Regular follow-up after curative resection of nonsmall cell lung cancer: a real benefit for patients?

Even though complete resection is regarded as the only curative treatment for nonsmall cell lung cancer (NSCLC), >50% of resected patients die from a recurrence or a second primary tumour of the lung within 5 yrs. It remains unclear, whether follow-up in these patients is cost-effective and whether it can improve the outcome due to early detection of recurrent tumour. The benefit of regular follow-up in a consecutive series of 563 patients, who had undergone potentially curative resection for NSCLC at the University Hospital, was analysed. The follow-up consisted of clinical visits and chest radiography according to a standard protocol for up to 10 yrs. Survival rates were estimated using the Kaplan-Meier analysis method and the cost-effectiveness of the follow-up programme was assessed. A total of 23 patients (6.4% of the group with lobectomy) underwent further operation with curative intent for a second pulmonary malignancy. The regular follow-up over a 10-yr period provided the chance for a second curative treatment to 3.8% of all patients. The calculated costs per life-yr gained were 90,000 Swiss Francs. The cost-effectiveness of the follow-up protocol was far above those of comparable large-scale surveillance programmes. Based on these data, the intensity and duration of the follow-up was reduced.

AMR-Me inhibits PI3K/Akt signaling in hormone-dependent MCF-7 breast cancer cells and inactivates NF-κB in hormone-independent MDA-MB-231 cells

AMR-Me, a C-28 methylester derivative of triterpenoid compound Amooranin isolated from Amoora rohituka stem bark and the plant has been reported to possess multitude of medicinal properties. Our previous studies have shown that AMR-Me can induce apoptosis through mitochondrial apoptotic and MAPK signaling pathways by regulating the expression of apoptosis related genes in human breast cancer MCF-7 cells. However, the molecular mechanism of AMR-Me induced apoptotic cell death remains unclear. Our results showed that AMR-Me dose-dependently inhibited the proliferation of MCF-7 and MDA-MB-231 cells under serum-free conditions supplemented with 1 nM estrogen (E2) with an IC50 value of 0.15 µM, 0.45 µM, respectively. AMR-Me had minimal effects on human normal breast epithelial MCF-10A + ras and MCF-10A cells with IC50 value of 6 and 6.5 µM, respectively. AMR-Me downregulated PI3K p85, Akt1, and p-Akt in an ERα-independent manner in MCF-7 cells and no change in expression levels of PI3K p85 and Akt were observed in MDA-MB-231 cells treated under similar conditions. The PI3K inhibitor LY294002 suppressed Akt activation similar to AMR-Me and potentiated AMR-Me induced apoptosis in MCF-7 cells. EMSA revealed that AMR-Me inhibited nuclear factor-kappaB (NF-κB) DNA binding activity in MDA-MB-231 cells in a time-dependent manner and abrogated EGF induced NF-κB activation. From these studies we conclude that AMR-Me decreased ERα expression and effectively inhibited Akt phosphorylation in MCF-7 cells and inactivate constitutive nuclear NF-κB and its regulated proteins in MDA-MB-231 cells. Due to this multifactorial effect in hormone-dependent and independent breast cancer cells AMR-Me deserves attention for use in breast cancer prevention and therapy

CECOG experts' recommendations on the use of denosumab in the prevention of skeletal-related events in bone metastases of lung cancer

Purpose Skeletal-related events represent a substantial burden for patients with advanced cancer. Randomized, controlled studies suggested superiority of denosumab over zoledronic acid in the prevention of skeletal-related events in metastatic cancer patients, with a favorable safety profile. Experts gathered at the 2012 Skeletal Care Academy in Istanbul to bring forward practical recommendations, based on current evidence, for the use of denosumab in patients with bone metastases of lung cancer. Recommendations Based on current evidence, use of denosumab in lung cancer patients with confirmed bone metastases is recommended. It is important to note that clinical judgment should take into consideration the patient’s general performance status, overall prognosis, and live expectancy. Currently, the adverse event profile reported for denosumab includes hypocalcemia and infrequent occurrence of osteonecrosis of the jaw. Therefore, routine calcium and vitamin D supplementation, along with dental examination prior to denosumab initiation are recommended. There is no evidence for renal function impairment due to denosumab administration. At present, there is no rationale to discourage concomitant use of denosumab and surgery or radiotherapy.

EGFR exon-level biomarkers of the response to bevacizumab/erlotinib in non-small cell lung cancer

Activating epidermal growth factor receptor (EGFR) mutations are recognized biomarkers for patients with metastatic non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitors (TKIs). EGFR TKIs can also have activity against NSCLC without EGFR mutations, requiring the identification of additional relevant biomarkers. Previous studies on tumor EGFR protein levels and EGFR gene copy number revealed inconsistent results. The aim of the study was to identify novel biomarkers of the response to TKIs in NSCLC by investigating whole genome expression at the exon-level. We used exon arrays and clinical samples from a previous trial (SAKK19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response: EGFR, V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and vascular endothelial growth factor (VEGFA). We identified the expression of EGFR exon 18 as a new predictive marker for patients with untreated metastatic NSCLC treated with bevacizumab and erlotinib in the first line setting. The overexpression of EGFR exon 18 in tumor was significantly associated with tumor shrinkage, independently of EGFR mutation status. A similar significant association could be found in blood samples. In conclusion, exonic EGFR expression particularly in exon 18 was found to be a relevant predictive biomarker for response to bevacizumab and erlotinib. Based on these results, we propose a new model of EGFR testing in tumor and blood.

Carboplatin and paclitaxel plus ASA404 as first-line chemotherapy for extensive-stage small-cell lung cancer: a multicenter single arm phase II trial (SAKK 15/08)

INTRODUCTION Small-cell lung cancer (SCLC) is a highly vascularized tumor. ASA404 is a tumor vascular disrupting agent. This is the first trial to report the effects of combining chemotherapy with ASA404 in SCLC. METHODS Patients with untreated metastatic SCLC were treated with carboplatin (area under curve, 6) plus paclitaxel (175 mg/m(2)) plus ASA404 (1800 mg/m(2)) on day 1 every 21 days for up to 6 cycles. The primary endpoint was the progression-free survival (PFS) rate at 24 weeks. RESULTS Median age was 61 years; 53% were women, 41% had weight loss; and 96% had a performance status of 0-1. Twelve patients completed all 6 cycles, and most adverse events were related to chemotherapy. Median PFS and time to progression were 7.0 months (95% CI, 5.7-9.4 months) and 7.5 months (95% CI, 5.7-9.4 months), respectively. The progression-free survival (PFS) rate at 24 weeks was 41% (95% CI, 18%-65%). The overall response rate was 94%. The median overall survival time was 14.2 months (95% CI, 8.2-16.0 months) and 1-year survival was 57%. The median follow-up time was 17.7 months. Due to negative results with ASA404 in non-small-cell lung cancer trials, the trial was stopped prematurely after 17 of 56 planned patients were being accrued. CONCLUSIONS This is the first report of a clinical trial with a vascular disrupting agent in SCLC. No unexpected toxicity was observed. PFS was not prolonged with carboplatin and paclitaxel plus ASA404.

Lung cancer screening with CT: evaluation of radiologists and different computer assisted detection software (CAD) as first and second readers for lung nodule detection at different dose levels

OBJECTIVES To find the best pairing of first and second reader at highest sensitivity for detecting lung nodules with CT at various dose levels. MATERIALS AND METHODS An anthropomorphic lung phantom and artificial lung nodules were used to simulate screening CT-examination at standard dose (100 mAs, 120 kVp) and 8 different low dose levels, using 120, 100 and 80 kVp combined with 100, 50 and 25 mAs. At each dose level 40 phantoms were randomly filled with 75 solid and 25 ground glass nodules (5-12 mm). Two radiologists and 3 different computer aided detection softwares (CAD) were paired to find the highest sensitivity. RESULTS Sensitivities at standard dose were 92%, 90%, 84%, 79% and 73% for reader 1, 2, CAD1, CAD2, CAD3, respectively. Combined sensitivity for human readers 1 and 2 improved to 97%, (p1=0.063, p2=0.016). Highest sensitivities--between 97% and 99.0%--were achieved by combining any radiologist with any CAD at any dose level. Combining any two CADs, sensitivities between 85% and 88% were significantly lower than for radiologists combined with CAD (p<0.03). CONCLUSIONS Combination of a human observer with any of the tested CAD systems provide optimal sensitivity for lung nodule detection even at reduced dose at 25 mAs/80 kVp.

Variability in the Treatment of Elderly Patients with Stage IIIA (N2) Non–Small-Cell Lung Cancer

INTRODUCTION: We evaluated treatment patterns of elderly patients with stage IIIA (N2) non-small-cell lung cancer (NSCLC). METHODS: The use of surgery, chemotherapy, and radiation for patients with stage IIIA (T1-T3N2M0) NSCLC in the Surveillance, Epidemiology, and End Results-Medicare database from 2004 to 2007 was analyzed. Treatment variability was assessed using a multivariable logistic regression model that included treatment, patient, tumor, and census track variables. Overall survival was analyzed using the Kaplan-Meier approach and Cox proportional hazard models. RESULTS: The most common treatments for 2958 patients with stage IIIA (N2) NSCLC were radiation with chemotherapy (n = 1065, 36%), no treatment (n = 534, 18%), and radiation alone (n = 383, 13%). Surgery was performed in 709 patients (24%): 235 patients (8%) had surgery alone, 40 patients (1%) had surgery with radiation, 222 patients had surgery with chemotherapy (8%), and 212 patients (7%) had surgery, chemotherapy, and radiation. Younger age (p < 0.0001), lower T-status (p < 0.0001), female sex (p = 0.04), and living in a census track with a higher median income (p = 0.03) predicted surgery use. Older age (p < 0.0001) was the only factor that predicted that patients did not get any therapy. The 3-year overall survival was 21.8 ± 1.5% for all patients, 42.1 ± 3.8% for patients that had surgery, and 15.4 ± 1.5% for patients that did not have surgery. Increasing age, higher T-stage and Charlson Comorbidity Index, and not having surgery, radiation, or chemotherapy were all risk factors for worse survival (all p values < 0.001). CONCLUSIONS: Treatment of elderly patients with stage IIIA (N2) NSCLC is highly variable and varies not only with specific patient and tumor characteristics but also with regional income level.

Prognostic role of FGFR1 amplification in early-stage non-small cell lung cancer.

Background:Recently, fibroblast growth factor receptor 1 (FGFR1) was discovered in squamous cell carcinomas (SCC) of the lung with FGFR1 amplification described as a promising predictive marker for anti-FGFR inhibitor treatment. Only few data are available regarding prevalence, prognostic significance and clinico-pathological characteristics of FGFR1-amplified and early-stage non-small cell lung carcinomas (NSCLC). We therefore investigated the FGFR1 gene status in a large number of well-characterised early-stage NSCLC.Methods:FGFR1 gene status was evaluated using a commercially available fluorescent in situ hybridisation (FISH) probe on a tissue microarray (TMA). This TMA harbours 329 resected, formalin-fixed and paraffin-embedded, nodal-negative NSCLC with a UICC stage I-II. The FISH results were correlated with clinico-pathological features and overall survival (OS).Results:The prevalence of an FGFR1 amplification was 12.5% (41/329) and was significantly (P<0.0001) higher in squamous cell carcinoma (SCC) (20.7%) than in adenocarcinoma (2.2%) and large cell carcinoma (13%). Multivariate analysis revealed significantly (P=0.0367) worse 5-year OS in patients with an FGFR1-amplified NSCLC.Conclusions:FGFR1 amplification is common in early-stage SCC of the lung and is an independent and adverse prognostic marker. Its potential role as a predictive marker for targeted therapies or adjuvant treatment needs further investigation.

[Anal metastasis from a lung cancer]

We report an anal metastasis from a lung cancer which was diagnosed on symptoms mimicking an acute anal abcess. The diagnosis was based on specific immunohistochemistry.

Survival in patients with high-risk prostate cancer is predicted by miR-221, which regulates proliferation, apoptosis, and invasion of prostate cancer cells by inhibiting IRF2 and SOCS3

A lack of reliably informative biomarkers to distinguish indolent and lethal prostate cancer is one reason this disease is overtreated. miR-221 has been suggested as a biomarker in high-risk prostate cancer, but there is insufficient evidence of its potential utility. Here we report that miR-221 is an independent predictor for cancer-related death, extending and validating earlier findings. By mechanistic investigations we showed that miR-221 regulates cell growth, invasiveness, and apoptosis in prostate cancer at least partially via STAT1/STAT3-mediated activation of the JAK/STAT signaling pathway. miR-221 directly inhibits the expression of SOCS3 and IRF2, two oncogenes that negatively regulate this signaling pathway. miR-221 expression sensitized prostate cancer cells for IFN-γ-mediated growth inhibition. Our findings suggest that miR-221 offers a novel prognostic biomarker and therapeutic target in high-risk prostate cancer.