bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of EGFR tyrosine kinase inhibitors on skeletal-related events in EGFR mutation-positive non-small cell lung cancer patients with bone metastases.
Authors: Yoshida Tatsuya , Yoh Kiyotaka , Goto Koichi , Umemura Shigeki , Niho Seiji , Ohmatsu Hironobu , Nagai Kanji , Ohe Yuichiro
Published: March 2020

e18054

Background: Clinical outcome of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients with bone metastases is less well known. The purpose of this study was to evaluate the clinical outcome of EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR tyrosine kinase inhibitors (TKIs). Methods: From January 2008 to December 2010, 127 patients received first-line chemotherapy for advanced or postoperative recurrent NSCLC with bone metastasis at our institution. EGFR mutational status was analyzed using a PCR-based assay for EGFR exons 18 to 21. Clinical outcome including the incidence of skeletal-related events (SREs), time to the first SREs from first-line chemotherapy and overall survival (OS) was evaluated by the EGFR TKIs-sensitive mutations status (either exon 19 deletion or L858R in exon 21). SREs were defined as a pathologic fracture, spinal cord compression, surgery to bone, radiation therapy (RT) to bone, other radiological intervention, and hypercalcemia of malignancy. Results: Sixty-two (50%) of the 125 patients were sensitive EGFR mutations positive. 39 of 62 (63%) EGFR mutation-positive patients were treated with EGFR TKIs (gefitinib or erlotinib) as first-line chemotherapy, and most of negative patients received cytotoxic agents such as platinum-based chemotherapy. Zoledronic acid were administered in 50 % of EGFR mutation-positive patients, and in 57 % of negative patients, respectively (P= 0.59). With a median follow-up of 13 months, the incidence of SREs were 21% in EGFR mutation-positive patients, and 38% in negative patients, respectively (P<0.05). Additionally, median time to first SREs from first-line chemotherapy in EGFR mutation-positive patients was significantly longer than negative patients (13 months versus 6 months, P<0.05). Median OS in mutation-positive patients was 26 months, as opposed to 12 months in negative patients (P<0.05). Conclusions: Our study indicated that EGFR mutation-positive NSCLC patients with bone metastases who were treated with EGFR TKIs have favorable clinical outcome on SREs compared with mutation-negative patients.
Utility of nonsurgical diagnostic specimens in cellular differentiation and molecular profiling (EGFR mutation and EML4-ALK detection) of NSCLC.
Authors: Cohen Victor , Levitt Amanda , Kasymjanova Goulnar , Agulnik Jason Scott , Al Banna Amr , Small David I. , Pepe Carmela , Spatz Alan , Brandao Guilherme
Published: March 2020

e18061

Background: The utility of different non-surgical specimens for the accurate determination of cellular and molecular attributes in NSCLC has yet to be established. The primary objective of this study was to determine and compare the yield of non-surgical specimens for the accurate cellular differentiation of NSCLC and analysis of EGFR and EML4-ALK mutations. Methods: Patients with a histologic diagnosis of NSCLC from January 2004 to September 2010 were included. Diagnosis was based on cytological characteristics and IHC analysis. Fragment analysis and real-time PCR methods were used for EGFR mutation detection. EML4-ALK rearrangements were detected by FISH. Diagnostic specimens were divided into pathology specimens (PS) and cytology specimens (CS). PS included surgical and non-surgical biopsies. CS included FNA (TBNA and TTNA) and body fluid samples. These groups were compared using χ2 analyses. Yield of histologic analysis was compared in a subgroup of patients who underwent both surgical and non-surgical procedures. Results: 715 patients were included in the study. The yield of CS when compared to PS was lower for cellular differentiation (76% vs. 91%, p <0.0001) and IHC (70% vs. 89%, p <0.0001). Among the CS, TTNA provided better yield than TBNA for cellular differentiation (89% vs. 67%, p < 0.0001) and IHC (85% vs. 72%, p = 0.023). 94 patients underwent both surgical and non-surgical procedures. As compared to surgical biopsies, the yield of non-surgical procedures for cellular classification was 81% in body fluid samples, 68% in FNA, and 88% in non-surgical biopsies. 320 patients were tested for both EGFR and EML4-ALK mutations. The yield of CS versus PS was lower for EGFR mutation status (74% vs. 93% p < 0.0001). Among the CS, TTNA provided better yield than TBNA for EGFR mutation analysis (90% vs. 70%, p = 0.045) and body fluid samples were least likely (59%) to provide EGFR mutation status. Three EML4-ALK FISH-positive cases were identified. All samples were PS. All EML4-ALK positive cases tested negative for EGFR mutations. Conclusions: Non-surgical lung biopsy specimens can yield sufficient samples for histologic assignment and mutational analysis.
KRAS mutations as predictive biomarker in patients with EGFR wild-type stage IV nonsquamous non-small cell lung cancer (NSCLC) recruited in a phase II clinical study with carboplatin-docetaxel-bevacizumab.
Authors: Domine Manuel , Izarzugaza Yann , Rojo Federico , Lobo Francisco , Fernandez-Acenero Maria Jesus , Casado Victoria , Rubio Gustavo , Arranz Juan Luis , Leon Ana , Martin-Valades Jose Ignacio , Serrano Gloria , Carames Cristina , Cordova Sharon , Madoz Juan , Zazo Sandra , Rincon Raul , Canadas Carmen , Campos Angel , Perez-Gonzalez Nuria , Garcia-Foncillas Jesus ,   Oncology Department. Hospital Universitario. Fundación Jiménez Díaz. Universidad Autónoma de Madrid. Spain
Published: March 2020

e18069

Background: KRAS mutation are harbored in ~30% of NSCLC patients, and have been described associated with an upregulation of genes involved in angiogenesis, including vascular endothelial growth factor/vascular permeability factor (VEGF/VPF). Bevacizumab (BVZ) is a recombinant monoclonal humanized antibody targeted against VEGF and added to carboplatin-paclitaxel chemotherapy has demonstrated to improve outcome in non-squamous NSCLC. The objectives of this study were to analyze the impact of KRAS mutations in response rate (RR) and time to progression (TTP) in a cohort of patients homogeneously treated with BVZ in combination with carboplatin-docetaxel. Methods: Patients treated with up to 6 cycles of carboplatin (AUC 5), docetaxel (75 mg/m2) and BVZ (7.5 mg/kg) on day 1, every 21 days. Patients with RR or stable disease continued maintenance BVZ (7.5 mg/kg) every 21 days until disease progression. KRAS mutations at codons 12, 13 and 61 were analyzed by COBAS KRAS Mutation Test (Roche) from DNA purified from diagnostic samples. Results: 30 patients were enrolled (24 male, 6 female); median age was 62 years (range 44-82); ECOG 1/2: 22/8. 27 were adenocarcinomas and 3, undifferentiated large cell carcinoma. Smoking habit: 1 non-smoker, 16 current-smoker, and 13 former-smoker. Seven patients were KRAS mutated (23.3%). Carboplatin-docetaxel-bevacizumab therapy showed a significant improved efficacy in KRAS wild-type compared to mutated patients (RR: 85.7% vs 14.3%, p=0.045; and TTP: 9.38 months vs 7.46 months, p=0.033), but did not impact on overall survival (12.4 months in wild type vs 11.06 months in KRAS mutated, p= 0.780). Conclusions: KRAS mutations predict RR and TTP in wild-type EGFR stage IV non-squamous NSCLC patients treated with bevacizumab-based therapy.
Sorafenib (SOR) in advanced non-small cell lung cancer (NSCLC): A phase II study of patient progress after several lines of treatment.
Authors: Vazquez-Estevez Sergio , Varela Silvia , Campos Begoña , Álvarez Elena , Quintero Guillermo , Mel Jose Ramón
Published: March 2020

e18070

Background: Sorafenib is a potent inhibitor of c-Raf, b-Raf VEGFR-1/2/3 and PDGFR-β. In NSCLC, proliferative signaling through the Ras/Raf/MEK/ERK pathway is often activated from K-ras mutations. Their efficacy as monotherapy to treat advanced NSCLC has been demonstrated in several trials. In them, SOR improved the rate of disease stabilization in patients who had previously been treated with chemotherapy. Our objective is to confirm the clinical and safety results in the daily clinical activity. Methods: Between October 2008 and December 2011, patients with metastatic NSCLC and measurable disease, ECOG 0-1 were treated after having received two or more prior chemotherapy regimens for metastatic disease. SOR was administered at a starting dose of 400 mg bid continuously in 28-day cycles.The primary end points were Overall Survival (OS) and Progression Free Survival (PFS). Survival medians were estimated by the Kaplan-Meier method and comparisons between subgroups were assessed by the log-rank test. Results: Fifteen Caucasian patients were enrolled, with a mean age at diagnosis of 61 (SD = 13.5) years and most of them were males (n = 10, 67%). The predominant histologic type was adenocarcinoma (n = 9, 60%). Twelve (80%) patients were in stage IV at diagnosis. The predominant metastatic sites were lung (n = 8, 53%), lymph nodes, (n = 5, 33%), pleura (n =3, 20%) and bone (n=3, 20%).Patients received a median of 3 (range: 2 to 4) treatment lines prior to the SOR regimen, with a median duration of 80.5 (range: 9 to 247) days.Median OS and median PFS were 98 and 84 days, respectively. No significant differences in survival were found according to gender, smoking, histologic type, stage, metastatic site, ECOG nor presence of biomarkers.The toxicity profile was mild. Adverse events CTC G3/4 were dyspnea (n = 4, 27%), skin toxicity (n = 1, 7%) and vomiting (n = 1, 7%). Conclusions: In this study, patients with metastatic NSCLC receiving SOR had a median PFS of 3 months. The safety profile is acceptable, reversible and manageable without unexpected adverse events to this therapy. While still waiting for the results of ongoing trials, we can say thatSOR is safe, so far, in patients who have been widely treated.
Effect of cancer-associated fibroblasts on cell proliferation and resistance to EGFR-TKI in direct coculture with lung cancer cell lines.
Authors: Lee Jinseon , Choi So-Jung , Kim Jhingook , Kim Sung-Hyun
Published: March 2020

e18083

Background: Identical lung cancer cells may get diversified depending on tumor microenvironments. We hypothesized that diversity of cancer associated fibroblasts renders identical lung cancer cells various tumor characteristics such as drug responsiveness and proliferation rate. To test this hypothesis, we isolated cancer associated fibroblasts from 20 different lung cancers, and compared their effects on the proliferation and drug responsiveness of lung cell lines. Methods: Cancer associated fibroblasts were isolated from 20 solid tumors of NSCLCs, and treated with Mitomycin to control the overgrowth during cocultures. H358 and A549 cells were mixed with cancer associated fibroblasts in 1:1 ratio and co-cultured for 4-7 days. Cell number was scored by time-lapse photography, and cell morphology was observed under fluorescent microscope. Expression of cell type markers were examined. Responsiveness to Erlotinib was examined in coculture condistions. Results: Cancer associated fibroblasts stimulated cancer cell proliferation ranging from almost no effects to approximately 3 folds. Coculture in transwell with no direct contacts with cancer cells showed minimal stimulatory effects. Direct contacts induced dramatic changes in cancer cell morphology from cohesive epithelial colonies to dispersed fibroblastic single cells. EMT markers such as down-regulation of Cytokeratins and up-regulation of Vimentin were detected in GFP positive cells. A549 cells that were sensitive to 15 uM Erlotinib (IC50=7.5uM) became resistant when co-cultured with cancer associated fibroblasts. Conclusions: In this study, cancer associated fibroblasts isolated from different lung cancers induced significant changes in tumor cell characteristics such as proliferation, EMT, and drug responsiveness.
Safety and efficacy of paclitaxel liposome monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer: A prospective, multicenter, uncontrolled phase II study.
Authors: Ding Zhenyu , Zhou Lin , Lu You
Published: March 2020

e18086

Background: Recently, a novel form of paclitaxel encapsuled within liposome was developed with increased solubility and a longer half life in vivo. The aim of this study was to evaluate the safety and efficacy of paclitaxel liposome as a single agent chemotherapy for elderly patients with NSCLC. Methods: This study was a prospective, uncontrolled, open-label, multi-center, registered phase II trial (ChiCTR-TNC-00000226).Patients aged over 70 years with metastatic or recurrent non-small cell lung cancer were enrolled. Eligibility criteria included presence of measurable lesions, an ECOG PS of 0-2 as well as adequate organ function. Patients received paclitaxel liposome at an escalating dose of 135mg/m2, 150 mg/m2 and 175 mg/m2 every 3 weeks, and were monitored for safety and efficacy. Results: From 8 participating centers, 42 patients were enrolled with a median age of 73 years (range 70-81). A total of 89 cycles of chemotherapy was administered. No complete response was observed. 6.7%, 14.2% and 7.7% of patients obtained partial response, and 13.3%, 42.9% and 38.5% had stable disease from the escalating dose groups, respectively. The toxicity was mainly neutropenia, thrombopenia and digestive tract toxicity.There were 4 (26.7%), 3 (21.4%) and 3 cases (25%) of grade 3 or 4 neutropenia in the three dose group. Other non-hematological toxicities over grade 3 were rare. Pre-mature cease of chemotherapy occurred in 1 (7.1%) and 2 (16.6%) patients from the dose group of 150 mg/m2 and 175 mg/m2 respectively, all because of persistent toxicity. Median follow-up was 12.4 months (1.0-22.3 months). TTP in three dose group was 1.2 months (95%CI, 1.1-1.3 months), 1.2 months (95%CI, 0.9-1.3 months) and 1.9 months (95%CI, 1.4-2.3 months). Median OS in the dose group of 135 mg/m2 was 4.9 months (95%CI, 1.0-11.5 month), and not reached in the other groups. Conclusions: Paclitaxel liposome administered at the dose of 150 mg/m2 every 3 weeks seems to be safe and effective among these three dose levels. Although the toxicity profile was mild, the overall therapeutic effects were disappoiting.
Circulating endothelial cells and serum caspase-cleaved CK18 to predict for response and survival in non-small cell lung cancer patients receiving endostatin and paclitaxel-carboplatin combined chemotherapy.
Authors: Chu Tianqing , Ding Hao , Gu Aiqin , Pei Jun , Han Baohui , Du Weidong
Published: March 2020

e18088

Background: Combinations of anti-angiogenic drugs with chemotherapeutics are widely used for cancers control. Whether can better efficacy of such a combinated modality be achieved and predicted earlier is a great challenge. Circulating endothelial cells (CECs) and cytokeratins (CKs) might have a role in tumour angiogenesis and in tumour cell death. Measurement of CECs and CKs in the blood of patients with tumors could be a simple, non-invasive approach to monitor or predict responses and survival to treatment. Methods: One hundred and seven patients with primary advanced non-small cell lung cancer (NSCLC) were enrolled, randomly assigned to either the endostatin treatment group (paclitaxel+ carboplatin+ endostatin) or the control group (paclitaxel+carboplatin). CEC count and serum CK8, caspase-cleaved CK18 (ccCK18) and uncleaved CK18 (CK18) were measured in the 107 subjects at before treatment (baseline), week 3, and week 6 of treatment, respectively. Results: Higher baseline CEC count was observed in patients with good tumor response (p=0.002 for all the 107 patents; p=0.000 in the treatment group). When compared with the baseline level, after 6 weeks therapy in the endostatin group, CECs decreased significantly (p=0.000), but the CKs levels increased. The increased levels of ccCK18 and CK18 at week 6 reached significance in the treatment group (p=0.001 and p=0.048, respectively). Tumor response showed strong correlation with the reduction extent of CECs (p=0.000) and the increase value of ccCK18 (p=0.040) after endostatin therapy. The best cut-off values of the changes of CECs and ccCK18 for prediction of survival were designed being 0.58/ul and 19.6ng/ml, respectively. Furthermore, obvious reduction of CECs and more rise of ccCK18 significantly correlated with the longer median survival (p= 0.013 and p = 0.016 for PFS, p = 0.009 and p=0.012 for OS, respectively). Conclusions: CECs and CKs would be the impressive biomarkers to explore for selecting NSCLC patients who might benefit from endostain in combination with paclitaxel plus carboplatin treatment.
Role of cMET expression in non-small cell lung cancer patients treated with EGFR tyrosine kinase inhibitors.
Authors: Chang Hyun , Zhang Xianglan , Kim Da Rae , Kim Gun Min , Kim Se Hyun , Kim Joo-Hang , Cho Byoung Chul
Published: March 2020

e18092

Background: We performed this study to investigate whether activation of cMET is associated with sensitivity to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in non-small-cell lung cancer (NSCLC) patients. Methods: This retrospective study included 69 NSCLC patients with available tumor tissue, treatment response and survival data. cMET and hepatocyte growth factor (HGF) status was evaluated by immunohistochemistry. Results: A positive cMET, cMET[pY1003], cMET[pY1234/1235] and HGF were identified in 89%, 44%, 20% and 89% of cases, respectively. Positive cMET[pY1003] expression was associated with better objective response rate (OR) and clinical benefit rate (CBR) (OR, P = 0.033 and CBR, P = 0.039). Positive cMET[pY1234/1235] was significantly associated with a longer overall survival (OS) (P = 0.012) and time-to progression (TTP) (P = 0.031). Multivariable model confirmed that cMET[pY1234/235]-positive patients had a significant reduction in the risk of death and disease progression than cMET[pY1234/1235] –negative patients [OS; hazard ratio(HR)=0.29, P = 0.008 and TTP; HR=0.43; P=0.024] Conclusions: cMET expression in tumor tissue could be useful for predicting the clinical outcome of EGFR-TKIs treatment. Our results suggest that cMET expression in tumor tissue could be used to refine the selection of NSCLC patients expected to benefit from EGFR-TKIs treatment.
Response prediction by MALDI-TOF-MS serum peptide profiling of combination treatment with sorafenib and erlotinib in patients with non-small cell lung cancer.
Authors: Rovithi Maria , Lind Joline S. , Pham Thang V , Knol Jaco C , Verheul Henk M.W. , Smit Egbert F , Jimenez Connie R.
Published: March 2020

e18094

Background: Mass spectrometry can be used to generate diagnostic peptide peak profiles "signatures" of serum samples1. Peak profiles can be used to compare different sera and correlate samples (i.e., patient groups) with clinical data to assist in diagnosis, monitoring, and/or prediction. Indeed, in recent studies, we and other researchers have successfully combined serum peptide profiling by mass spectrometry (MS) with bioinformatics and have established distinctive serum polypeptide MS patterns that correlate with cancer types and clinically relevant outcomes2. We performed serum peptide profiling of patients with advanced stage non-small cell lung cancer (NSCLC) treated with erlotinib and sorafenib in a previously reported clinical trial at baseline, after one week of treatment, and after three weeks of treatment, to establish treatment efficacy signatures. Methods: Using automated magnetic C18 bead-assisted serum peptide capture coupled to matrix-assisted laser desorption/ ionization time of flight mass spectrometry (MALDI-TOF MS), serum peptide profiling1 of 50 NSCLC patients was conducted and peptide mass profiles (spectra) obtained. Data analyses of pretreatment serum peptide profiles, as well as dynamic changes in peptide abundance during treatment, were performed to establish support-vector machine-based algorithms that can predict treatment efficacy. Results: A 13 ion-peptide signature could discriminate with a sensitivity of 93% and specificity of 71% a training group of patients with short progression free survival (n=14) and long progression free survival (n=14). The signature shows discriminative power for the remaining non-overlapping set of 22 patients, as well as for the complete dataset of 50 patients. Pattern analysis of overall responses and toxicity is ongoing. Conclusions: Serum peptidome profiling using MALDI-TOF-MS coupled to pattern diagnostics may provide biomarkers predictive of response to targeted treatment in patients with NSCLC, thus enabling pretreatment selection of appropriate subgroups.
Risk of skeletal-related events (SREs) in patients with lung cancer (LC) and newly diagnosed metastases to bone.
Authors: Richert-Boe Kathryn E. , Edelsberg John , Taneja Charu , Lamerato Lois , Glass Andrew , Wolff Greg G. , Czapski Natalie , Chung Karen , Richhariya Akshara , Oster Gerry
Published: March 2020

e18107

Background: Bone is a common site of metastatic involvement in patients (pts) with LC. Bony metastases (mets) are often associated with SREs (spinal cord compression [SCC], pathologic fracture [PF], surgery to bone [SB], radiotherapy to bone [RT]). Skeletal complications cause significant morbidity and mortality. Current estimates of SRE risk come principally from randomized clinical trials. Information from routine clinical practice is limited. Methods: Using the tumor registry and electronic data stores at a large U.S. Midwest healthcare system that serves approximately 800,000 persons, we retrospectively identified all pts aged ≥18 yrs with primary LC and newly diagnosed bone mets between 1/1/95 and 12/31/09. Electronic medical records were reviewed by trained abstractors for evidence of SREs between date of bone mets diagnosis and death, loss to follow-up, or end of study. Cumulative incidence of SREs was estimated in the presence of competing risk of death. Results: We identified a total of 272 pts with primary LC and newly diagnosed bone mets; 66 pts had evidence of SREs at initial diagnosis of bone mets and were excluded from the analyses. Among the remaining 206 pts, mean (SD) age was 65.7 yrs (10.5 yrs) and 66% were male; 47% were Caucasian and 50% were African-American. Median duration of follow-up after diagnosis of bone mets was 3.0 months (mos). At 6 mos, cumulative incidence of SREs was 45.6% (SCC, 6.9%; PF, 20.6%; SCC and/or PF, 25.0%; SB, 4.1%; RT, 34.7%) (Table). Corresponding figures at 12 mos were 50.8% (SCC, 6.9%; PF, 24.1%; SCC and/or PF, 28.3%; SB, 4.1%; RT, 39.8%). Relatively few pts (17.5%) received intravenous bisphosphonates prior to SRE. Conclusions: Pts with LC in routine clinical practice are at high risk of SREs following initial diagnosis of bone mets. [Table: see text]
EGFR gene mutation and epithelial to mensenchymal transition (EMT) markers in advanced NSCLC patients treated with erlotinib.
Authors: Fidler Mary J. , Dave Manish J , Basu Sanjib , Hensing Thomas A. , Pool Mark , Mahon Brett , Borgia Jeffrey A , Walters Kelly Kaiser , Escarzaga Diana , Batus Marta , Bonomi Philip D.
Published: March 2020

e18117

Background: TTF-1 is a transcription factor involved in regulating epithelial to mesenchymal transition (EMT). Previous work in a clinically enriched non-small cell lung cancer (NSCLC) population suggested low probability of an EGFR activating gene mutation in the absence of TTF-1 positivity (Somaiah ASCO 2011). This study's goal was to validate the relationship of TTF-1 and other immunohistochemical (IHC) markers of EMT to the presence of an EGFR activating gene mutation in a diverse group of NSCLC patients treated with erlotinib. Methods: Patients receiving erlotinib at two midwest institutions were retrospectively analyzed by IHC for TTF-1 (Greater than 5% of tumor cells with moderate (2+) or strong (3+) nuclear staining considered positive) and for PTEN, Ecadherin,vimentin, beta catinin, and snail (frequency(0-4) times intensity(0-4)). Exon 19 and L858R mutations were detectedusing single-strand conformation polymorphism and sequence-specific polymerase chain reaction (PCR)).Fisher’s exact testand logistic regression wereused to correlate TTF-1(positive or negative) and the remaining EMT markers with the presence of EGFR mutation. Results: 216 patients were analyzed for EGFR activating gene mutations: 15% squamous, 80% smokers. EGFR mutation was found in 11.6% of cases. TTF-1 was present in 8% of squamous cell patients and 71% of adenocarcinoma patients. TTF-1 correlated with prolonged progression free survival (log rank p=.004). TTF-1 positivity was strongly correlated with the presence of mutation (p=.0006, negative predictive value=97.7%). Increasing Ecadherin and increasing PTEN expression by IHC correlated with the presence of EGFR gene mutation when measured on continuum (p=.006 and p=.04, respectively). Conclusions: Though retrospective, our work confirms the negative predictive value of TTF-1 for an EGFR activating gene mutation in a NSCLC cohort representative of a North American population.Though high PTEN and Ecadherin expression also correlated with EGFR mutation, TTF-1 positivity may be a more straight-forward marker that can select patients who should be screened for the mutation prior to initiation of first line therapy.
Clinical significance of hyperpigmentation due to pemetrexed treatment in advanced nonsquamous non-small cell lung cancer in China.
Authors: Hu Qiong , Li Aiwu , Ren Shengxiang , Chen Xiaoxia , Gao Guanghui , Garfield David H. , Zhou Caicun
Published: March 2020

e18123

Background: Previous publications have demonstrated the efficacy of pemetrexed (PEM) as first-line, second-line and maintenance therapy in advanced non-small cell lung cancer (NSCLC). A recent study found skin toxicities compromised continuation of PEM treatment. The purpose of this study is to investigate the clinical significance of hyperpigmentation (HP) in advanced nonsquamous (NS) NSCLC receiving PEM-based therapy in China. Methods: Medical records of patients with advanced NSNSCLC who received PEM-based treatment in Shanghai Pulmonary Hospital were retrospectively studied. Chi-square test, Pearson’s test as well as Kaplan-Meier method and Cox Proportional Hazards model were performed for statistical analysis. Results: A total of 101 patients were collected with a median age of 58 years old. Among them, 53 (52.5%) were female and 65 (64.4%) were nonsmokers. 52 (51.5%) patients received first-line treatment. Presence of HP was associated with better ORR (22% vs 7.1%, p=0.043) and DCR (84.7% vs 54.8%, p=0.001). Patients with HP had longer PFS (186 days versus 96 days, p<0.0001). There were no significant differences according to grade of HP in ORR, DCR and PFS. There was a higher incidence of hyperpigmentation in patients who received first-line treatment (73.1%% vs 42.9%, p=0.023) and doublet agent (43.1% vs 74.0%, p=0.002). Multivariate analysis demonstrated HP was an independent factor for better clinical outcomes (vs absence, Hazard Ratio [HR] 0.417, 95% Confidential Interval [CI] 0.255-0.690, p=0.001). Conclusions: HP due to PEM is frequent in advanced NSNSCLC receiving PEM. It is an independent predictive factor for better clinical outcomes in Pemetrexed-treated advanced NSNSCLC in China.
Number of cycles of chemotherapy in patients with advanced non-small cell lung caner: Efficacy and relationship with histology.
Authors: Richardet Eduardo , Richardet Martin Eduardo , Castagneris Nicolas , Cortes Matias Nicolas , Laura Perelli , Molina Matias
Published: March 2020

e18125

Background: Platinum based regimens are standard first-line treatment in patients with advanced non mall cell lung cancer. We intend to evaluate their effectiveness according to the number of cycles administered, and investigate whether histology is a predictor of benefit from a greater number of infusions. Methods: 124 patients with stage IV NSCLC were evaluated retrospectively. They were divided according to whether they made 4 or 6 cycles of chemotherapy. The schemes used were: Cisplatin / Gemcitabine and Carboplatin / Paclitaxel, at standard doses. We studied the efficacy in both groups according to the most common histologies (adenocarcinoma and squamous cell carcinoma). PFS (progression-free survival) and OS (overall survival) were calculated by the Kaplan-Meier curves and compared by the Log Rank Test. Results: Those who underwent 4 cycles had a PFS of 7.77 months and OS of 12.2 months vs. 8.64 and 10.8 months those who received 6 cycles (p = 0.47, p = 0.76). Within the subgroup with squamous histology (n = 43), PFS and OS were 7.38 and 13.38 months respectively in the group that received 4 cycles vs. 7.97 and 9.76 months in those receiving 6 (p = 0.70, p = 0.32 ). Within adenocarcinoma histology (n = 81), those who received 4 cycle, has a PFS of 8.17 months and they lived 11.56 month, vs 8.96 and 10.79 months for those receiving 6 cycles (p = 0.29, p = 0.88) Conclusions: In our population, a greater number of cycles showed no advantages in terms of progression-free survival or overall survival. Histology is not a predictive factor for deciding how many chemotherapy cycles administer.
Predictors of early discontinuation of chemotherapy (EDC) in patients (pts) age 65 or older with stage IV non-small cell lung cancer (NSCLC).
Authors: Gajra Ajeet , Tew William P. , Hardt Molly , Mohile Supriya Gupta , Owusu Cynthia , Klepin Heidi D. , Gross Cary P. , Lichtman Stuart M. , Katheria Vani , Hurria Arti ,   on behalf of the Cancer and Aging Research Group (CARG)
Published: March 2020

e18133

Background: NSCLC accounts for the highest cancer related mortality. Older pts suffer higher chemotherapy (chemo) toxicity (tox). Inability to complete a planned chemo course is associated with poor outcome. We studied factors associated with EDC (defined as chemo duration of ≤ 6 weeks) in pts ≥ age 65 with stage IV NSCLC. Methods: We conducted a subset analysis of pts with stage IV NSCLC (n=100) enrolled in a multi-site prospective study (n=500) which identified predictors of chemo tox in pts age > 65 (Hurria et al, JCO 2011). Bivariate analysis and multivariate logistic regression were utilized to identify factors associated with EDC among pts with stage IV NSCLC including: sociodemographics, chemo factors (1st vs. 2nd + line; single vs doublet), labs (hemoglobin [Hb], liver function, creatinine clearance, albumin) and geriatric assessment (GA) variables (functional status, comorbidity, social support, psychological, cognitive and nutritional status). Results: Of the 100 pts (median age 73, range 65-89) with stage IV NSCLC, 33 had EDC. Of these 67% was for disease progression, 15% tox and 15% for both progression and tox. Majority received 1st line (58%) and doublet chemo (67%). In bivariate analysis (p values <0.01 for all), pts with EDC were more likely to receive single agent (52% vs. 24%) and 2nd + line chemo (70% vs 28%)and have lower mean Hb (11.3 vs 12.7 g/dl) and albumin levels (3.4 vs 4.0 g/dl). GA variables associated with EDC include poorer physical function [lower score on Medical Outcomes Study physical health (MOS physical), MD rated Karnofsky performance status (KPS), self rated KPS, and MOS social activity, and need assistance with instrumental activities of daily living; p<0.01 for each variable]. On multivariate analysis, factors independently associated with EDC include 2nd + line chemo (OR=5.93; 95%CI = 2.25-15.61) and lower MOS physical score of <70 (OR= 4.19; 95% CI= 1.56-11.29). Conclusions: In older pts with NSCLC, factors associated with chemo duration of < 6 weeks include 2nd+ line chemo and poor physical function best assessed by MOS physical in this cohort. These simple factors may help the practicing oncologist identify older pts with NSCLC at greatest risk for EDC.
KRAS mutations and outcomes for patients with stage IV NSCLC treated with frontline platinum/pemetrexed based chemotherapy.
Authors: Levy Benjamin , Seetharamu Nagashree , Richardson Stacie , Becker Daniel Jacob , Choi Walter , Evans Andrew , Bhora Faiz Y. , Connery Cliff P. , Grossbard Michael L. , Chachoua Abraham
Published: March 2020

e18139

Background: KRAS mutations are the most common driver mutation indentified in NSCLC, occurring in 20 - 30% of adenocarcinomas. While several studies suggest KRAS predicts for lack of response to TKI therapy, few data exist regarding its association with outcomes for patients treated with cytotoxic chemotherapy. This study explores the association between KRAS mutations and outcomes (RR, PFS) in a cohort of patients treated with frontline platinum/pemetrexed (PPm) based therapy. Methods: In this retrospective chart review, we evaluated RR and PFS for 16 KRAS + EGFR – pts treated with carboplatin (AUC 5-6) or Cisplatin 75mg/m2 and (Pm)pemetrexed (500 mg/m2) +/- (B)bevacizumab 15mg/kg. For comparators, we identified 19 KRAS - EGFR - patients treated with the same regimen. Maintenance therapy with Pm or Pm+B was given at the discretion of the treating physician. KRAS and EGFR mutational status were assessed by RT-PCR on tumor tissue collected at first diagnosis. RR was assessed using RECIST criteria. Kaplan-Meier estimates for PFS were evaluating using log rank test. Fisher exact test was used to assess the association between KRAS mutation status and response rate. Results: The groups were similar in age (KRAS + mean 61 vs. 60; p=0.87), gender (62% vs. 57% F; p= 0.9), ECOG 2 (0 vs. 10%,p=0.47), smoking hx (93% vs. 94% current/former smokers, p=0.7), brain mets (0% vs. 18% p=0.22), mean number induction cycles (4 in each, p=0.6), cisplatin and bevacizumab use (12% vs 10%, p > 0.1;10% vs. 40%, p=0.10). Pm maintenance was used in 31% KRAS+ (5/16) and 26% KRAS-(5/19) (p=0.79). P+B maintenance was used in 12% (2/16) and 5% (1/19) (p=0.70). RR was 56% in the KRAS + (9/16) vs. 36% KRAS- (7/19) respectively (p=0.3). There was a statistically significant improvement in PFS in the KRAS + group (10.3 mos vs. 5.7 mos, p =0.03). Conclusions: In this small retrospective review, KRAS mutations appeared to be associated with a non-significant improvement in RR and significant improvement in PFS for patients treated with frontline PPm based therapy. Future prospective studies should investigate and validate the predictive value of KRAS for this cytotoxic regimen. [Table: see text]
GGCP041/09: A Galician study of second-line erlotinib in patients with advanced non-squamous non-small cell lung cancer (nsNSCLC).
Authors: Vazquez Estevez Sergio , Villanueva Silva Maria Jose , Firvida Perez Jose Luis , Lazaro Quintela Martin , Varela Ferreiro Silvia , Huidobro Vence Gerardo , Fernandez Calvo Ovidio , Campos Balea Begona , Casal Rubio Joaquin , Areses Manrique Carmen ,   Galician Lung Cancer Group
Published: March 2020

e18146

Background: Efficacy of oral erlotinib has been conclusively established in 2nd line setting (BR.21 and TRUST studies) and the outcomes are similar to those provided by other approved chemotherapeutical agents (TITAN study). Higher responses rates have been found in p with Asian ethnicity, adenocarcinoma, women and never smokers, where predictive EGFR mutations occur more frequently; even though erlotinib has a significant effect on survival in all subgroups of patients. This observational study evaluates the efficacy of 2nd line erlotinib in unselected p with nsNSCLC in 4 Galician institutions. Methods: Unselected p with advanced nsNSCLC were treated with 150 mg/day of erlotinib as 2nd line therapy until unacceptable toxicity or progressive disease. EGFR mutational status was retrospectively tested when feasible, and serum carcinoembryonic antigen (CEA) monitored during the treatment period. Results: Baseline characteristics of 45 p included at the time of this analysis: mean age of 61.7 yrs. (range: 38-83); 80% male; 73.3% adenocarcinoma; 71.1% stage IV; 7/69/24% PS ECOG 0/1/2; 29/33/38 % never/current/former smokers. EGFR activating mutation testing was performed in 24 p (53%) and 2 positive cases were found (8%), both with metastatic adenocarcinoma (stage IV). The median PFS was 3.3 (95% CI: 1.6-5.1) and the median OS 10 months (95% CI: 7.5-12.5). Among p without EGFR mutations, erlotinib conferred a median OS of 8.1 months (95% CI: 1.4-14.9). Out of 31 p evaluable, radiologic response was achieved in 7 p (22.6%), for an overall disease control rate of 45.2 %. No unexpected toxicities were reported: 60 % of p experienced cutaneous toxicity (6.6 % grade ¾), 22.2% asthenia (4.4% grade ¾) and 17.8% diarrhea (2.2% grade ¾). Only 3 p discontinued due to adverse events. Conclusions: This study confirms the efficacy and safety of 2nd line erlotinib in a clinical practice scenario and the outcomes in p with non-squamous NSCLC are equivalent to those reported with the chemotherapy for salvage therapy. Moreover, the absence of mutations does not preclude the benefit from the drug. Updated data of the study will be presented.
A single-institution experience with the hyper-CVAD regimen in aggressive NHL.
Authors: Younas Mariam , Gregory Stephanie A. , Jajeh Ahmad , Larson Melissa L. , Al-Rifai Taha
Published: March 2020

e18510

Background: Hyper-CVAD (± rituximab) is a chemotherapy regimen designed as a treatment for aggressive hematological malignancies. It consists of 8 cycles. Cycle 1, 3, 5, 7 (3-4 weeks/cycle) includes cyclophosphamide 300mg/m2 IV over 2 hours (hrs) every 12 hrs for 6 doses on day 1-3 + Mesna 600mg/m2 per day continuous IV on days 1-3 to start 1 hr before cyclophosphamide till 12 hrs after completion of cyclophosphamide + vincristine 2mg IV on days 4 and 11 + doxorubicin 50mg/m2 IV over 24 hrs on Day 4 + dexamethasone 40mg daily orally on days 1-4 and days 11-14. Cycle 2, 4, 6, 8 (3-4 weeks/cycle) consist of high dose methotrexate (MTX) (200mg/m2) IV over 2 hrs followed by 800mg/m2 continuous IV infusion over 22 hrs on day 1 + cytarabine 3gm/m2 (1gm/m2 for patient age over 60 years old) IV over 2 hrs every 12 hrs for doses on days 2 and 3 + leucovorin 50mg IV every 6 hrs starting 12 hrs after completion of MTX till MTX level < 0.05µM. Hyper-CVAD is a short intensified regimen given over eight months compared to known therapy for ALL and Burkitt lymphoma. Methods: Retrospective review of all cases of acute lymphoblastic leukemia/lymphoma and Burkitt’s lymphoma between 2000 and 2012 was done. It included all patients and evaluated response to therapy including Hyper-CVAD. Results: A total of 79 patients with aggressive acute lymphoblastic leukemia/lymphoma and Burkitt’s NHL were analyzed. Mean age 39 years (range 15-75 years). All patients were admitted at least twice with febrile neutropenia. Prolonged cytopenias were observed in more than 50% of patients. Conclusions: Hyper-CVAD is an intense regimen that produces high rates of clinical remission in less than 8 months of therapy compared to established regimen for aggressive hematological malignancies. [Table: see text]
Gastrointestinal tract NK/t cell lymphoma: Clinical features, management, and prognosis of 47 patients.
Authors: Jiang Ming , Zou Li qun
Published: March 2020

e18514

Background: The gastrointestinal tract is the most common primary sites of extranodal lymphomas, while gastrointestinal NK/T cell lymphomas (GINKT) are relatively rare. So far, the researches on this disease are few and the number of cases is small. In this article, we examined the clinical features andprognostic conditions of GINKT. Methods: A retrospective analysis was carried out on clinical data from 47 cases of confirmed GINKT. Results: Patients had a median age of 37 years. 35 cases were men (74.5%) and 12 cases were women (25.5%). The common clinical manifestations included fever (78.7%), abdominal pain (76.6%). Seventeen cases have intestinal perforation (36.2%). All patients showed ulcerative lesions, the most common site of involvement was the colon (27/47; 57.4%), followed by the jejunoileum and ileocecum (14/47; 29.8%). The median survival was 2.83(95% CI, 0.27–29) months. The log-rank univariate analysis showed older than 60 years, perforation, increased LDH level, high ECOG and NKIPI score, without chemotherapy, without surgery before perforation, late stage according to Musshoff or Lugano stage system had relatively poor prognoses. Cox multivariate analysis shown that age, perforation, B syndrome, stage according to Lugano system and surgery were independent prognostic risk factor for GINKT. Conclusions: GINKT is a rare type of lymphoma, is prone to perforation, hemorrhage and other complications, the prognosis is very poor. Lugano staging is a relatively suitable staging system. Surgery before Perforation is a key therapy factor which affected prognosis. Although values of chemotherapy and radiotherapy are unclear, combination therapy maybe is necessary.
Outcome in different molecular subtypes of diffuse large B-cell lymphoma: Indian experience.
Authors: Prakash Gaurav , Sharma Atul , Raina Vinod , Kumar Lalit , Sharma Mehar C
Published: March 2020

e18518

Background: DLBCL has emerged as a heterogeneous disease and gene expression profiling has divided it into distinct molecular subtypes of Germinal center B-Cell (GCB) and Non-GCB- cell origin. These subtypes are reported to vary in the treatment responses and outcome. Methods: We analysed 97 consecutive patients of DLBCL who had satisfactory paraffin block of baseline biopsy. After reviewing diagnosis of DLBCL, sequential immunohistochemical staining with CD10, bcl6 and MUM1 was performed in all the cases. Using these markers the cases were sub-classified into GCB and non-GCB types as per Hans’ algorithm. Baseline presentation, stage, international prognostic score and treatment outcome were recorded. Survival was assessed by Kaplan-Meier survival curves and results were compared using log-rank test. Results: Thirty-three (34%) patients were classified in GCB group while 64(66%) patients in non-GCB group. Median age in both the groups was 50 years. High IPI score2-5 (GCB-34%, non GCB-72%;p 0.005) and stage 3,4 (GCB-39%,nonGCB-61%;p 0.04) were higher in non-GCB group. All the patients were treated with 6-8 cycles of CHOP based regimen and involved field radiotherapy wherever required. Complete remission rate (GCB-52%, nonGCB-27%; p0.02) was higher in GCB group. Three year overall survival, 75% and 63 %( p0.04), and event free survival was 63% and 43 %( p0.02) in GCB and non GCB subtypes, respectively. There was no difference in between two groups for performance status, LDH level and age. Conclusions: In our study, GCB-DLBCL patients had better response rate, EFS and OS in comparison to non GCB subtype. There were higher number of patients with advanced stage and high IPI score in non-GCB subtype which might have contributed to the poorer outcome.
Central nervous system lymphoma: Prognostic factors.
Authors: Huelves Miriam , Millán Isabel , Cantos Blanca , Doger de Speville Bernard Gaston , Ibeas Patricia , Lopez-Gonzalez Ana , Mendez Miriam , Sánchez Antonio , Maximiano Constanza , Provencio Mariano
Published: March 2020

e18521

Background: CNSL constitute less than 2% of all the NHL and 3% of the tumors of the CNS. We studied the prognostic factors of these patients. Methods: This is a retrospective study, we analyzed data from 21 patients, diagnosed on the last 20 years. We used the test of Chi-square corrected by Yachts and Fisher's exact test for qualitative variables and the contrast t of Student and the contrast not parametric U of Mann-Whitney for quantitative variables. The curves of survival were estimated by Kaplan-Meier's method. Results: 62% were males, with a median age of 53.4 years (range 31-72), and the 90.5% were HIV negative. The most frequent histological type (52.4 %) was the Diffuse Large B-cells Lymphoma. Most of them, 75%, were treated with High dose-Metotrexate (HD-MTX). Patients treated with other schedules obtained less disease free survival (DFS) and overall survival (OS). Many prognostic factors were analyzed, but only high LDH values at diagnosis was associated to worse prognostic (p=0.021). The OS and DFS at the first year were 88.2 % and 67.7 % respectively. Conclusions: The best results were obtained in patients treated with HD–MTX. Because of difficult management of these patients, we believe they must be treated in reference centers.
Preclinical development of an anti-CD30/anti-CD16A bispecific tetravalent TandAb antibody for the treatment of Hodgkin lymphoma.
Authors: Knackmuss Stefan , Reusch Uwe , Burkhardt Carmen , Fucek Ivica , Le Gall Fabrice , Pauels Hans-Gerd , Little Melvyn , Zhukovsky Eugene
Published: March 2020

e18532

Background: CD30 is a validated tumor target that is expressed on both Hodgkin’s Lymphoma cells and some activated immune cells. To improve antibody-based therapies targeting CD30, Affimed developed an NK cell-recruiting bispecific antibody. Methods: To enhance the recruitment and activation of NK cells for tumor cell lysis, we isolated a human antibody that is highly specific for the A isoform of FcgRIII (CD16A). Its variable domain (Fv) was used to construct a tetravalent bispecific TandAb, consisting of four Fvs linked in tandem, with two binding sites for both the CD16A on NK cell and the CD30 target cell antigens. The resulting anti-CD30/anti-CD16A bispecific tetravalent TandAb AFM13 was compared to both an anti-CD30/anti-CD16A bispecific diabody and an Fc-enhanced anti-CD30 IgG in binding and cytotoxicity assays in vitro. Pharmacokinetics and safety of the TandAb were investigated in Cynomolgus monkeys. Results: AFM13 is retained longer on NK cells than either the anti-CD30 IgG or the bispecific diabody due to its bivalency for CD16A; it binds both CD16A alleles (158F, 158V) equally well indicating the potential for broader patient response than that achieved with current therapeutic mAbs. AFM13 did not induce systemic activation of NK cells. It displays higher potency (EC50) and higher efficacy (maximal lysis) than either the anti-VD30 IgGs or the bispecific diabody in a cytotoxicity assay. The cytotoxic activity of AFM13 is unaffected by physiological concentrations of polyclonal IgG, whereas that of anti-CD30 IgGs is dramatically reduced. Cynomolgus monkeys were identified as the only relevant species for toxicity testing. Pharmacokinetics studies reveal AFM13 half-lives of up to 22.9 h after repeated dosing. MTD was not reached in a single dose escalation study ranging to 100 mg/kg maximum. A 28 days toxicity study, with dosing up to 10 mg/kg every other day, revealed an excellent safety profile. No signs of immunotoxicity or systemic cytokine release were observed. Conclusions: AFM13 may be a more effective treatment for Hodgkin’s Lymphoma that is refractory to treatment with anti-CD30 IgGs and is under evaluation in a Phase I clinical trial.