), and a 2-year survival rate of 11 percent (95 percent confidence interval, 8 to 12 percent). The response rate and survival did not differ significantly between patients assigned to receive cisplatin and paclitaxel and those assigned to receive any of the three experimental regimens. Treatment with cisplatin and gemcitabine was associated with a significantly longer time to the progression of disease than was treatment with cisplatin and paclitaxel but was more likely to cause grade 3, 4, or 5 renal toxicity (in 9 percent of patients, vs. 3 percent of those treated with cisplatin plus paclitaxel). Patients with a performance status of 2 had a significantly lower rate of survival than did those with a performance status of 0 or 1. Conclusions: None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non–small-cell lung cancer. (N Engl J Med 2002;346:92-8.) [ABSTRACT FROM AUTHOR]

Abstract: Introduction: We conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel, docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen. Methods: We retrospectively analyzed data from E1594, a front-line phase III study in which advanced NSCLC patients were randomized to receive one of four regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel. Patients were classified into four histology groups: squamous cell (SCC), adeno- (AC), large cell (LCC) and others including not otherwise specified (O/NOS) carcinoma. Logrank test was performed to compare overall survival (OS) and progression free survival (PFS) distributions according to histology as well as treatment. Results: Of 1139 patients including 716 men and 423 women, AC was the most common subtype (56.8%), followed by SCC (19.7%), O/NOS (17.0%) and LCC (6.5%). Men were more likely to have SCC and women were more likely to have AC (p =0.002). Among the four histology groups, there was no imbalance in regard to race, performance status, weight loss, brain metastasis or treatment. In each histology group, we found no significant difference in OS and PFS between the four chemotherapy regimens. Conversely, in each treatment arm, the survival outcome was similar between the four histology subtypes. Conclusions: Our analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel, docetaxel or gemcitabine. [Copyright &y& Elsevier]

Sunitinib in combination with docetaxel enhances antitumor activity in xenograft models of human breast and non-small cell lung cancer. We assessed the maximum tolerated doses (MTDs), safety, pharmacokinetic profiles, and preliminary efficacy of sunitinib plus docetaxel in patients with advanced solid tumors. In this phase I study, successive patient cohorts received sunitinib 25, 37.5, or 50 mg/day for 4 weeks of a 6-week cycle (Schedule 4/2, 4 weeks on, 2 weeks off) or for 2 weeks of a 3-week cycle (Schedule 2/1, 2 weeks on, 1 week off) with docetaxel 60 or 75 mg/m2 IV q21d to determine the MTDs of this treatment combination. Fifty patients enrolled: 10 on Schedule 4/2 and 40 on Schedule 2/1. MTDs were established as sunitinib 25 mg on Schedule 4/2 with docetaxel 60 mg/m2 q21d, and as sunitinib 37.5 mg on Schedule 2/1 with docetaxel 75 mg/m2 q21d. On Schedule 2/1, the most frequent dose-limiting toxicity was neutropenia (±fever; grade [G]3/4, n = 5) and the most common G3/4 non-hematologic adverse event (AE) was fatigue (G3, n = 8). Hematologic AEs were managed with growth factor support in 11 of 23 (48%) patients treated at Schedule 2/1 MTD. Three patients achieved a partial response at the Schedule 2/1 MTD. There were no pharmacokinetic drug–drug interactions with either schedule. Oral sunitinib 37.5 mg/day on Schedule 2/1 with docetaxel 75 mg/m2 IV q21d is a clinically feasible regimen with a manageable safety profile, no pharmacokinetic drug–drug interactions, and shows antitumor activity in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

People who suffer from disease have often been stigmatised. The internalisation of stigma leads to the experience of self-blame. The relationship among stigma, self-blame and adjustment was framed with two theoretical perspectives: the looking-glass self and learned helplessness models. These models were studied in 96 lung, 30 breast and 46 prostate cancer patients. Consistent with the looking-glass-self model, we predicted that perceived stigma and self-blame would be associated with poorer psychological adjustment; the data supported these hypotheses. Consistent with the learned helplessness model, we predicted that self-blame would mediate the link between perceived stigma and psychological adjustment; data supported these hypotheses. The mediation model explained a greater percentage of the variance in adjustment in the lung cancer sample compared to the breast and prostate cancer sample. Participants who reported internal causal attributions reported poorer psychological adjustment. Lung cancer patients were more likely than breast or prostate cancer patients to report internal causal attributions for their cancer. Future research and cancer care are discussed in light of these findings. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of cancer mortality in the US. For the majority of patients with advanced non-small cell lung cancer, chemotherapy with or without radiation therapy is the mainstay of treatment. Despite the modest improvement in survival for these patients, prognosis remains dismal. However, the expanding knowledge of tumor biology in recent years has resulted in the promising development of a new class of “molecularly targeted” agents, which selectively target cancer cells at the molecular, biochemical, and genetic level, thus minimizing toxic effects on normal tissues. A wide range of molecularly targeted agents are being actively investigated in lung cancer therapy as single agents or in combination with conventional modalities. In this review, we discuss some of the agents furthest along in development: epidermal growth factor receptor inhibitors, anti-angiogenic agents, inhibitors of biologically important enzymes such as matrix metalloproteinases and farnesyltransferase, gene therapy including gene replacement and antisense therapy, and cell cycle disruptors. [Copyright &y& Elsevier]

The article presents a case study of a 53-year-old Asian woman with brain and bone metastases and large lung mass. The patient experienced a progressive brain metastases after taking erlotinib and osimertinib. Evidence for continuing or stopping tyrosine kinase inhibitors (TKIs) or targeted therapy in patients with progressive lung cancer are discussed.

Background: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer.Methods: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline.Results: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006).Conclusions: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Societal perceptions may factor into the high rates of nontreatment in patients with lung cancer. To determine whether bias exists toward lung cancer, a study using the Implicit Association Test method of inferring subconscious attitudes and stereotypes from participant reaction times to visual cues was initiated. Participants were primarily recruited from an online survey panel based on US census data. Explicit attitudes regarding lung and breast cancer were derived from participants’ ratings (n = 1778) regarding what they thought patients experienced in terms of guilt, shame, and hope (descriptive statements) and from participants’ opinions regarding whether patients ought to experience such feelings (normative statements). Participants’ responses to descriptive and normative statements about lung cancer were compared with responses to statements about breast cancer. Analyses of responses revealed that the participants were more likely to agree with negative descriptive and normative statements about lung cancer than breast cancer (P<0.001). Furthermore, participants had significantly stronger implicit negative associations with lung cancer compared with breast cancer; mean response times in the lung cancer/negative conditions were significantly shorter than in the lung cancer/positive conditions (P<0.001). Patients, caregivers, healthcare providers, and members of the general public had comparable levels of negative implicit attitudes toward lung cancer. These results show that lung cancer was stigmatized by patients, caregivers, healthcare professionals, and the general public. Further research is needed to investigate whether implicit and explicit attitudes and stereotypes affect patient care. [ABSTRACT FROM AUTHOR]

Purpose Preclinical studies demonstrated anti-tumor efficacy of the combination of the histone deacetylase (HDAC) inhibitor romidepsin plus erlotinib in non-small cell lung cancer (NSCLC) models that were insensitive to erlotinib monotherapy. We therefore studied this combination in a phase 1 clinical trial in previously treated advanced NSCLC. Methods Romidepsin (8 or 10 mg/m 2 ) was administered intravenously on days 1, 8, and 15 every 28 days in combination with erlotinib (150 mg orally daily), with romidepsin monotherapy lead-in during Cycle 1. Correlative studies included peripheral blood mononuclear cell HDAC activity and histone acetylation status, and EGFR pathway activation status in skin biopsies. Results A total of 17 patients were enrolled. Median number of prior lines of therapy was 3 (range 1–5). No cases had a sensitizing EGFR mutation. The most common related adverse events were nausea, vomiting, and fatigue (each 82%), diarrhea (65%), anorexia (53%), and rash (41%). Dose-limiting nausea and vomiting occurred at the romidepsin 10 mg/m 2 level despite aggressive antiemetic prophylaxis and treatment. Among 10 evaluable patients, the best response was stable disease ( n = 7) and progressive disease ( n = 3). Median progression-free survival (PFS) was 3.3 months (range 1.4–16.5 months). Prolonged PFS (>6 months) was noted in a KRAS mutant adenocarcinoma and a squamous cell cancer previously progressed on erlotinib monotherapy. Romidepsin monotherapy inhibited HDAC activity, increased histone acetylation status, and inhibited EGFR phosphorylation. Conclusions Romidepsin 8 mg/m 2 plus erlotinib appears well tolerated, has evidence of disease control, and exhibits effects on relevant molecular targets in an unselected advanced NSCLC population. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC).Methods: Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test.Results: From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively.Conclusions: On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background: Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC.Methods: Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs).Results: Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival.Conclusion: Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC. [ABSTRACT FROM AUTHOR]

Background Although stigma may have negative psychosocial and behavioral outcomes for patients with lung cancer, its measurement has been limited. A conceptual model of lung cancer stigma and a patient-reported outcome measure are needed to mitigate these sequelae. This study identified key stigma-related themes to provide a blueprint for item development through a thematic analysis of semi-structured interviews and focus groups with lung cancer patients. Methods Participants were recruited from two outpatient oncology clinics and included (i) 42 lung cancer patients who participated in individual interviews and (ii) 5 focus groups (inclusive of 23 new lung cancer patients). Never smokers, long-term quitters, recent quitters, and current smokers participated. Individual interviews facilitated theme development and a conceptual model of lung cancer stigma, whereas subsequent focus groups provided feedback on the conceptual model. Qualitative data analyses included iterative coding and validation with existing theory. Results Two main thematic elements emerged from interviews with lung cancer patients: perceived (felt) stigma and internalized (self) stigma. Discussions of perceived stigma were pervasive, whereas those of internalized stigma were more commonly endorsed among current and recently quit smokers. Participants also discussed maladaptive (e.g., decreased disclosure) and adaptive (e.g., increased advocacy) stigma-related consequences. Conclusions Results indicate widespread acknowledgment of perceived stigma among lung cancer patients but varying degrees of internalized stigma and associated consequences. Next steps for patient-reported outcome measure development are item consolidation, item development, expert input, and cognitive interviews before field testing and psychometric analysis. Future work should address stigma-related consequences and interventions for reducing lung cancer stigma. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: In this study, the authors examined the effectiveness of an online support system (Comprehensive Health Enhancement Support System [CHESS]) versus the Internet in relieving physical symptom distress in patients with non-small cell lung cancer (NSCLC).Methods: In total, 285 informal caregiver-patient dyads were assigned randomly to receive, for up to 25 months, standard care plus training on and access to either use of the Internet and a list of Internet sites about lung cancer (the Internet arm) or CHESS (the CHESS arm). Caregivers agreed to use CHESS or the Internet and to complete bimonthly surveys; for patients, these tasks were optional. The primary endpoint-patient symptom distress-was measured by caregiver reports using a modified Edmonton Symptom Assessment Scale.Results: Caregivers in the CHESS arm consistently reported lower patient physical symptom distress than caregivers in the Internet arm. Significant differences were observed at 4 months (P = .031; Cohen d = .42) and at 6 months (P = .004; d = .61). Similar but marginally significant effects were observed at 2 months (P = .051; d = .39) and at 8 months (P = .061; d = .43). Exploratory analyses indicated that survival curves did not differ significantly between the arms (log-rank P = .172), although a survival difference in an exploratory subgroup analysis suggested an avenue for further study.Conclusions: The current results indicated that an online support system may reduce patient symptom distress. The effect on survival bears further investigation. [ABSTRACT FROM AUTHOR]

BACKGROUND: In this study, the authors examined the effectiveness of an online support system (Comprehensive Health Enhancement Support System [CHESS]) versus the Internet in relieving physical symptom distress in patients with non-small cell lung cancer (NSCLC). METHODS: In total, 285 informal caregiver-patient dyads were assigned randomly to receive, for up to 25 months, standard care plus training on and access to either use of the Internet and a list of Internet sites about lung cancer (the Internet arm) or CHESS (the CHESS arm). Caregivers agreed to use CHESS or the Internet and to complete bimonthly surveys; for patients, these tasks were optional. The primary endpoint-patient symptom distress-was measured by caregiver reports using a modified Edmonton Symptom Assessment Scale. RESULTS: Caregivers in the CHESS arm consistently reported lower patient physical symptom distress than caregivers in the Internet arm. Significant differences were observed at 4 months ( P = .031; Cohen d = .42) and at 6 months ( P = .004; d = .61). Similar but marginally significant effects were observed at 2 months ( P = .051; d = .39) and at 8 months ( P = .061; d = .43). Exploratory analyses indicated that survival curves did not differ significantly between the arms (log-rank P = .172), although a survival difference in an exploratory subgroup analysis suggested an avenue for further study. CONCLUSIONS: The current results indicated that an online support system may reduce patient symptom distress. The effect on survival bears further investigation. Cancer 2013. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background Because the efficacy of carboplatin and cisplatin in the treatment of advanced non-small-cell lung cancer (NSCLC) has not been proven to be equivalent, an individual patient data meta-analysis comparing the two treatments was performed. Methods Randomized trials comparing carboplatin to cisplatin in first-line treatment of advanced NSCLC were identified and their electronic databases obtained. A general variance-based method was used to estimate the summary hazard ratios (HRs), odds ratios (ORs), and their 95% confidence intervals (CIs) for mortality, objective response, and toxicity. Cochran's chi-square test (Q test) was used to test for heterogeneity among trials, and the /2 index, which expresses the proportion of variability of the results due to heterogeneity, was calculated. A random-effects model that takes into account interstudy variation was also applied. All statistical tests were two-sided. Results Nine trials that included a total of 2968 patients were analyzed; overall median follow-up was 1021 days. The objective response rate was higher for patients treated with cisplatin than for patients treated with carboplatin (30% versus 24%, respectively; OR = 1.37; 95% Cl = 1.16 to 1.61; P<.001). Carboplatin treatment was associated with a non-statistically significant increase in the hazard of mortality relative to treatment with cisplatin (HR = 1.07; 95% Cl = 0.99 to 1.15; P= .100). In patients with nonsquamous tumors and those treated with third-generation chemotherapy, carboplatin-based chemotherapy was associated with a statistically significant increase in mortality (HR = 1.12; 95% Cl= 1.01 to 1.23 and HR = 1.11; 95% Cl = 1.01 to 1.21, respectively). Cisplatin-based chemotherapy was associated with more severe nausea and vomiting and nephrotoxicity; severe thrombocytopenia was more frequent during carboplatin-based chemotherapy. Conclusions Our individual patient data meta-analysis suggests that cisplatin-based chemotherapy is slightly superior to carboplatin-based chemotherapy in terms of response rate and, in certain subgroups, in prolonging survival without being associated with an increase in severe toxic effects. Therefore, cisplatin-based third-generation regimens should remain the standard reference for the treatment of selected patients with advanced-stage NSCLC and of those with earlier-stage disease. [ABSTRACT FROM AUTHOR]

Summary: Purpose: We sought to determine the association of C/EBPα expression status with clinical, pathologic and molecular characteristics, as well as outcomes, in non-small-cell lung cancer (NSCLC). This is the first comprehensive study of this transcription factor in patients with NSCLC. Patients and methods: Our cohort originated from ECOG 3590 (randomized trial of postoperative adjuvant therapy with thoracic radiation or cisplatin and etoposide plus thoracic radiation in patients with completely resected stages II and IIIA NSCLC; and its laboratory correlate, ECOG 4592). One hundred and sixty four tumor samples contained sufficient material for immunohistochemical (IHC) analysis. C/EBPα tumor staining was compared to that of basal bronchial cells (3+). 0 or 1+ (weak) suggested lack of, while 2 or 3+ (strong) suggested C/EBPα expression. Results: Ninety tumors (55%) had 0 or 1+ C/EBPα staining, and the remaining 74 (45%) 2 or 3+. Patients with squamous cell carcinomas had a higher percentage of weak C/EBPα IHC staining compared to other histologies (p =0.048) and there was a trend for loss of C/EBPα in poorly differentiated compared to well differentiated tumors (p =0.07). There was no association between C/EBPα IHC and mutations in p53 or K-ras. The median disease-free survival for patients with weak and strong C/EBPα IHC expression was 29.6 and 30.6 months, respectively (p =0.94). The median overall survival between the weak and strong groups was 43.5 and 38.5 months, respectively (p =0.83). Conclusions: Loss of expression of C/EBPα is seen in over half of stage II and IIIA NSCLC, specifically in squamous cell carcinomas and poorly differentiated tumors. Since down-regulation of C/EBPα is a common event in NSCLC, further elucidation of the involvement of C/EBPα in the pathogenesis and progression of lung cancer may identify novel therapeutic targets. [Copyright &y& Elsevier]

Background. Docetaxel and topotecan are drugs with different mechanisms of action and significant activity against various tumour types. Topotecan may influence docetaxel metabolism by inhibiting the CYP3A4 enzyme. We designed a phase I study to evaluate the maximum tolerated dose of this combination and to assess the impact of pharmacokinetic interactions of the two drugs on toxicity. Methods. Docetaxel and topotecan were administered intravenously on day 1, and days 1 – 5 respectively, using a phase I dose escalation design. Plasma samples were analysed to determine docetaxel and topotecan concentration by HPLC with subsequent pharmacokinetic analysis using NONMEM. Results. Of the 17 patients enrolled in the trial, 11 had grade 3 and 4 neutropenia and 1 had grade 4 thrombocytopenia. Nonhaematological toxicities were less frequent. The maximum tolerated dose for docetaxel and topotecan were 60 mg/m2 on day 1 and 0.75 mg/m2 days 1 – 5, respectively. One patient had stable disease. Subjects with grade ≥ 3 haematologic toxicity had higher plasma docetaxel or topotecan area under the curve (AUC) (docetaxel 1.03 ± 0.11 mg-hr/L versus 0.73 ± 0.13 mghr/L; topotecan 65.8 ± 14.6 mcg-hr/L versus 41.6 ± 13.9 mcg-hr/L). There was no additive effect of the AUC of the two drugs on the likelihood of grade ≥ 3 haematologic toxicity by multiple logistic regression. Conclusion. The dose-limiting toxicity seen with the combination of docetaxel and topotecan was myelosuppression. Future trials will require growth factor support if this combination is pursued. [ABSTRACT FROM AUTHOR]

Context: More persons in the United States die from non–small cell lung cancer (NSCLC) than from breast, colorectal, and prostate cancer combined. In preclinical testing, oral gefitinib inhibited the growth of NSCLC tumors that express the epidermal growth factor receptor (EGFR), a mediator of cell signaling, and phase 1 trials have demonstrated that a fraction of patients with NSCLC progressing after chemotherapy experience both a decrease in lung cancer symptoms and radiographic tumor shrinkages with gefitinib. Objective: To assess differences in symptomatic and radiographic response among patients with NSCLC receiving 250-mg and 500-mg daily doses of gefitinib. Design, Setting, and Patients: Double-blind, randomized phase 2 trial conducted from November 2000 to April 2001 in 30 US academic and community oncology centers. Patients (N = 221) had either stage IIIB or IV NSCLC for which they had received at least 2 chemotherapy regimens. Intervention: Daily oral gefitinib, either 500 mg (administered as two 250-mg gefitinib tablets) or 250 mg (administered as one 250-mg gefitinib tablet and 1 matching placebo). Main Outcome Measures: Improvement of NSCLC symptoms (2-point or greater increase in score on the summed lung cancer subscale of the Functional Assessment of Cancer Therapy-Lung [FACT-L] instrument) and tumor regression (>50% decrease in lesion size on imaging studies). Results: Of 221 patients enrolled, 216 received gefitinib as randomized. Symptoms of NSCLC improved in 43% (95% confidence interval [CI], 33%-53%) of patients receiving 250 mg of gefitinib and in 35% (95% CI, 26%-45%) of patients receiving 500 mg. These benefits were observed within 3 weeks in 75% of patients. Partial radiographic responses occurred in 12% (95% CI, 6%-20%) of individuals receiving 250 mg of gefitinib and in 9% (95% CI, 4%-16%) of those receiving 500 mg. Symptoms improved in 96% of patients with partial radiographic responses. The overall survival at 1 year was 25%. Th... [ABSTRACT FROM AUTHOR]

Small cell lung cancer (SCLC) is highly sensitive to chemotherapy. Despite a dramatic initial response, however, most patients relapse. Given the activity of gemcitabine in non-small cell lung cancer (NSCLC), and early clinical trials suggesting activity of gemcitabine in chemo-naive SCLC patients, we conducted a phase II study to determine the efficacy and toxicities of gemcitabine in SCLC patients who have failed first-line chemotherapy. Gemcitabine 1250 mg/m2 was given intravenously on days 1 and 8, every 3 weeks. Eligibility criteria included prior treatment with only one chemotherapy regimen and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients with brain metastases were eligible. Results: Between April 1998 and October 2001, 27 patients were enrolled: 15 patients with sensitive (S) disease (recurred>3 months after first-line chemotherapy) and 12 patients with refractory (R) disease (failed<3 months after first-line chemotherapy). Median age was 61 (range 45–74). All patients had received prior platinum-based therapy involving etoposide and either cisplatin or carboplatin. There were one early death and two early withdrawals because of toxicity. No responses were observed. Of 24 patients who received at least two cycles of gemcitabine, only three achieved stable disease after six cycles while 21 progressed. The median time to progression (TTP) was 6 weeks in S group, 5.6 weeks in R group, and 6 weeks overall. After a minimum potential follow-up of almost 1 year for all patients, the median survival was 8.8 months in S group, 4.2 months in R group, and 6.4 months for the whole group. One-year survival rate was 33.3% in S group, 16.7% in R group, and 25.4% for all patients. Myelosuppression was the most commonly observed adverse effect, with grade 3/4 neutropenia in 30%, and grade 3 thrombocytopenia in 30%. One patient (3.7%) developed neutropenic fever. Respiratory failure and death, possibly related to pulmonary toxicity, was observed in one patient (3.7%). Conclusion: monotherapy gemcitabine as second-line agent has limited activity in previously treated SCLC. [Copyright &y& Elsevier]

Importance: Nomogram prognostic models can facilitate cancer patient treatment plans and patient enrollment in clinical trials. Objective: The primary objective is to provide an updated and accurate prognostic model for predicting the survival of advanced non-small-cell lung cancer (NSCLC) patients, and the secondary objective is to validate a published nomogram prognostic model for NSCLC using an independent patient cohort. Design: 1817 patients with advanced NSCLC from the control arms of 4 Phase III randomized clinical trials were included in this study. Data from 524 NSCLC patients from one of these trials were used to validate a previously published nomogram and then used to develop an updated nomogram. Patients from the other 3 trials were used as independent validation cohorts of the new nomogram. The prognostic performances were comprehensively evaluated using hazard ratios, integrated area under the curve (AUC), concordance index, and calibration plots. Setting: General community. Main outcome: A nomogram model was developed to predict overall survival in NSCLC patients. Results: We demonstrated the prognostic power of the previously published model in an independent cohort. The updated prognostic model contains the following variables: sex, histology, performance status, liver metastasis, hemoglobin level, white blood cell counts, peritoneal metastasis, skin metastasis, and lymphocyte percentage. This model was validated using various evaluation criteria on the 3 independent cohorts with heterogeneous NSCLC populations. In the SUN1087 patient cohort, the continuous risk score output by the nomogram achieved an integrated area under the receiver operating characteristics (ROC) curve of 0.83, a log-rank P -value of 3.87e−11, and a concordance index of 0.717. In the SAVEONCO patient cohort, the integrated area under the ROC curve was 0.755, the log-rank P -value was 4.94e−6 and the concordance index was 0.678. In the VITAL patient cohort, the integrated area under the ROC curve was 0.723, the log-rank P -value was 1.36e−11, and the concordance index was 0.654. We implemented the proposed nomogram and several previously published prognostic models on an online Web server for easy user access. Conclusions: This nomogram model based on basic clinical features and routine lab testing predicts individual survival probabilities for advanced NSCLC and exhibits cross-study robustness. [ABSTRACT FROM AUTHOR]

Importance: Nomogram prognostic models can facilitate cancer patient treatment plans and patient enrollment in clinical trials. Objective: The primary objective is to provide an updated and accurate prognostic model for predicting the survival of advanced non-small-cell lung cancer (NSCLC) patients, and the secondary objective is to validate a published nomogram prognostic model for NSCLC using an independent patient cohort. Design: 1817 patients with advanced NSCLC from the control arms of 4 Phase III randomized clinical trials were included in this study. Data from 524 NSCLC patients from one of these trials were used to validate a previously published nomogram and then used to develop an updated nomogram. Patients from the other 3 trials were used as independent validation cohorts of the new nomogram. The prognostic performances were comprehensively evaluated using hazard ratios, integrated area under the curve (AUC), concordance index, and calibration plots. Setting: General community. Main outcome: A nomogram model was developed to predict overall survival in NSCLC patients. Results: We demonstrated the prognostic power of the previously published model in an independent cohort. The updated prognostic model contains the following variables: sex, histology, performance status, liver metastasis, hemoglobin level, white blood cell counts, peritoneal metastasis, skin metastasis, and lymphocyte percentage. This model was validated using various evaluation criteria on the 3 independent cohorts with heterogeneous NSCLC populations. In the SUN1087 patient cohort, the continuous risk score output by the nomogram achieved an integrated area under the receiver operating characteristics (ROC) curve of 0.83, a log-rank P -value of 3.87e−11, and a concordance index of 0.717. In the SAVEONCO patient cohort, the integrated area under the ROC curve was 0.755, the log-rank P -value was 4.94e−6 and the concordance index was 0.678. In the VITAL patient cohort, the integrated area under the ROC curve was 0.723, the log-rank P -value was 1.36e−11, and the concordance index was 0.654. We implemented the proposed nomogram and several previously published prognostic models on an online Web server for easy user access. Conclusions: This nomogram model based on basic clinical features and routine lab testing predicts individual survival probabilities for advanced NSCLC and exhibits cross-study robustness. [ABSTRACT FROM AUTHOR]

The article demonstrates a simple method for detection of a membrane protein from cell membrane extracts and crude cell lysates. The method does not require matched pairs of antibodies, as is required for surface-based fluorescence assays, nor does it require the complex instrumentation associated with methods, such as mass spectroscopy or surface plasmon spectroscopy. Because liquid crystals can be used to image regions of surfaces that have micrometer dimensions, high sensitivities are theoretically possible using the methods reported in this paper.

Background: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been shown to benefit patients with a variety of cancers. Methods: Between July 2001 and April 2004, the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study in which 878 patients with recurrent or advanced non–small-cell lung cancer (stage IIIB or IV) were assigned to chemotherapy with paclitaxel and carboplatin alone (444) or paclitaxel and carboplatin plus bevacizumab (434). Chemotherapy was administered every 3 weeks for six cycles, and bevacizumab was administered every 3 weeks until disease progression was evident or toxic effects were intolerable. Patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status, >1) were excluded. The primary end point was overall survival. Results: The median survival was 12.3 months in the group assigned to chemotherapy plus bevacizumab, as compared with 10.3 months in the chemotherapy-alone group (hazard ratio for death, 0.79; P=0.003). The median progression-free survival in the two groups was 6.2 and 4.5 months, respectively (hazard ratio for disease progression, 0.66; P<0.001), with corresponding response rates of 35% and 15% (P<0.001). Rates of clinically significant bleeding were 4.4% and 0.7%, respectively (P<0.001). There were 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group, including 5 from pulmonary hemorrhage. Conclusions: The addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with non–small-cell lung cancer has a significant survival benefit with the risk of increased treatment-related deaths. (ClinicalTrials.gov number, NCT00021060.) N Engl J Med 2006;355:2542-50. [ABSTRACT FROM AUTHOR]