bluuebunny/crossref_metadata_2025 huggingface dataset:
Health care utilization and economic burden of dermatologic adverse drug reactions (ADRs) in patients with NSCLC treated with an epidermal growth factor receptor inhibitor (EGFRI).
Authors: Bonthapally Vijayveer , Guerin Annie , Wu Eric Q. , Gauthier Genevieve , Cloutier Martin , Holen Kyle D. , Ray Saurabh
Published: March 2020

e16571

Background: Non Small Cell Lung Cancer (NSCLC) patients treated with EGFRI therapies may develop dermatologic ADRs. ADRs negatively affect patients’ quality of life, require medical care, and may lead to a substantial economic burden. The objective of this study is to assess the economic burden of dermatologic ADRs in patients with NSCLC. Methods: Continuously enrolled adult patients with ≥ 1 NSCLC diagnosis initiated on an EGFRI therapy (i.e., erlotinib, gefitinib) were selected from a large US claims dataset. Patients were classified into two mutually exclusive cohorts depending on whether or not they had dermatologic ADR during the period following EGFRI initiation. Dermatologic ADRs were identified using ICD-9-CM codes. Patients were observed from the index date up to the end of the health plan enrollment, or data availability, or 90 days after the EGFRI discontinuation, whichever occurred first. Incidence rate ratios (IRRs) for healthcare resource utilization were estimated using Poisson regression models. Incremental costs (2010 USD) were estimated on a monthly basis using generalized linear or two-part models. Multivariate regressions controlled for age, gender, comorbidities, and baseline healthcare utilization and costs. Results: A total of 635 and 2,688 patients were included in the dermatologic ADR and ADR-free cohorts, respectively. After adjusting for confounding factors, compared to patients in the ADR-free cohort, patients in the ADR cohort had higher incidence of emergency room visits (IRR=1.28 ( CI 1.13-1.45); p=.0001),higher incidence of outpatient visits (IRR=1.28 (1.25-1.3); p<.0001), and higher incidence of other medical services ( IRR=1.15 (1.11-1.19); p<.0001). Moreover, patients in the ADR cohort incurred higher total healthcare costs by an estimated $3,210 (p=.003) per patient per month. Conclusions: ComparedtoADR-free patients, dermatologic ADR patients with NSCLC incurred a substantial economic burden related to higher healthcare resource utilization and costs. Efforts to improve the dermatologic side effect profile of EGFRI are needed to control this burden.
Management of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) in community services: Retrospective study of 130 patients from a single institution.
Authors: Al-Ameri Ali , Patel Neema , Kanaan Zeyad , Haller Nairmeen Awad
Published: March 2020

e17004

Background: Acute myeloid leukemia (AML) is a heterogeneous disease resulting from accumulation of blast cells in the marrow Age greater than 75 years and cytogenetics are the most important factors in the prognosis, whereby increased age and monosomal karyotypes carry the worst prognosis The most favorable cytogenetics are patients with normal karyotypes and can receive standard therapy Aim Study the over survival (OS) of AML/High risk MDS treated according to standard of care at a community Service Methods: An IRB-approved retrospective study of AML &High risk MDS patients treated at an Akron General Medical Center during 2002-2010 reviewed patient demographics diagnosis types/subtypes, treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetics background using WHO criteria. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis Results: Charts of 130 pts, we are able to classify 98 (75%) pts 52 (53%) as high risk and low-intermediate risk. 46(47%) low risk the latter include intermediate risk. Median age was 55 years (range: 19-90), 43 (45%) pts were older than 75 years. AML pts made up 71%, 45 patients (35%) in total had complex cytogenetics, and 15% had AML arise from MDS. Median survival overall was 22.4 weeks, 14.4 weeks for high risk and 53.8 weeks for low risk (p<0.01). Median survival for pts greater than 75 years was 11.5 weeks compared to 35.8 weeks for those younger than 75 years (p<0.05) Conclusions: Overall survival was low in the study population, with survival in high risk patients and those greater than 75 years being significantly lower than low risk and younger than 75 years respectively These results may support early referral to a specialized center, possible clinical trials
Survival outcome of veterans with myelodysplastic syndrome (MDS) treated with statins.
Authors: Abbas Kanza S , Li Ang , Rivero Gustavo , Mitsiades Nicholas , Yellapragada Sarvari
Published: March 2020

e17018

Background: Recent studies have shown promising risk modifying effects of statin in various hematologic and solid tumors, such as its ability to induce apoptosis in acute myeloid leukemia cells in-vitro. The impact of statin on MDS treatment outcome has not been evaluated. In this retrospective study, we have examined the overall survival (OS) in veteran MDS patients (pts) with and without exposure to statin with the initial hypothesis that it may impact OS. Methods: After IRB approval, data was collected from Michael E DeBakey VAMC Cancer Registry from January 2000 to October 2011. Pts were included if they had morphological evidence of MDS at the time of diagnosis. Statin exposure was defined as concurrent statin use for at least 6 months prior to and at the time of diagnosis. The primary end-point was OS before and after adjustment with MDS Co-morbidity Index (MDS-CI). Prism 5 was used for statistical analysis. Results: 104 pts with MDS were identified with baseline characteristics depicted in the table. OS of pts exposed to statin was significantly longer when compared with pts not exposed to statin (950d vs 419d, p<0.05). This improvement was especially prominent in pts with higher comorbidities (MDS-CI score>2) (1062d vs 219d, p<0.05) and specifically in those with higher cardiac comorbidities. OS in pts with lower MDS-CI scores was higher in patients on statin but there was no statistical significance (901d vs 663d, p=0.57). Conclusions: In this retrospective study, concurrent statin exposure significantly improved OS in pts with MDS. This improvement, however, was statistically significant in pts with higher overall and cardiovascular co-morbidities. These findings suggest a limited direct anti-tumor benefit of statin in MDS, although the results may have been influenced by the sample size and retrospective design. Prospective studies after stratification by IPSS and MDS-CI are needed to further evaluate the risk-modifying effects of statin in MDS. [Table: see text]
Early detection of lung cancer based on three-dimensional, morphometric analysis of cells from sputum following x-ray CT screening.
Authors: Urbine Terry Francis , Meyer Michael , Tourovskaia Anna , Steinhauer David , Hayenga Jon , Presley Chris , Hawthorne Ben , Neumann Thomas , Nelson Alan
Published: March 2020

e17529

Background: A major advance against lung cancer was made with the announcement of results from the National Lung Cancer Screening Trial. A 20% reduction in mortality was shown in a screened population using low dose CT (LDCT) compared to screened chest x-rays. Approximately 95% of the positive findings of LDCT, however, turned out not to be cancer. We propose to use 3D morphometric analysis of cells from enriched sputum to distinguish benign from malignant nodules found using LDCT and to identify cancers that were not identified with LDCT. Methods: Sputum from 30 patients with non-small cell lung cancer were studied. Fluorescence activated cell sorting was used to enrich sputum for epithelial cells. The enriched cells, stained with hematoxylin, were automatically imaged using VisionGate’s 3D cell imaging system (Cell-CT) which unambiguously renders individual cells with isometric, sub-micron resolution. Image libraries of cells were created and 530 morphology features were computed for each cell. Abnormal (moderate and severe dysplasia and cancer) status for each cell was determined by a cytotechnologist and added to the feature set. Cross-validated classifiers were created that combine a sub-set of the features into a single score that best correlated with the binary cell diagnoses. Results: Study of enriched sputum from cancer patients using the Cell-CT shows cancer cells in at least 75% of the cases with cancer cells present in raw sputum. Classifier cell specificity exceeding 98% and a 70% cancer cell detection rate were measured. A 70% cell detection rate translates into a 90% detection rate for the specimen since multiple abnormal cells are present in sputum. Overall detection rate for cancer cell positive sputum is: 68%, computed by finding the product of the rate of cancer cell positive enriched sputum (0.75) with the rate of detection by the classifier (0.90). Conclusions: Automated, 3D morphometric analysis of cells from sputum provides high sensitivity and specificity detection of lung cancer. Adjunctive use with LDCT will aid in determination of the malignancy status of indeterminate pulmonary nodules.
A strategy to reduce acute toxicity from chemoradiation therapy for limited-stage small cell lung cancer.
Authors: Corradetti Michael Nino , Xanthopoulos Eric , Grover Surbhi , Fernandes Annemarie Therese , Kim Miranda , Simone Charles B. , Christodouleas John Paul , Lin Lilie L. , Rengan Ramesh
Published: March 2020

e17534

Background: The standard of care for limited stage SCLC as outlined in the Intergroup 0096 trial involves twice daily radiation therapy, delivered to two out of four fields at a time, which results in high rates of clinically significant acute toxicity. This study examines acute esophagitis and treatment breaks in patients treated with radiation therapy as outlined by Intergroup 0096 vs those treated with a slight modification to this technique. Methods: We identified SCLC patients who received 45 Gy in 1.5 Gy bid fractions from an institutional database. Associations were assessed via Chi-squared test. A break was defined as an interruption of 3+ days. Results: 74 SCLC patients were treated with 3D-conformal radiation therapy from 2004 to 2010. 16 patients did not satisfy criteria described in the Methods and were excluded. 28 patients were treated per Intergroup 0096 with AP/PA fields bid for 1 week followed by AP/PA treatment in the AM and 2 oblique fields in the PM for 2 weeks. 28 patients were treated with the same approach except all four fields were treated with each fraction. Patient characteristics were well distributed as outlined below (Table). 54% of patients had CTCAE grade 3 esophagitis with the Intergroup 0096 approach vs 23% in patients treated with a 4-field approach (p = 0.01). 29% vs 7% patients had a treatment break (p = 0.03). 32% of grade 3 esophagitis patients had breaks vs 8% with esophagitis grades 0 – 2 (p = 0.02). There was no difference in survival or distant/local failure. Conclusions: Grade 3 esophagitis and treatment breaks were reduced in patients receiving continuous 4-field treatment. Future investigation is required to determine whether the observed reduction in breaks could translate to a local control or survival benefit if applied to a larger patient sample. [Table: see text]
Bronchial neuroendocrine tumors: A retrospective review of management and outcomes in 116 patients.
Authors: Pericleous Marinos , Lumgair Heather , Reiner Johnathan , Marelli Laura , Caplin Martyn , Meyer Tim , Toumpanakis Christos
Published: March 2020

e17543

Background: Bronchial neuroendocrine tumours, represent 1–3% of all primary lung tumours and 25% of all neuroendocrine tumours (NETs). They are classified into: typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell lung carcinomas (SCLC). The aim of our study was to assess diagnostic features, management and outcome, focusing on the differences between TC and AC. Methods: 116 patients were identified from our NET database. WHO histopathological classification was used. Follow-up was complete in all patients (mean follow-up 59.8 months). Disease-free survival (DFS), and progression-free survival (PFS) were evaluated for each therapy. Results: The average age of presentation was 55.30 years (range 16-85 years, M:F ratio=1:1.5). The commonest presenting symptom was cough (19%) followed by haemoptysis (18%). 36% were TC, 45% AC, and 19% LCNEC/SCLC. 16% TC and 28% AC patients had metastases at diagnosis. Octreoscan was positive in 76% TC and 66% AC. In 2 patients with TC and negative Octreoscan, Ga-68 Octreotate PET showed avid uptake in lung lesions. 46 patients had surgery. In 35 of AC, the disease relapsed (DFS=29.8 months) compared to 24% TC (DFS=48months). 12 patients received somatostatin analogues (SSTA) with PFS for TC 60 months and AC 21 months. 16 patients received systemic chemotherapy with PFS for TC 72 months and AC 21 months. 4/5 patients achieved disease stability with 90Yttrium-DOTAoctreotate. 5-years survival after surgery, chemotherapy or SSTA, was 91%, 86% and 81% respectively. Overall five year survival was 91% (100 % TC, 75% AC). Conclusions: AC and SCLC/LCLC more often present with metastatic disease with shorter DFS and PFS compared to TC. Molecular imaging is helpful for staging and predicting appropriateness for SSTA or radionuclide targeted therapy. Surgery confers the best survival rates. AC have higher relapse rates and metastatic potential. Further clinical trials are required to define the best treatment algorithm.
Surgical pathology findings of neoadjuvant full-dose irinotecan and cisplatin (IP) with concurrent thoracic radiation therapy (C-TRT) in stage III non-small cell lung cancer (NSCLC).
Authors: Walker Paul R. , Ben-Or Sharon , Moran Jon , Williams Richard Fred , Biswas Tithi , Fried Daniel B. , Rosenman Julian , Russo Suzanne M. , Aljumaily Raid , Bowling Mark , Eubanks Susan , Nelson Zenith , Parent Teresa
Published: March 2020

e17550

Background: Neoadjuvant C-TRT in stage IIIA NSCLC has become a standard of care. C-TRT sterilizes N2 nodes far better than primary tumors. TRT dose does seem to make a difference. In Intergroup 0139 with 45 Gy pre-op TRT, ypT0N0 was 18% and ypN0 46% (Albain et al Lancet 2009). Pre-op TRT dose escalation to 60+ Gy improves ypN0 clearance up to 80% and ypT0N0 to 45% (Sonett et al Ann Thorac Surg 2004; Cerfolio et al Ann Thorac Surg 2005). However there is no known difference in pathologic response and outcome with different chemotherapy approaches. Irinotecan with radiation therapy has been studied in locally advanced NSCLC with similar outcomes as with any cisplatin doublet and no undue toxicities (Langer et al J Thorac Oncol 2007; Bastos et al J Thorac Oncol 2010). We reviewed our multidisciplinary thoracic oncology program experience with neoadjuvant full-dosing IP and C-TRT in stage IIIA NSCLC assessing ypTN response. Methods: All patients with stage IIIA NSCLC undergoing pre-operative IP and C-TRT between September 2008 and December 2011 were searched through our program database and included. 14 patients were identified. Irinotecan 65mg/m2 and cisplatin 30mg/m2 D1 and D8 q 21 days with C-TRT 60-66 Gy was administered followed by surgical resections. Pathologic response (ypT0N0) was assessed. Results: Median age 61 (36-72). 85% males; 85% squamous. PET N2 positive in 85% with 2 patients T3N1. 6/14 (43%) pathologic complete response (pCR)/ypT0N0; plus 4 with < 10% primary tumor viability (one isolated tumor cells on IHC staining, two with just 3 mm residual islands); 70% of patients had a pCR or had < 10% primary tumor viability. 11/12 (91%) downstaged PET N2 to ypN0. Conclusions: Full dose IP with C-TRT 60+ Gy is a very effective neoadjuvant treatment with very high pathologic complete responses and N2 clearance in squamous cell lung cancers. Just as in stage IV NSCLC, histology-based chemotherapy in stage IIIA/IIIB NSCLC C-TRT could well achieve outcome differences.
Outcomes of non-small cell lung cancer patients with adenocarcinoma histology compared with other histologies: SEER registry data 2004-2008.
Authors: Joshi Monika , Varlotto John M. , Ali Suhail M. , Toth Jennifer , Reed Michael , Lipton Allan , Belani Chandra Prakash
Published: March 2020

e17560

Background: For convenience, the majority of lung cancers are commonly lumped together as non-small lung cancer (NSCLC). Patients with adenocarcinoma of the lung have a higher incidence of driver mutation as compared to those with squamous histology. In addition pemetrexed containing regimens have preferential activity in this histology and agents such as bevacizumab are administered to this subgroup only based on toxicity. The currentanalysis was performed to compare outcomes for patients in the SEER database between 2004 and 2008 with adenocarcinoma (Adenoca), squamous cell carcinoma (SCCA) and NSCLC not otherwise specified (NOS). Methods: Data for 161,175 patients was available in SEER database between 2004 and 2008 with 38 different histology ICD codes. 134,947 patients (83.7%) were included in the study. NSCLC NOS (ICD-3 8046) n=36,408, SCCA (ICD-3 8070) n= 36, 454 and Adenoca (ICD-3 8140) n=62,085. Overall survival (OS) and lung cancer specific survival (LCSS) were analyzed using cox proportional Hazard model for the 3 groups. Results: Patients in the three groups were age-matched. Male gender was more common in patients who had SCCA compared to Adenoca (62.6% vs. 49.5%). Percentage of poorly differentiated tumors was higher in patients with SCCA (35.9%) compared to NSCLC NOS (32%) and Adenoca (27.5%). SCCA had fewer stage IV patients at diagnosis (29.5%) vs. 51.4 % for NSCLC NOS and 45% for Adenoca. OS and LCSS are listed in the table below with Hazard ratio (HR) and p value. Total of 23.54% (n=31,768) patients underwent surgical resection. Stage I patients who underwent surgery (n=18,517) also had similar results. Conclusions: NSCLC patients who have adenocarcinoma histology have significantly better overall outcome when compared to other histologies. The difference is more pronounced in an earlier stage disease. [Table: see text]
Predicting the risk of secondary malignancies associated with stereotactic body radiation therapy.
Authors: Horowitz David Paul , Ng John , Shuryak Igor , Chao K. S. Clifford , Brenner David J. , Cheng Simon
Published: March 2020

e17562

Background: Treatment of early-stage non-small cell lung cancer (NSCLC) with stereotactic body radiation therapy (SBRT) is associated with high rates of local control and long-term overall survival. With increasing frequency, SBRT is a treatment option for operable tumors which raises the question of the risk of long-term toxicities such as radiation-induced secondary malignancies. There has been no previous risk assessment or epidemiological studies of secondary malignancies with high-dose hypofractionated SBRT. In this study, we seek to quantify the predicted rates of secondary lung malignancies in patients treated with SBRT for stage I-II NSCLC. Methods: Treatment plans for 14 stage I-II NSCLC patients treated with definitive-intent SBRT at Columbia University Medical Center were retrospectively assessed. Median patient age was 73 years (range 54 - 86) with median tumor size of 2.8 cm (range 1.2 - 5.0). SBRT doses ranged from 40-60 Gy in 3-5 fractions. Dose-volume histograms for target PTV and normal lung were generated from planning CT scans. A biologically-based mathematical model of spontaneous and radiation-induced carcinogenesis was used to determine the excess absolute risk and the median lifetime estimated relative risk of secondary lung malignancies for each plan. These risks were then compared using 2-sided t-tests. Results: For all patients, the median lifetime estimated absolute risk of secondary lung malignancy was 1.06% (95% CI 0.62%-1.98%), and the median lifetime estimated relative risk of secondary lung malignancy was 1.61 (95% CI 1.47-1.75) after SBRT. For patients aged less than 65 years, median estimated absolute risk of secondary malignancies was higher (2.8%) than for patients age 65 and older (0.37%), p < 0.001. PTV volume less than 50 cc vs greater than 50 cc, T1 vs T2 tumors, and gender were not significantly associated with differences in estimated absolute risk or estimated relative risk of secondary malignancies. Conclusions: As SBRT is potentially indicated in younger medically operable patients, the long-term late toxicities need to be determined. This study suggests that the risk of second lung malignancies from high-dose SBRT even in younger patients would be minimal.
Qol and adherence to i.v. or oral chemotherapy treatment in elderly patients with advanced NSCLC.
Authors: Bordonaro Sebastiano , Butera Alfredo , Spinnato Francesca , Antonelli Giovanna , Gebbia Vittorio , Caruso Michele , Sciacca Dorotea , Tralongo Paolo
Published: March 2020

e18002

Background: In elderly patients with advanced stage NSCLC the identification of the best treatment-related quality of life becomes the main discriminating endpoint. Methods: In this multicentre study, 53 elderly (≥ 70 yrs) patients with advanced (IIIB-IV) NSCLC were randomly allocated to receive as first-line treatment either Gemcitabine intravenously (1000 mg/m2) or oral Vinorelbine (60 mg/m2) both on days 1 and 8, every 21 days. The primary objective was the evaluation of the QoL, while the secondary one was the assessment of treatment adherence. The EORTC QLQ-C30 v 2.0 and QLQ-LC13 questionnaires have been used to evaluate the quality of life and an “ad hoc” questionnaire for the estimate of adherence/compliance to treatment in patients receiving oral Vinorelbine. The questionnaires were filled in at baseline and every 3 cycles. Results: Forty-one patients (thirty-six males), median age of 75.7 years, have been considered suitable for evaluation. All patients filled in the QoL questionnaires at baseline, 18 of them after three cycles of treatment. Differences of mean score values of items recorded at each assessment were calculated. Referring to QLQ-C30, patients enrolled in the Vinorelbine arm displayed higher mean scores as compared to those of Gemcitabine. There was a gain of 5.6 points as regards Physical Function and 16.9 points for Social Function in the Vinorelbine arm as compared to 3 and 1.6 points in the Gemcitabine arm. A higher improvement of the symptoms Nausea and Vomiting and Sleep Disturbance in the Vinorelbine arm in comparison with Gemcitabine (- 7 vs. + 3.2 and – 21.3 vs. + 7.7, respectively) was also observed. Patients treated with oral Vinorelbine showed improvements of the majority of QLQ-LC13 scores and completed a higher number of cycles as compared to Gemcitabine. Most patients (93.5%) responded positively to the satisfaction questionnaire of oral Vinorelbine. Conclusions: Oral Vinorelbine may provide an advantage in terms of patient preference since, without reducing the effectiveness, is able to maintain an acceptable toxicity profile which results in a gain of the level of quality of life.
Phase II trial of bevacizumab plus docetaxel in patients with previously treated nonsquamous non-small cell lung cancer.
Authors: Ohyanagi Fumiyoshi , Tanimoto Azusa , Sakatani Toshio , Kawano Yuko , Saito Ryota , Kaburaki Kyohei , Yanagitani Noriko , Kudo Keita , Horiike Atsushi , Hagiwara Sachiko , Horai Takeshi , Nishio Makoto
Published: March 2020

e18004

Background: The additional effects of bevacizumab (B) as first line chemotherapy for non-squamous (Nsq) non-small cell lung cancer (NSCLC) have been established. However, the efficacy of bevacizumab as a second- or more line chemotherapeutic agent has not been well examined. Docetaxel (D) is a standard second line treatment for NSCLC, a synergistic effect of the combination of D and B being shown in preclinical models. Therefore, this phase II study was conducted to evaluate the efficacy and safety of DB in patients with previously treated Nsq NSCLC. Methods: Patients with histologically or cytologically confirmed Nsq NSCLC, 20 to 74 years of age, ECOG performance status 0-2, with at least one prior chemotherapy, were eligible for the study. Patients were treated with D (60 mg/m²) and B (15 mg/kg) on day 1, repeated every 3 weeks until progressive disease (PD)or unacceptable toxicity occurred. The primary endpoint was the response rate (RR), and planned sample size was 28 patients. Results: Between May 2010 and July 2011, 28 patients (16 males/12 females; median age 65 years; PS 0/1/2: 19/9/0; ad/other: 22/6, no. of prior chemotherapy 1/2/3/4/5: 16/5/2/1/4) were enrolled in the study. Among these patients, 28 were included in analysis of toxicities and 27 patients were evaluated for response. Objective response was observed in 18 patients (PR; 18, SD; 8, PD 1), the response rate and disease control rate being 66.7% and 96%, respectively. With a median follow-up of 12.7 months, the median progression free survival was 7.9 months and overall survival did not reach median. Main toxicities of this regimen were myelosuppression (G3/4 neutropenia 85.7% and febrile neutropenia 21%). Mild non-hematological toxicity with no severe bleeding was also observed. Conclusions: The combination of D plus B is a very active regimen in previously treated Nsq NSCLC, warranting further study.
Bevacizumab in combination with first-line metastatic chemotherapy in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Results from the cohort study EOLE.
Authors: Chouaid Christos , Schott Roland , Falchero Lionel , Bonnetain Franck , Neaume Julien , Bennouna Jaafar , Tagieva Naila
Published: March 2020

e18005

Background: EOLE, a large cohort of 423 patients included in 1 year (July 2010 – July 2010) with locally advanced, metastatic or recurrent non-squamous NSCLC, aimed to describe the targeted population receiving first-line bevacizumab (Bev) in addition to chemotherapy with regards to progression-free survival, overall survival, safety and quality of life in real clinical practice. Methods: Patients who received physician’s choice of 1st-line Bev-containing treatment were included in this cohort study. Results: This analysis describes the inclusion data of 417 patients consisting of adenocarcinoma (92%), large cell carcinoma (4%), undifferentiated carcinoma in predominantly non-squamous (3%), bronchoalveolar carcinoma (1%). Patient characteristics were as follow: the median age being 60 (years) [32; 84], more males than females (68%), 40% had a baseline ECOG Performance Status (PS) 0, 47% of PS 1 and 12% of PS 2, most patients had Stage IV disease (91%), 13% of patients had never smoked. Tumor location was reported as central for 17% of patents and among them 4% was in contact with the large vessels. For 3% of the lesions a cavitation was notified; and 20% of included patients had brain metastases. The main comorbidities at the inclusion were: cardiovascular (45%), arterial thromboembolic and /or venous (20%) with pulmonary embolism (3%); related to the tumor lesion - bloody sputum (4%) and hemoptysis (1%). 68% of patients have received the dose of Bev 7.5mg/kg q3w; for 49% of patients Bev was combined with cisplatin/pemetrexed, 24% with carboplatin/paclitaxel, 13% with carboplatin/pemetrexed and 7% with cisplatin/gemcitabine. The EGFR mutation analysis was carried out for about 50% of patients. Conclusions: Compared to AVAil and SAil studies, EOLE cohort included more patients classified as having: a baseline PS of 2 (p <0.0001, Fisher test), a never smoked status (p<0.0001, chi2 test) and an adenocarcinoma (92%) (p<0.0001, chi2 test). Around a half of included patients received combination Bev - cisplatin /pemetrexed.
Identification of a microRNA (miRNA) based signature for survival in advanced non-small cell lung cancer (NSCLC) patients (pts) treated with cisplatin-vinorelbine: A ELCWP study.
Authors: Berghmans Thierry , Willems Luc , Paesmans Marianne , Ameye Lieveke , Lafitte Jean-Jacques , Meert Anne-Pascale , Scherpereel Arnaud , CsToth Ingrid , Cortot Alexis B. , Mascaux Celine , Leclercq Nathalie , Sculier Jean Paul ,   European Lung Cancer Working Party
Published: March 2020

e18006

Background: Main prognostic factors for survival in NSCLC pts are stage and performance status (PS) while sex, histology and others are reported. However, these variables do not allow predicting individual prognosis, justifying further research. MiRNA are small non-coding RNAs regulating gene expression. As a secondary aim of a prospective study, we looked at the prognostic value of tumour miRNA on survival in NSCLC pts treated by cisplatin (60 mg/m2 D1) and vinorelbine (25 mg/m2, D1+8) 1st line chemotherapy. Methods: During the diagnostic bronchoscopy, a biopsy was lysed into Tripure Isolation Reagent (Roche Diagnostics) on ice, snap frozen and stored at -80°C. MiRNA expression was assessed using TaqMan Low Density Arrays (756 human miRNA panel, Applied Biosystems) and normalized using the delta delta CT method to RNU48 (SNORD48) CT value for every sample. Survival was measured from the registration date. Results: The main characteristics of 38 eligible pts were: median age 60 years, male 27 (71%), 80-100 Karnofsky PS in 26 (68%), adenocarcinoma 20 (53%), stage IV 30 (79%). At time of analysis, 25 pts were dead. After stepwise selection among 756 analysed miRNA, a combination of 4 miRNA including miR-200c, miR-424, miR-29c and miR-124 provided a prognostic signature for survival. Using a linear combination of the miRNA CT values with Cox's regression coefficients as weights, we constructed a prognostic score. With a cut-off of 52, the signature distinguished pts with good (n = 18) and poor (n = 20) prognosis with respective median survival of 47.3 months (95% CI 29.8-52.4) and 15.5 months (95% CI 9.1-22.8) (p <0.001; hazard ratio 21.1, 95% CI 4.7-94.9). The same signature discriminated pts with “good progression-free survival” (median 19.8 months; 95% CI 15.3-33.8) from the others (median 9.1 months; 95% CI 6.3-15.5) (p <0.001; hazard ratio 3.8, 95% CI 1.7-8.7). Conclusions: A 4 miRNA signature is associated with improved survival in patients with advanced stage NSCLC treated with 1st line cisplatin and vinorelbine. These results need confirmation in an independent cohort and the signature has to be compared to conventional prognostic factors.
Differential effect of erlotinib on survival of patients with non-small cell lung cancer in terms of EGFR status: A meta-analysis.
Authors: Tun Nay Min , Nayak Asha
Published: March 2020

e18024

Background: Erlotinib is a small-molecule tyrosine kinase inhibitor that inhibits the protein kinase activity of epidermal growth factor receptor (EGFR). The primary objective of this meta-analysis is to compare the response of patients with EGFR-positive versus EGFR-negative advanced non-small-cell lung cancer (NSCLC) to erlotinib in terms of overall survival (OS) and progression-free survival (PFS). Methods: A Medline search using the MeSH terms “erlotinib” and “lung” in the title field, filtered by ‘clinical trial’, yielded 108 articles. Clinical trials involving erlotinib with available survival data on EGFR-positive versus EGFR-negative NSCLC were searched for. The intervention effect estimate and standard error of each study was derived from the hazard ratio (HR) and p value. Generic inverse variance method was applied to compute the overall effect size and HR with 95% confidence interval (CI). Fixed or random effects model was used according to the level of between-study heterogeneity. Results: 3 studies including 504 patients were eligible for the analysis. All patients received erlotinib in a single arm. EGFR gene mutation was tested in 326 patients (35 mutation-positive, 188 wild-type, 103 indeterminate). EGFR gene amplification by fluorescent in-situ hybridization (FISH) was studied in 353 patients (100 positive), and EGFR protein expression by immunohistochemistry (IHC) in 368 patients (290 positive). Patients with EGFR gene mutation had significantly longer PFS (HR = 0.4, CI 0.25-0.64, p = 0.0001) but not OS (HR = 0.59, CI 0.18-1.95, p = 0.39). In contrast, EGFR FISH-positivity was associated with better PFS as well as OS (HR = 0.52, CI 0.39-0.71, p < 0.00001 and HR = 0.65, CI 0.47-0.88, p = 0.006, respectively). Conclusions: Results of EGFR gene amplification by FISH rather than EGFR gene mutation by PCR may be a better predictor of survival for advanced NSCLC patients receiving erlotinib. Subgroup analyses of erlotinib's differential effect on NSCLC patients with regard to their EGFR status (as measured by PCR, FISH or IHC) are further warranted in randomized controlled trials.
Activity and safety of CPBev regimen (cisplatinum, pemetrexed, and bevacizumab) as first-line therapy for locally advanced or metastatic adenocarcinoma of the lung: Final results of a phase II study.
Authors: Bordonaro Roberto , Soto-parra Hector , Giannitto-Giorgio Carmelo , Cinieri Saverio , Latteri Fiorenza , Sergi Concetta , Pappagallo Giovanni L. , Cordio Stefano Sergio , Salice Placida , Sambataro Daniela , Potenza Enrico
Published: March 2020

e18026

Background: During the past five years the paradigms of advanced lung cancer therapy dramatically changed; Bevacizumab and Pemetrexed, when administered separately in association with platinum salts, demonstrated to improve survival in patients with non-squamous histologies. In the aim to investigate activity and safety of a three-drugs-regimen containing both these agents and cis-platinum, we conducted a multi-institutional phase II study started on november 2007. Methods: chemonaive patients with non-squamous non-small cell lung cancer were considered eligible We adopt the two-stage of Simon model as statistical design of the study; activity of the regime, expressed as overall response rate and safety were the main end-points. Administered doses were 75 and 500 mg/p.s.m for cis-platinum and pemetrexed respectively and 7.5 mg./kg for Bevacizumab, for 3 - 6 cycles. G-CSF were administered only after the first cycle of therapy, whereas vitamin supplementation started from day 1 of the first cycle. No maintenance therapy was allowed. Results: We registered 9 partial responses among the first 15 patients treated so, accordingly with the design of the study, we completed the enrollment up to 32 patients. Patients characteristics are: male/female: 20/12, median age (years): 59 (r. 36 - 77), ECOG-WHO/PS 0/1: 21/11. One hundred eighty-three cycles of CPBev were administered: we registered only 13 cases of grade 3 adverse events. No grade 4 toxicities were observed. One case of allergic reaction to cis-platinum were observed. In terms of response rate, we registered 20/32 (62.5%) partial responses, 8/32 (25%) stable diseases and 4/32 (12.5%) progressive diseases, with a clinical benefit rate of 28/32 (87.5%). Results in terms of outcome parameters expressed by progression-free and overall survival will be presented at the meeting. Conclusions: On the basis of our data, CPBev have a good toxicity profile and seems to be extremely active in advanced non-squamous lung carcinomas.
Endostar plus gemcitabine/cisplatin (GP) with maintenance endostar as first-line therapy for advanced non-small cell lung cancer (NSCLC): Preliminary results of a phase II study.
Authors: Lu You , Huang Meijuan , Fan Qingxia , Wu Qi , Wang Jin , Li Lu , Zhang Xi , Guo Chengye , Li Wenhui , Peng Feng , Ouyang Xuenong , Yu Ding , Cai Xiaohong , Xu Yong , Hou Mei , Luo Rongcheng , Zhang Tao
Published: March 2020

e18033

Background: Endostar is a recombinant human endostatin. We conducted a multi-centre trial to investigate the efficacy and safety of Endostar plus GP with maintenance Endostar as first- line therapy for advanced NSCLC Methods: Chemotherapy-naïve patients with histologically or cytologically confirmed, measurable, stage ‡W NSCLC were enrolled from 11 centers in China. All patients received gemcitabine 1,000 mg/m2 (days 1 and 8) plus cisplatin 25 mg/m2 (days 1-3) every 21 days. Patients achieving objective response or disease stabilization following initial 2 cycles of GP were given Endostar (15 mg) on days 1–14 every 21 days in combination with another 2 cycles of GP. Then, patients who did not progress received maintenance endostar (15 mg) on days 1–14 every 21 days until disease progression or unacceptable toxicity. The primary was progression-free survival (PFS). Secondary endpoints were treatment-related toxicity and median overall survival (OS). Results: Between Oct.2008 and Sep. 2010, we enrolled 85 patients (median age: 52.2 years; median KPS score: 80; stage IV with M1b: 94.1%; adenocarcinoma: 64.6%). 48 (56.5%) patients complete 4 cycles of GP plus 2 cycles of Endostar and 33(38.8%) patients were treated with maintenance Endostar. For 38 patients receiving maintenance therapy, median PFS throughout the study period by independent review was 5.97 month and 1-year survival rate was 75.8%. Median PFS were 3.97 months for all 85 patients, while 1-year survival rate was 64.7%. No treatment related death occurred. 28(32.9%) patients had at least one grade 3/4 adverse events; the grade 3/4 hematologic toxicity included anemia in 32.9%, thrombocytopenia in 25.9%, neutropenia in 4.7% of patients. The grade 3/4 non-hematologic toxicities included nausea/vomiting in 18.8%, rash in 5.9%, hepatic impairment in 3.5%, diarrhea in 1.2%, hemorrhage in 1.2% of patients. Conclusions: This regimen, involving maintenance Endostar, didn’t significantly improve PFS in advanced NSCLC patients as compared to historic control although associated acceptable toxicity has been demonstrated
CEA levels and EGFR mutations associated with patients in nonsmokers lung cancer.
Authors: Han Baohui , Dong Yu , Zhang Yanwei , Jin Bo
Published: March 2020

e18038

Background: Background: As the non-smoking Asian patients with adenocarcinoma of the EGFR gene tend to have higher mutation rate, and serum CEA levels in patients with lung cancer, especially adenocarcinoma, high expression in many recent years, studies have also found that serum CEA levels in EGFR-changes before and after TKI therapy efficacy and treatment are closely related. However, whether serum CEA level and EGFR gene mutations is a correlation between two biomarkers. This study attempts to explore its relevance between EGFR gene mutations and analysis of serum CEA levels in non-smoking patients with lung cancer and it’s various clinical and pathological features. Methods: 84 cases of histologically confirmed non-smoking history in newly diagnosed lung cancer patients, respectively, serum CEA levels and histological detection of EGFR gene. According to the expression level of serum CEA patients were divided into high expression and did not express two groups were compared in patients with EGFR gene mutations. Results: 58/84 cases were found with activity EGFR gene mutations, the overall mutation rate was 69.0%, serum CEA levels high expression of EGFR gene mutation was significantly higher than non-expression group (serum CEA levels were <5ng/ml, ≥ 5ng/ml <20ng/ml, ≥ 20ng/ml patients with EGFR gene mutations histology were 63.2%, 70.8%, 81.8%). Conclusions: Non-smoking lung cancer patients with serum CEA levels and EGFR gene mutations was positively correlated.
Periodic measurement of N-telopeptides of type I collogen in serum (sNTx) for early diagnosis of bone metastasis in patients with lung cancer.
Authors: Takeda Koji , Tokunaga Shinya , Daga Haruko , Okada Hideaki , Taira Koichi , Miyamoto Natsuko , Hattori Michiyo , Tamiya Motohiro , Kobayashi Masashi , Okamoto Norio , Sasada Shinji , Suzuki Hidekazu , Morishita Naoko , Matsuura Yuka , Hirashima Tomonori
Published: March 2020

e18042

Background: The bone resorption biomarker sNTx has been previously shown to add value as an aid in the diagnosis of bone metastasis in patients with lung cancer. The objective of this prospective study was to determine if periodic sNTx measurements could lead to early diagnosis of bone metastasis in patients with lung cancer. Methods: Patients with newly diagnosed organ-confined lung cancer were enrolled. sNTx values were determined once each month using the OSTEOMARKTM serum NTx assay (Alere Medical). The presence or absence of bone metastasis was determined by monthly physical examination and by bone scintigraphy every 3 months for 12 months. All patients were required to provide written informed consent. Results: Forty patients were enrolled between June and December 2010. One patient withdrew early and was excluded from analysis. The mean +/- 1 SD baseline level of sNTx was 17.5 +/- 4.4 nM BCE/L. Five patients developed bone metastasis (as characterized by bone scintigraphy) during the study period. The level of sNTx in subjects with bone metastasis was slightly increased (21.6 +/- 3.2 nM BCE/L), however, in these patients, there was no statistically significant difference between sNTx values at baseline (18.2 +/- 4.2 nM BCE/L) and when metastasis was diagnosed. (p=0.176). When a cut-off value of sNTx was set to 22.0 nM BCE/L, the sensitivity and the specificity of detection of bone metastasis were 80.0% and 41.2%, respectively. Using this cut-off, the elevation of sNTx could predict bone metastasis at least one month before diagnosis by bone scintigraphy in all 5 patients, however, the specificity was relatively low for clinical implementation. Additionally, the sensitivity and the specificity of early detection of systematic spread of disease (including bone metastasis) were 70.6% and 45.5%, respectively. Conclusions: Periodic determination of sNTx in patients with organ confined lung cancer did not provide sufficient specificity for it to be used for the early diagnosis of bone metastasis or disease progression.
Metastatic NSCLC: Can molecular biology guide surgical decision making?
Authors: Ulivi Paola , Mattioli Sandro , Puccetti Maurizio , Capelli Laura , Zoli Wainer , Ricci Marianna , Calistri Daniele , Amadori Dino , Milandri Carlo
Published: March 2020

e18045

Background: Guidelines do not recommend surgical resection of metastatic non-small cell lung cancer (NSCLC), with the exception of single brain or adrenal gland lesions, and further resection in the event of a new lung metastasis is generally not indicated. A different therapeutic approach is used in patients with multiple primary lesions. Can molecular alterations help to distinguish between independent primary tumors and metastatic lesions? Methods: A 74-year old woman underwent bilateral inferior lobectomy in May 2008 for two different synchronous NSCLC (adenocarcinoma and adenocarcinoma in situ, formally known as “bronchioloalveolar carcinoma” – J Thorac Oncol 2011;6:244–285). Three months after surgery the patient developed a single symptomatic brain metastasis. A CT scan also highlighted a suspect lingular lesion of the lung. Stereotaxic brain radiotherapy was carried out followed by systemic platinum-based chemotherapy. The brain metastasis showed very good radiological partial remission (PR) while the lung lesion remained stable after 4 cycles of chemotherapy. After two years’ follow-up the brain metastasis remained in PR whereas the lung lesion had progressed, and fine needle aspirate revealed adenocarcinoma. Results: Molecular analysis showed that EGFR gene status was wild type in all three tumors, whereas K-ras gene status differed. With regard to the two synchronous tumors, a barely visible G12C K-ras gene mutation was found in the bronchioloalveolar carcinoma, while a G12D K-ras mutation was detected in the adenocarcinoma. Moreover, K-ras gene status in the lingular node revealed a G12A mutation. On the basis of these results we hypothesized the presence of a third lung cancer and it was decided to proceed with surgery. The patient underwent laparoscopic lingulectomy which confirmed the diagnosis of adenocarcinoma with the same G12A K-ras mutation. Conclusions: This case highlights the importance of the molecular characterization of tumors in patients with multiple lesions. Different alterations within a single gene in different lesions are indicative of an independent clonal origin and suggestive of separate primary tumors rather than secondary lesions, thus facilitating treatment decision making.
Two genetic polymorphisms of EGFR as useful predictive biomarkers for NSCLC patients receiving EGFR TKIs.
Authors: Kang Jin Hyoung , Shin Jung-Young , Kim Jeong-Oh , Oh Ji-Eun , Zhang Xiang-Hua , Hong Sook Hee , Jeon Eun Kyoung , Cho Eun Kyung
Published: March 2020

e18050

Background: The EGFR mutation on particular exons has been known as a strong predictive biomarker to EGFR TKIs (tyrosine kinase inhibitors) in NSCLC pts. However, some pts having wild type EGFR do not infrequently show clinically favorable outcome to EGFR TKIs. Accordingly, we hypothesized that clinical outcome and skin toxicity to EGFR TKIs might be related to specific single nucleotide polymorphisms regulating the expression of EGFR gene as well as EGFR sensitive mutation. Methods: In 211 advanced or metastatic NSCLC pts receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using PNA clamping method and direct sequencing. Six different SNPs in genomic DNA extracted from peripheral blood were analyzed; promoter 191C>A, 216 G>T, CA repeat number, exon 13 R497K, exon 20 2607G>A, and exon 25 D994D. Results: M:F ratio was 106:105 and mean age was 63.2 (35.0-82.0). Histological subtypes are as follows: 175 adenocarcinoma, 32 squamous cell ca. and 3 large cell ca. Objective response (CR+PR) was observed in 78 pts (36.9%) and SD in 69 pts (32.7%). Median PFS and OS were 8.7 ± 11.3 and 15.9 ± 14.8 months, respectively. Of 167 pts in whom EGFR mutation was analyzed, 68 pts (40.7%) had EGFR harboring sensitive mutation. In R497K, wild type (RR) was 35 (21.0%) and K alleles (RK + KK) were 132 (79.0%). In D994D, wild type (GG) was 76 (45.5%) and heterozygote and homozygote variants (GA+AA) were 91(54.5%). Statistically significant differences of PFS and OS were observed between wild and hetero-/homozygote variants of R497K (11.9 m vs. 36.2 m, p=0.037 and 23.7 m vs. 39.1 m, p=0.054, respectively) in the pts harboring mutant type EGFR. Meanwhile, in the pts harboring wild type EGFR, GA+ AA genotype of D994D demonstrated much longer PFS and OS compared with GG genotype (PFS: 18.5 vs. 3.7 m, p=0.013 and 37.6 vs. 15.2 m, p=0.035, respectively). In addition, skin rash showed statistically significant association with R497K polymorphism (P=0.031). Conclusions: Our data suggest that two germline genetic variations of EGFR gene, R497K and D994D, be useful pharmacogenetic biomarker to predict longer PFS and OS for EGFR TKIs in advanced NSCLC pts harboring mutant type and wild type EGFR, respectively.