Kong FM, Lally BE, Chang JY, et al.
ACR Appropriateness Criteria® radiation therapy for small-cell lung cancer.
Am J Clin Oncol. 2013; 36(2):206-13 [PubMed]

The current standard of care for small cell lung cancer is combined-modality therapy, including the use of chemotherapy, surgery (in selected cases of limited stage of disease), and radiation therapy. This review will focus on the role, dose fractionation, technology and timing of thoracic radiation, and the role and dose regimen of prophylactic cranial irradiation for both limited and extensive stage of diseases. Consensus recommendation from experts is summarized in the tables for 2 typical case scenarios. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

Yoshida T, Yoh K, Goto K, et al.
Safety and efficacy of platinum agents plus etoposide for patients with small cell lung cancer with interstitial lung disease.
Anticancer Res. 2013; 33(3):1175-9 [PubMed]

BACKGROUND: The safety and efficacy of combination of platinum agents plus etoposide for patients with small cell lung cancer (SCLC) with pre-existing interstitial lung disease (ILD) is uncertain.
PATIENTS AND METHODS: Fifty-two patients received platinum agents plus etoposide as first-line chemotherapy for SCLC with pre-existing ILD. The clinical characteristics, treatment outcome and survival of these patients were retrospectively reviewed.
RESULTS: During first-line chemotherapy, only one (2%) out of the 52 patients developed an acute exacerbation of ILD. The median number of treatment cycles was four. The overall response rate was 69%. The median progression-free survival period was 4.5 months. The median survival time was 9.4 months. Thirty-three patients (63%) received at least one subsequent chemotherapy regimen, and five of these patients developed acute exacerbation of ILD.
CONCLUSION: The combination of platinum agents plus etoposide is feasible and effective in SCLC patients with pre-existing ILD, compared with regimens after second-line chemotherapy.

Noro R, Yoshimura A, Yamamoto K, et al.
Alternating chemotherapy with amrubicin plus cisplatin and weekly administration of irinotecan plus cisplatin for extensive-stage small cell lung cancer.
Anticancer Res. 2013; 33(3):1117-23 [PubMed]

BACKGROUND: A phase II study was conducted in order to determine the tumor efficacy and tolerance of alternating chemotherapy for extensive-stage small cell lung cancer (ED-SCLC).
PATIENTS AND METHODS: Twenty patients with previously-untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of amrubicin and cisplatin with weekly administration of irinotecan and cisplatin at 3- or 4-week intervals.
RESULTS: The overall response rate was 85.0% (17/20). The median duration of overall survival and progression-free survival were 359 days and 227 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 20 (100%), 4 (20%) and 6 (30%) patients, respectively. With regard to non-hematological adverse events, grade 3 or 4 anorexia, diarrhea, febrile neutropenia and infection were observed in 5 (25%), 2 (10%), 2 (10%) and 2 (10%) patients, respectively. No treatment-related death occurred during either regimen.
CONCLUSION: The novel alternating non-cross-resistant chemotherapy was probably active against ED-SCLC and had acceptable toxicities. Further evaluation of this treatment for ED-SCLC in randomized phase III trials is warranted.

Houghton AM
Mechanistic links between COPD and lung cancer.
Nat Rev Cancer. 2013; 13(4):233-45 [PubMed]

Numerous epidemiological studies have consistently linked the presence of chronic obstructive pulmonary disease (COPD) to the development of lung cancer, independently of cigarette smoking dosage. The mechanistic explanation for this remains poorly understood. Progress towards uncovering this link has been hampered by the heterogeneous nature of the two disorders: each is characterized by multiple sub-phenotypes of disease. In this Review, I discuss the nature of the link between the two diseases and consider specific mechanisms that operate in both COPD and lung cancer, some of which might represent either chemopreventive or chemotherapeutic targets.

Kiani A, Khosravi A, Moghaddam AS, et al.
Long-term survival of a small cell lung cancer patient with proper endobronchial management.
Pneumologia. 2012 Oct-Dec; 61(4):245-8 [PubMed]

Small cell lung cancer (SCLC) is considered as a disease with poor prognosis and early metastasis with a very short survival. Endobronchial involvement is fairly common finding in SCLC and can cause respiratory symptoms. In this report we present a 47-year-old man diagnosed with small cell lung cancer. In the disease course, primary involvement of right bronchus spread to left bronchus and carina. Scheduled sessions of bronchoscopic interventions with electrocautery and argon plasma coagulation were used to maintain his large airways open. The intrabronchial interventions were accompanied by six courses of cisplatin-based chemotherapy as a standard treatment. Although patient's definite diagnosis was extensive SCLC, he remained in a good condition for 5 years. In last year of his follow up, headache and dizziness were added to his occasional respiratory symptoms. Brain MRI identified metastatic lesion in his brain. Hence, brain radiotherapy was suggested, but he refused further aggressive treatment. Seven months later, he died of brain metastatic lesion. Considering long survival of this patient with adequate and proper scheduled endobronchial interventions along with standard courses of chemotherapy, we conclude that this combined treatment strategy in patients with endobronchial involvement might increase survival.

Sakaeda M, Sato H, Ishii J, et al.
Neural lineage-specific homeoprotein BRN2 is directly involved in TTF1 expression in small-cell lung cancer.
Lab Invest. 2013; 93(4):408-21 [PubMed]

Thyroid transcription factor 1 (TTF1) plays crucial roles in thyroid, lung, and developing brain morphogenesis. Because TTF1-expressing neoplasms are generated from organs and tissues that normally express TTF1, such as the thyroid follicular epithelium and peripheral lung airway epithelium, TTF1 is widely used as a cell lineage-specific and diagnostic marker for thyroid carcinomas and for lung adenocarcinomas with terminal respiratory unit (TRU) differentiation. However, among lung neuroendocrine tumors, small-cell carcinomas (small-cell lung cancers (SCLCs)), most of which are generated from the central airway, also frequently express TTF1 at high levels. To clarify how SCLCs express TTF1, we investigated the molecular mechanisms of its expression using cultivated lung cancer cells and focusing upon neural cell-specific transcription factors. Both SCLC cells and lung adenocarcinoma cells predominantly expressed isoform 2 of TTF1, and TTF1 promoter assays in SCLC cells revealed that the crucial region for activation of the promoter, which is adjacent to the transcription start site of TTF1 isoform 2, has potent FOX-, LHX-, and BRN2-binding sites. Transfection experiments using expression vectors for FOXA1, FOXA2, LHX2, LHX6, and BRN2 showed that BRN2 substantially upregulated TTF1 expression, whereas FOXA1/2 weakly upregulated TTF1 expression. BRN2 and FOXA1/2 binding to the TTF1 promoter was confirmed through chromatin immunoprecipitation experiments, and TTF1 expression in SCLC cells was considerably downregulated after BRN2 knockdown. Furthermore, the TTF1 promoter in SCLC cells was scarcely methylated, and immunohistochemical examinations using a series of primary lung tumors indicated that TTF1 and BRN2 were coexpressed only in SCLC cells. These findings suggest that TTF1 expression in SCLC is a cell lineage-specific phenomenon that involves the developing neural cell-specific homeoprotein BRN2.

Joshi M, Ayoola A, Belani CP
Small-cell lung cancer: an update on targeted therapies.
Adv Exp Med Biol. 2013; 779:385-404 [PubMed]

Lung cancer is the leading cause of cancer-related deaths world-wide and small-cell lung cancer (SCLC) accounts for up to 25% of lung cancer deaths. There has been a considerable amount of research in the understanding of the depth of biology of SCLC and utilizing this knowledge to develop targeted approaches. The treatment of SCLC remains a challenge, despite remarkable initial efficacy to combination chemotherapy and radiation therapy. The response is usually short-lived and the prognosis of SCLC has not changed over the past few decades, necessitating the critical need for evaluating novel agents/therapies. Several signaling pathways have been found to be activated in SCLC tumor cells, forming a rationale for blocking some of the drugable targets. Molecular changes and biological markers have been identified but remain to be validated. Novel and targeted agents have been evaluated but without much success. Increasing understanding of the biology and potential clinical evaluation of biomarkers will pave the way for more effective treatments.

Komaki R, Khalid N, Langer CJ, et al.
Penetration of recommended procedures for lung cancer staging and management in the United States over 10 years: a quality research in radiation oncology survey.
Int J Radiat Oncol Biol Phys. 2013; 85(4):1082-9 [PubMed]

PURPOSE: To document the penetration of clinical trial results, practice guidelines, and appropriateness criteria into national practice, we compared the use of components of staging and treatment for lung cancer among patients treated in 2006-2007 with those used in patients treated in 1998-1999.
METHODS AND MATERIALS: Patient, staging work-up, and treatment characteristics were extracted from the process survey database of the Quality Research in Radiation Oncology (QRRO), consisting of records of 340 patients with locally advanced non-small cell lung cancer (LA-NSCLC) at 44 institutions and of 144 patients with limited-stage small cell lung cancer (LS-SCLC) at 39 institutions. Data were compared for patients treated in 2006-2007 versus those for patients treated in 1998-1999.
RESULTS: Use of all recommended procedures for staging and treatment was more common in 2006-2007. Specifically, disease was staged with brain imaging (magnetic resonance imaging or computed tomography) and whole-body imaging (positron emission tomography or bone scanning) in 66% of patients with LA-NSCLC in 2006-2007 (vs 42% in 1998-1999, P=.0001) and in 84% of patients with LS-SCLC in 2006-2007 (vs 58.3% in 1998-1999, P=.0011). Concurrent chemoradiation was used for 77% of LA-NSCLC patients (vs 45% in 1998-1999, P<.0001) and for 90% of LS-SCLC patients (vs 62.5% in 1998-1999, P<.0001). Use of the recommended radiation dose (59-74 Gy for NSCLC and 60-70 Gy as once-daily therapy for SCLC) did not change appreciably, being 88% for NSCLC in both periods and 51% (2006-2007) versus 43% (1998-1999) for SCLC. Twice-daily radiation for SCLC was used for 21% of patients in 2006-2007 versus 8% in 1998-1999. Finally, 49% of patients with LS-SCLC received prophylactic cranial irradiation (PCI) in 2006-2007 (vs 21% in 1998-1999).
CONCLUSIONS: Although adherence to all quality indicators improved over time, brain imaging and recommended radiation doses for stage III NSCLC were used in <90% of cases. Use of full thoracic doses and PCI for LS-SCLC also requires improvement.

Schaefer EA, Stohr S, Meister M, et al.
Stimulation of the chemosensory TRPA1 cation channel by volatile toxic substances promotes cell survival of small cell lung cancer cells.
Biochem Pharmacol. 2013; 85(3):426-38 [PubMed]

TRPA1, a member of the transient receptor potential (TRP) family of cation channels, has mainly been characterized as a chemosensory protein in neuronal cells. TRPA1 is activated by toxic or irritating volatile agents like allyl isothiocyanate (AITC), tear gas, formalin, or cigarette smoke. To date, little is known about a function of TRPA1 in non-neuronal cells in the respiratory system and even less regarding a possible role in cancer biology. Here, we show that TRPA1 is expressed in a panel of human small cell lung cancer (SCLC) cell lines. Of note, TRPA1 mRNA was also significantly higher expressed in tumor samples of SCLC patients as compared to non-SCLC tumor samples or non-malignant lung tissue. Stimulation of SCLC cells with AITC led to a rise of the intracellular calcium concentration. This calcium response was inhibited by TRPA1 antagonists. Furthermore, AITC or formalin stimulated ERK1/2 in TRPA1-expressing HEK293 cells and in SCLC cells via a Src- and calcium-dependent mechanism. More importantly, TRPA1 activation in SCLC cells prevented apoptosis induced by serum starvation and thus promoted cell survival, an effect which could be blocked by inhibition of TRPA1 or ERK1/2. Vice versa, down-regulation of TRPA1 severely impaired anchorage-independent growth of SCLC cells. Since TRPA1 appears to play a pivotal role for cell survival in SCLC cells we propose that this channel could represent a promising target for therapeutic interventions. Furthermore, our data suggest that exogenous, inhalable activators of TRPA1 could be able to exert tumor promoting effects in SCLC cells.

Adams J, Wu HH
The utility of fine-needle aspiration in the diagnosis of primary and metastatic tumors to the lung: a retrospective examination of 1,032 cases.
Acta Cytol. 2012; 56(6):590-5 [PubMed]

BACKGROUND: With the emergence of improved treatment strategies for patients with malignant lung tumors, it has become increasingly important to adequately diagnose and subclassify lung lesions. In our large retrospective study, we assessed the utility of fine-needle aspiration (FNA) in the diagnosis of primary and metastatic tumors to the lung.
METHODS: A computerized search of our laboratory informatics system was performed to identify cases from FNA of the lung and FNA of metastatic lung cancers to other sites. All of the corresponding surgical pathology reports were also reviewed. All of the cases were categorized as atypical (A), benign (B), malignant (M), nondiagnostic (ND), or suspicious (S) for data analysis purposes.
RESULTS: A total of 1,032 FNA cases were categorized as follows: 34 (3.3%) A, 142 (13.8%) B, 717 (69.5%) M, 121 (11.7%) ND, and 18 (1.7%) S. Of the 717 cases of malignant FNA, a specific tumor type was able to be rendered on cytomorphology alone or with the help of immunostains in 99% as follows: adenocarcinoma (296 cases, 41%), squamous cell carcinoma (158 cases, 22%), metastatic tumors (123 cases, 17%), small cell carcinoma (56 cases, 8%), non-small cell lung carcinoma (NSCLC) (58 cases, 8%), neuroendocrine carcinoma (15 cases, 2%), and poorly differentiated carcinoma (4 cases, 1%). Out of all NSCLC cases, 89% were able to be subclassified as either adenocarcinoma or squamous carcinoma. The most frequent origins of metastatic tumors to the lung were renal cell carcinoma (n = 22), melanoma (n = 17), colon (n = 15), breast (n = 14), and urothelial carcinoma (n = 10). There was also metastasis from 18 other organs with fewer than 5 cases each. There were 333 correlated histologic specimens including 191 small biopsies and 142 resection specimens. Diagnostic sensitivity and specificity for malignancy were 96 and 100%, respectively. Diagnostic accuracy was 97%. Sampling error resulted in 8 false-negative cases on FNA.
CONCLUSIONS: FNA is both sensitive and specific in the diagnosis and subclassification of both primary and metastatic lung tumors. Eighty-nine percent of NSCLC cases were able to be further subclassified as adenocarcinoma or squamous cell carcinoma by FNA.

Reymen B, Van Loon J, van Baardwijk A, et al.
Total gross tumor volume is an independent prognostic factor in patients treated with selective nodal irradiation for stage I to III small cell lung cancer.
Int J Radiat Oncol Biol Phys. 2013; 85(5):1319-24 [PubMed]

PURPOSE: In non-small cell lung cancer, gross tumor volume (GTV) influences survival more than other risk factors. This could also apply to small cell lung cancer.
METHODS AND MATERIALS: Analysis of our prospective database with stage I to III SCLC patients referred for concurrent chemo radiation therapy. Standard treatment was 45 Gy in 1.5-Gy fractions twice daily concurrently with carboplatin-etoposide, followed by prophylactic cranial irradiation (PCI) in case of non-progression. Only fluorodeoxyglucose (FDG)-positron emission tomography (PET)-positive or pathologically proven nodal sites were included in the target volume. Total GTV consisted of post chemotherapy tumor volume and pre chemotherapy nodal volume. Survival was calculated from diagnosis (Kaplan-Meier ).
RESULTS: A total of 119 patients were included between May 2004 and June 2009. Median total GTV was 93 ± 152 cc (7.5-895 cc). Isolated elective nodal failure occurred in 2 patients (1.7%). Median follow-up was 38 months, median overall survival 20 months (95% confidence interval = 17.8-22.1 months), and 2-year survival 38.4%. In multivariate analysis, only total GTV (P=.026) and performance status (P=.016) significantly influenced survival.
CONCLUSIONS: In this series of stage I to III small cell lung cancer patients treated with FDG-PET-based selective nodal irradiation total GTV is an independent risk factor for survival.

Stathopoulos GP, Trafalis D, Dimitroulis J, et al.
Combination of three cytotoxic agents in small-cell lung cancer.
Cancer Chemother Pharmacol. 2013; 71(2):413-8 [PubMed] Free Access to Full Article

PURPOSE: The established treatment for small-cell lung cancer has been a cisplatin-etoposide combination, as the most effective chemotherapy regimen. Paclitaxel has also been used in combination with cisplatin and etoposide but this has been unacceptable due to the toxicity. This toxicity could be attributed to the three consequent days of treatment with etoposide plus the doses of each of the three drugs. Our objectives were to determine an equal or longer survival and lower toxicity by administering all 3 drugs with low dosage on day one, compared to the established guideline of 3-day administration.
METHODS: We tested the aforementioned three-drug combination and avoided the toxicity in the majority of patients by administering all 3 drugs on day one. Fifty-one patients (50 evaluable) were recruited from 4 oncology clinics. All patients had histologically or cytologically confirmed small-cell lung cancer with limited and extensive disease in 40 and 60 % of the patients, respectively. The treatment was: cisplatin 75 mg/m(2), etoposide 120 mg/m(2) (maximum 200 mg), and paclitaxel 135 mg/m(2). The agents were administered on day one and repeated every 3 weeks for 6 cycles.
RESULTS: The median survival was 15 months (95 % CI 13.6-16.4) (mean 16 months). Forty-five (90 %) patients achieved a response: 20 (40 %) patients, a complete response and 25 (50 %), a partial response. Adverse reactions included grade 3 and 4 neutropenia in 12 and 2 % of the patients, respectively. Other side effects were of very low toxicity.
CONCLUSION: The 1-day, three-agent (cisplatin-etoposide-paclitaxel) treatment of small-cell lung cancer is beneficial with respect to response rate and survival, and the toxicity is low and well-tolerated.

Oshita F, Sugiura M, Murakami S, et al.
Phase II study of nedaplatin and irinotecan in patients with extensive small-cell lung cancer.
Cancer Chemother Pharmacol. 2013; 71(2):345-50 [PubMed]

BACKGROUND: The standard chemotherapy for Japanese patients with extensive disease of small-cell lung cancer (ED-SCLC) is cisplatin and irinotecan.
METHODS: Patients with untreated ED-SCLC were treated with nedaplatin (NP) at 50 mg/m(2) and irinotecan (CPT) at 50 mg/m(2) on days 1 and 8 every 4 weeks for four cycles.
RESULTS: Twenty-five patients were registered. Nineteen patients were male and six female, with a median age of 64 years (50-79 years). Two patients had a performance status of 2. Nineteen of them were able to receive 4 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia occurred in 8.0, 68.0, and 36.0 % of patients, respectively. Other grade 3 toxicities were SGOT, hyponatremia, fatigue, vomiting, diarrhea, hypotension, febrile neutropenia, oral hemorrhage, and pneumonia. Grade 4 fatigue occurred in one patient. There was no treatment-related death. The overall response rate was 100 %. The median progression-free and overall survivals were 6.6 and 16.0 months, respectively, and the 2-year survival rate was 28 %.
CONCLUSION: NP with CPT is effective and safe for patients with ED-SCLC.

Chen YT, Feng B, Chen LB
Update of research on drug resistance in small cell lung cancer chemotherapy.
Asian Pac J Cancer Prev. 2012; 13(8):3577-81 [PubMed]

Small cell lung cancer (SCLC) is characterized by a short cell doubling time, rapid progression and early occurrence of blood-borne and lymph metastasis. The malignancy is the highest of all lung cancer types. Although SCLC has a relatively good initial response to chemotherapy as well as radiotherapy, relapse or disease progression may occur quickly after the initial treatment. Drug resistance, especially multi-drug resistance, is the most important cause of failure of SCLC chemotherapy. This article provides a brief update of research on mechanisms of drug resistance in SCLC and reversal strategies.

Wang B, Peng XX, Sun R, et al.
Systematic review of β-elemene injection as adjunctive treatment for lung cancer.
Chin J Integr Med. 2012; 18(11):813-23 [PubMed]

OBJECTIVE: To evaluate the effectiveness and safety of β-elemene Injection as an adjunctive treatment for lung cancer by systematic review.
METHODS: We retrieved randomized controlled clinical trials related to the use of β-elemene Injection as an adjunctive treatment for lung cancer from Chinese Biomedical (CBMweb), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), ChinaInfo, Cochrane Central Register of Controlled Trials; MEDLINE, EMBASE, OVID and TCMLARS. We also referred to an unpublished conference proceeding titled Clinical Use and Basic: Elemene Injection. We then divided the studies into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) subgroups by RevMan 5.1 software.
RESULTS: A total of 21 source documents (1,467 patients) matched pre-specified criteria for determining the effectiveness and safety of β-elemene Injection as an adjunctive treatment for lung cancer. Five studies involving 285 NSCLC patients reported a higher 24-month survival rate (39.09%) with the adjunctive treatment than with chemotherapy alone (26.17%; RR, 1.51; 95% CI, 1.03 to 2.21). Four studies involving 445 patients reported that the increased probability for improved performance status for patients treated with elemene-based combinations was higher than that of patients treated with chemotherapy alone (RR, 1.82; 95% CI, 1.45 to 2.29). The results from a subgroup analysis on 12 studies involving 974 NSCLC patients and 9 studies involving 593 patients with both SCLC and NSCLC showed that the tumor control rate for NSCLC improved more in the elemene-based combinations treatment group (78.70%) than in the chemotherapy alone control group (71.31%; RR, 1.06; 95% CI, 1.00 to 1.12). The tumor response rate for NSCLC also improved more among patients treated with elemenebased combinations (50.71%) than among patients treated with chemotherapy alone (38.04%; RR, 1.34; 95%CI, 1.17 to 1.54). In addition, the main adverse reaction to β-elemene Injection was phlebitis, but usually only to a mild degree. An Egger's test showed no publication bias in our study (P=0.7030).
CONCLUSIONS: The effectiveness of chemotherapy for the treatment of lung cancer may improve when combined with β-elemene injection as an adjunctive treatment. The combined treatment can result in an improved quality of life and prolonged survival. However, these results require confirmation by rigorously controlled trials.

Lui GY, Obeidy P, Ford SJ, et al.
The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action.
Mol Pharmacol. 2013; 83(1):179-90 [PubMed]

Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors. To date, there have been no studies to investigate the effect of deferasirox on these types of tumors in vivo. Deferasirox demonstrated similar activity at inhibiting proliferation of DMS-53 lung carcinoma and SK-N-MC neuroepithelioma cell lines compared with DFO. Furthermore, deferasirox was generally similar or slightly more effective than DFO at mobilizing cellular (59)Fe and inhibiting iron uptake from human transferrin depending on the cell type. However, deferasirox potently inhibited DMS-53 xenograft growth in nude mice when given by oral gavage, with no marked alterations in normal tissue histology. To understand the antitumor activity of deferasirox, we investigated its effect on the expression of molecules that play key roles in metastasis, cell cycle control, and apoptosis. We demonstrated that deferasirox increased expression of the metastasis suppressor protein N-myc downstream-regulated gene 1 and upregulated the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) while decreasing cyclin D1 levels. Moreover, this agent increased the expression of apoptosis markers, including cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1. Collectively, we demonstrate that deferasirox is an orally effective antitumor agent against solid tumors.

Kubo T, Takigawa N, Osawa M, et al.
Subpopulation of small-cell lung cancer cells expressing CD133 and CD87 show resistance to chemotherapy.
Cancer Sci. 2013; 104(1):78-84 [PubMed]

Tumors are presumed to contain a small population of cancer stem cells (CSCs) that initiate tumor growth and promote tumor spreading. Multidrug resistance in CSCs is thought to allow the tumor to evade conventional therapy. This study focused on expression of CD133 and CD87 because CD133 is a putative marker of CSCs in some cancers including lung, and CD87 is associated with a stem-cell-like property in small-cell lung cancer (SCLC). Six SCLC cell lines were used. The expression levels of CD133 and CD87 were analyzed by real-time quantitative reverse transcription-polymerase chain reaction and flow cytometry. CD133+/- and CD87+/- cells were isolated by flow cytometry. The drug sensitivities were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Non-obese diabetic/severe combined immunodeficiency mice were used for the tumor formation assay. SBC-7 cells showed the highest expression levels of both CD133 and CD87 among the cell lines. CD133-/CD87-, CD133+/CD87-, and CD133-/CD87+ cells were isolated from SBC-7 cells; however, CD133+/CD87+ cells could not be obtained. Both CD133+/CD87- and CD133-/CD87+ subpopulations showed a higher resistance to etoposide and paclitaxel and greater re-populating ability than the CD133-/CD87- subpopulation. CD133+/CD87- cells contained more G0 quiescent cells than CD133-/CD87- cells. By contrast, CD133-/CD87- cells showed the highest tumorigenic potential. In conclusion, both CD133 and CD87 proved to be inadequate markers for CSCs; however, they might be beneficial for predicting resistance to chemotherapy.

Yoshimura A, Noro R, Miyanaga A, et al.
Combination chemotherapy of alternating etoposide and carboplatin with weekly administration of irinotecan and cisplatin in extensive-stage small-cell lung cancer.
Anticancer Res. 2012; 32(10):4473-8 [PubMed]

BACKGROUND: A phase II study was conducted to determine the tumor efficacy and tolerance of alternating chemotherapy in extensive-stage small-cell lung cancer (ED-SCLC).
PATIENTS AND METHODS: Thirty-six patients with previously untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of etoposide and carboplatin (EC) with weekly administration of irinotecan and cisplatin (IP) at 3- or 4-week intervals.
RESULTS: The overall response rate was 81.8%. The median duration of survival and progression-free survival were 314 days and 144 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 69.2, 25.6 and 23.1% of the patients, respectively. Severe diarrhea (10.8%) was remarkable during the IP regimen.
CONCLUSION: This novel alternating chemotherapy for patients with ED-SCLC showed moderate tumor efficacy and an acceptable safety profile.

Gilbert C, Yarmus L, Feller-Kopman D
Use of endobronchial ultrasound and endoscopic ultrasound to stage the mediastinum in early-stage lung cancer.
J Natl Compr Canc Netw. 2012; 10(10):1277-82 [PubMed]

Lung cancer remains the deadliest cancer, with more than 160,000 deaths and 226,000 newly diagnosed cases estimated in 2012. Because treatment and survival are directly linked to disease stage, accurate staging in all patients is crucial. The proper staging of early-stage lung cancer involves investigation for the presence of metastatic spread via lymph nodes within the thorax. Initial steps include CT and PET. Mediastinoscopy has previously been considered the gold standard for mediastinal lymph node sampling; however, over the past 10 years the use of ultrasound-guided lymph node sampling has been shown to be at least as sensitive, and has the added advantage of being able to access significantly more stations. This article reviews the current standards of lung cancer staging in 2012.

Reck M, Thatcher N, Smit EF, et al.
Baseline quality of life and performance status as prognostic factors in patients with extensive-stage disease small cell lung cancer treated with pemetrexed plus carboplatin vs. etoposide plus carboplatin.
Lung Cancer. 2012; 78(3):276-81 [PubMed]

BACKGROUND: Small cell lung cancer (SCLC) is associated with poor prognosis due to its early metastatic potential and lack of improved outcomes with newer cytotoxic agents. Identifying factors associated with clinical outcomes can help clinicians determine which patients are more likely to benefit from therapy. Functional Assessment of Cancer Therapy (FACT) subscales and Eastern Cooperative Oncology Group performance status (ECOG PS) were retrospectively analyzed as prognostic factors for overall survival (OS) and progression-free survival (PFS) in patients with extensive-stage disease (ED)-SCLC.
METHODS: Using data from a Phase III trial of pemetrexed-carboplatin vs. etoposide-carboplatin, the effect of the prognostic factors on OS and PFS was analyzed via Cox models. The Kaplan-Meier method was used to estimate OS and PFS parameters for the prognostic subgroups (defined by baseline FACT scores and ECOG PS).
RESULTS: Patients with higher baseline FACT-General (FACT-G) score (≥ median) had significantly higher OS (hazard ratio [HR]=0.62, P<.0001) and PFS (HR=0.83, P=.032) compared with patients with lower FACT-G score (CONCLUSIONS: Higher baseline FACT-G, FACT-PWB, and FACT-FWB scores were found to be favorable prognostic factors for survival in ED-SCLC. Higher FACT-PWB scores at baseline predicted better survival for patients with poorer PS.

Huang W, Hu J, Yang DW, et al.
Two microRNA panels to discriminate three subtypes of lung carcinoma in bronchial brushing specimens.
Am J Respir Crit Care Med. 2012; 186(11):1160-7 [PubMed]

RATIONALE: Effective treatment for lung cancer requires accuracy in subclassification of carcinoma subtypes.
OBJECTIVES: To identify microRNAs in bronchial brushing specimens for discriminating small cell lung cancer (SCLC) from non-small cell lung cancer (NSCLC) and for further differentiating squamous cell carcinoma (SQ) from adenocarcinoma (AC).
METHODS: Microarrays were used to screen 723 microRNAs in laser-captured, microdissected cancer cells from 82 snap-frozen surgical lung specimens. Quantitative reverse-transcriptase polymerase chain reaction was performed on 153 macrodissected formalin-fixed, paraffin-embedded (FFPE) surgical lung specimens to evaluate seven microRNA candidates discovered from microarrays. Two microRNA panels were constructed on the basis of a training cohort (n = 85) and validated using an independent cohort (n = 68). The microRNA panels were applied as differentiators of SCLC from NSCLC and of SQ from AC in 207 bronchial brushing specimens.
MEASUREMENTS AND MAIN RESULTS: Two microRNA panels yielded high diagnostic accuracy in discriminating SCLC from NSCLC (miR-29a and miR-375; area under the curve [AUC], 0.991 and 0.982 for training and validation data set, respectively) and in differentiating SQ from AC (miR-205 and miR-34a; AUC, 0.977 and 0.982 for training and validation data set, respectively) in FFPE surgical lung specimens. Moreover, the microRNA panels accurately differentiated SCLC from NSCLC (AUC, 0.947) and SQ from AC (AUC, 0.962) in bronchial brushing specimens.
CONCLUSIONS: We found two microRNA panels that accurately discriminated between the three subtypes of lung carcinoma in bronchial brushing specimens. The identified microRNA panels may have considerable clinical value in differential diagnosis and optimizing treatment strategies based on lung cancer subtypes.

Sos ML, Dietlein F, Peifer M, et al.
A framework for identification of actionable cancer genome dependencies in small cell lung cancer.
Proc Natl Acad Sci U S A. 2012; 109(42):17034-9 [PubMed] Free Access to Full Article

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of SCLC patients is devastating and no biologically targeted therapeutics are active in this tumor type. To develop a framework for development of specific SCLC-targeted drugs we conducted a combined genomic and pharmacological vulnerability screen in SCLC cell lines. We show that SCLC cell lines capture the genomic landscape of primary SCLC tumors and provide genetic predictors for activity of clinically relevant inhibitors by screening 267 compounds across 44 of these cell lines. We show Aurora kinase inhibitors are effective in SCLC cell lines bearing MYC amplification, which occur in 3-7% of SCLC patients. In MYC-amplified SCLC cells Aurora kinase inhibition associates with G2/M-arrest, inactivation of PI3-kinase (PI3K) signaling, and induction of apoptosis. Aurora dependency in SCLC primarily involved Aurora B, required its kinase activity, and was independent of depletion of cytoplasmic levels of MYC. Our study suggests that a fraction of SCLC patients may benefit from therapeutic inhibition of Aurora B. Thus, thorough chemical and genomic exploration of SCLC cell lines may provide starting points for further development of rational targeted therapeutic intervention in this deadly tumor type.

Almasi CE, Drivsholm L, Pappot H, et al.
The liberated domain I of urokinase plasminogen activator receptor--a new tumour marker in small cell lung cancer.
APMIS. 2013; 121(3):189-96 [PubMed]

The prognosis of small cell lung cancer (SCLC) remains poor with a 5-year survival rate of 4-6%. In non-small cell lung cancer (NSCLC), high levels of intact and cleaved forms of the receptor for urokinase plasminogen activator (uPAR) are significantly associated with short overall survival. Our aim was therefore to determine the prognostic value of the different uPAR forms in blood from SCLC patients. Serum samples from 92 treatment naive SCLC patients were analysed. Intact uPAR, uPAR(I-III), intact and cleaved uPAR, uPAR(I-III) + uPAR(II-III) and the liberated domain I, uPAR(I) were measured using time-resolved fluorescence immunoassays (TR-FIA 1-3). Assessment of association of the uPAR forms to overall survival (OS) was done using Cox regression analysis adjusted for clinical covariates [age, gender, stage, lactate dehydrogenase (LDH), WHO performance status (PS)]. Multivariate survival analysis demonstrated that high levels of uPAR(I) were significantly (p = 0.009) associated with short overall survival (OS). Patients with uPAR(I) levels above the second tertile had a hazard ratio (HR) of 1.9 (95% confidence interval (CI): 1.1-3.3), compared to patients with levels below the first tertile. High serum uPAR(I) levels are associated with short OS in SCLC patient, independent of LDH and PS.

Staaf J, Isaksson S, Karlsson A, et al.
Landscape of somatic allelic imbalances and copy number alterations in human lung carcinoma.
Int J Cancer. 2013; 132(9):2020-31 [PubMed]

Lung cancer is the worldwide leading cause of death from cancer and has been shown to be a heterogeneous disease at the genomic level. To delineate the genomic landscape of copy number alterations, amplifications, loss-of-heterozygosity (LOH), tumor ploidy and copy-neutral allelic imbalance in lung cancer, microarray-based genomic profiles from 2,141 tumors and cell lines including adenocarcinomas (AC, n = 1,206), squamous cell carcinomas (SqCC, n = 467), large cell carcinomas (n = 37) and small cell lung carcinomas (SCLC, n = 88) were assembled from different repositories. Copy number alteration differences between lung cancer histologies were confirmed in 285 unrelated tumors analyzed by BAC array comparative genomic hybridization. Tumor ploidy patterns were validated by DNA flow cytometry analysis of 129 unrelated cases. Eighty-nine recurrent copy number alterations (55 gains, 34 losses) were identified harboring genes with gene expression putatively driven by gene dosage through integration with gene expression data for 496 cases. Thirteen and 26 of identified regions discriminated AC/SqCC and AC/SqCC/SCLC, respectively, while 48 regions harbored recurrent (n > 15) high-level amplifications comprising established and putative oncogenes, differing in frequency and coamplification patterns between histologies. Lung cancer histologies displayed differences in patterns/frequency of copy number alterations, genomic architecture, LOH, copy-neutral allelic imbalance and tumor ploidy, with AC generally displaying less copy number alterations and allelic imbalance. Moreover, a strong association was demonstrated between different types of copy number alterations and allelic imbalances with tumor aneuploidy. In summary, these analyses provide a comprehensive overview of the landscape of genomic alterations in lung cancer, highlighting differences but also similarities between subgroups of the disease.

Olszewski U, Deally A, Tacke M, Hamilton G
Alterations of phosphoproteins in NCI-H526 small cell lung cancer cells involved in cytotoxicity of cisplatin and titanocene Y.
Neoplasia. 2012; 14(9):813-22 [PubMed] Free Access to Full Article

First-line treatment of small cell lung cancer (SCLC) with combination chemotherapy consisting of cis-diamminedichloroplatinum(II) (cisplatin) and etoposide is frequently followed by early relapses and a dismal prognosis. Survival of a fraction of tumor cells and development of chemoresistance may be influenced by an initial cellular stress response against the administered xenobiotics. Therefore, we compared the short-term effects of cisplatin and non-cross-resistant bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) on phosphorylation of 46 sites of a total of 38 signaling proteins in tumor suppressor protein 53 (p53)-wild-type NCI-H526 SCLC cells. The functional significance of selected kinases for the cytotoxicity of both drugs was tested using specific inhibitors and an activator. The cisplatin-induced cellular stress response involved activation of p38α mitogen-activated protein kinase, whereas Titanocene Y-triggered signaling affected c-Jun N-terminal kinase. Phosphorylation of adenosine monophosphate (AMP)-activated protein kinase α1 (AMPKα1) was increased by both drugs, which promoted cell survival, as indicated by results obtained using AMPK inhibitor compound C and AMPK activator 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside. This is in good agreement with previous reports, where AMPKα1 was demonstrated to represent an important factor for the sensitivity to cisplatin in colon and ovarian cancers, most likely by induction of autophagy. Thus, AMPKα1 constitutes a potential target to be exploited for chemotherapeutic treatment of SCLC to circumvent resistance to metal-based compounds.

Fukuda M, Nakamura Y, Kinoshita A, et al.
Phase II study of irinotecan and cisplatin with concurrent split-course radiotherapy in limited-disease small cell lung cancer.
Cancer Chemother Pharmacol. 2012; 70(5):645-51 [PubMed]

BACKGROUND: Irinotecan and cisplatin are one of active regimens for patients with extensive-stage small cell lung cancer (SCLC). To determine the efficacy and toxicity of irinotecan and cisplatin with concurrent split-course thoracic radiotherapy in limited-disease (LD) SCLC, we conducted a phase II study.
PATIENTS AND METHODS: Thirty-four patients fulfilling the following eligibility criteria were enrolled: chemotherapy-naïve, good performance status (PS 0-1), age ≤75, LD-SCLC, and adequate organ function. The patients received irinotecan 40 mg/m(2) i.v. on days 1, 8, and 15, and cisplatin 60 mg/m(2) i.v. on day 1. Four cycles of chemotherapy were repeated every 4 weeks. Split-course thoracic radiotherapy of once-daily 2 Gy/day commenced on day 2 of each chemotherapy cycle, with 26 and 24 Gy administered in the first and second cycles, respectively.
RESULTS: Thirty-four patients were eligible and assessable for response, toxicity, and survival. Patients' characteristics were as follows: male/female = 29/5; PS 0/1 = 18/16; median age (range) = 67 (50-73); and stage IB/IIA/IIB/IIIA/IIIB = 2/2/3/16/11. The overall response was 100 % (CR 8, PR 26). Grade 4 leukopenia, neutropenia, grade 3-5 pneumonitis, diarrhea, and esophagitis occurred in 24, 38, 6, 3, and 0 %, respectively. There were 2 treatment-related deaths from pneumonitis. The median time to tumor progression was 14.3 months. The median overall survival time and the 2- and 5-year survival rates were 44.5 months, 66.7 and 46.1 %, respectively. No tumor progression was observed in patients with CR.
CONCLUSION: Irinotecan plus cisplatin with concurrent split-course thoracic radiotherapy was effective and tolerable in untreated LD-SCLC.

Han M, Dai J, Zhang Y, et al.
Support vector machines coupled with proteomics approaches for detecting biomarkers predicting chemotherapy resistance in small cell lung cancer.
Oncol Rep. 2012; 28(6):2233-8 [PubMed]

The aim of this study was to identify serum protein fingerprints of small cell lung cancer (SCLC) and potential biomarkers related to chemotherapy resistance of SCLC with surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS). A total of 60 SCLC patients and 48 age- and sex-matched healthy individuals were enrolled. The chemotherapy regimen was cisplatin plus etoposide. All patients received two cycles of chemotherapy. Serum protein profiles were detected using SELDI-TOF MS and the spectra were analyzed with support vector machines (SVMs). Western blotting was performed to verify the results of SELDI-TOF MS. Three top scored peaks, at m/z of 6269, 9043 and 13124 Da, were finally selected as potential biomarkers for detection of SCLC. The SVM classifier separated the SCLC from the healthy samples in the blind test, with a sensitivity of 92.4% and a specificity of 92.5%. For the 56 eligible chemotherapy patients, 4 had a complete response (7.14%), 39 patients had a partial response (69.6%), 9 patients had a stable disease (16.1%) and 4 patients had a progressive disease (7.14%). The model constructed using two protein peaks with m/z of 8830 and 10468 Da separated the chemotherapy-resistant group from the chemotherapy-sensitive group with a sensitivity of 80.0% and a specificity of 80.0%. Initial protein database searching identified 10468 Da as S100-A9 which was confirmed by western blotting. The present results suggest that the combination of SELDI-TOF MS with SVM may provide a useful means in the search for serum biomarkers for predicting chemotherapy resistance in patients with SCLC.

Otani Y, Kijima T, Kohmo S, et al.
Suppression of metastases of small cell lung cancer cells in mice by a peptidic CXCR4 inhibitor TF14016.
FEBS Lett. 2012; 586(20):3639-44 [PubMed]

CXCL12 is a chemokine essential for the organ-specific spread of a variety of cancers including small cell lung cancer (SCLC). Here, we examined the anti-metastatic efficacy of TF14016, a small peptidic inhibitor of CXCL12 receptor CXCR4, in SCLC. Treatment of mice with TF14016 significantly suppressed pulmonary metastases of CXCR4-expressing SCLC in size and number. Furthermore, histological examination revealed that the expression of vascular endothelial cell growth factor and the density of CD31-positive microvessels in metastatic foci were both significantly reduced in TF14016-treated mice. Collectively, CXCR4 could be an attractive target for anti-metastatic and anti-angiogenic therapy in SCLC.

Lin H, Zhong WZ, Yang XN, et al.
A clinical model to estimate the pretest probability of lung cancer, based on 1198 pedigrees in China.
J Thorac Oncol. 2012; 7(10):1534-40 [PubMed]

INTRODUCTION: Computed tomography screening can detect lung cancer that is curable. However, some studies demonstrated that the risk for false-positives was about 50%. To make screening more efficient, we sought to create a forecasting model for individuals with different risks for lung cancer.
METHODS: We used multiple logistic regression analysis to identify independent predictors and to develop a prediction model. The pathological diagnoses in Guangdong Lung Cancer Institute were consecutively chosen as probands. All first-degree relatives of probands and their spouses were included as subjects. We divided the probands and their spouses into three subgroups according to the odds ratios (ORs), and the accuracy of lung cancer predictions for patients within the subgroups increased synchronously.
RESULTS: There were 633 proband pedigrees and 565 spouse pedigrees. Independent predictors of lung cancer included sex (OR, 1.6; 95% confidence interval [CI], 1.1-2.3), smoking history (light smoker: OR, 1.1; 95% CI, 0.7-1.8; heavy smoker: OR, 4.7; 95% CI, 3.1-7.1), lung disease history (OR, 5.3; 95% CI, 2.8-10.0), occupational exposure (OR, 1.6; 95% CI, 1.1-2.2), and number of affected individuals among first-degree relatives (n = 1: OR, 2.1; 95% CI, 1.3-3.4; n ≥ 2: OR, 4.7; 95% CI, 0.5-41.2). The accuracy of the pretest probability increased for those with higher ORs: low-OR subgroup, 68.3%; mid-OR subgroup, 84.0%; and high-OR subgroup, 91.9%.
CONCLUSIONS: Our prediction rule is recommended for estimating the pretest probability of lung cancer, thereby facilitating early screening.

Brasky TM, Baik CS, Slatore CG, et al.
Prediagnostic nonsteroidal anti-inflammatory drug use and lung cancer survival in the VITAL study.
J Thorac Oncol. 2012; 7(10):1503-12 [PubMed] Article available free on PMC after 01/10/2013

INTRODUCTION: Inflammation is important for lung oncogenesis. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to improve colorectal cancer survival. However, few studies have examined the association in lung cancer patients.
METHODS: The VITamins And Lifestyle (VITAL) cohort includes Washington State residents, aged 50 to 76 years, who completed a baseline questionnaire between 2000 and 2002. Participants responded on the frequency and duration of use of individual NSAIDs in the previous 10 years. Subjects of this study were 785 members of the cohort, who were identified with incident lung cancer from baseline through 2007 through linkage to a population-based cancer registry. Participants were followed for lung cancer death through linkage to state records of death through 2009. Adjusted proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAIDs and lung cancer death.
RESULTS: Five hundred and twenty-two participants (66%) died from lung cancer. Relative to nonuse, high (≥ 4 days/week and ≥ 4 years) prediagnostic use of regular-strength or low-dose aspirin (HR 0.99, 95% CI: 0.74-1.33 and HR 0.89, 95% CI: 0.67-1.17, respectively) or total nonaspirin NSAIDs (HR 1.20, 95% CI: 0.79-1.83) did not reduce lung cancer death. However, high use of ibuprofen was associated with a 62% increased risk of lung cancer death (HR 1.62, 95% CI: 1.01-2.58).
CONCLUSIONS: Long-term, prediagnostic NSAID use does not improve lung cancer survival overall. Use of ibuprofen may reduce survival from lung cancer. Our results underscore the need for further study of the mechanisms of action for individual NSAIDs with regard to cancer survival.