bluuebunny/crossref_metadata_2025 huggingface dataset:
Rare discrepancy in driving gene mutations between histologically heterogeneous primary lung cancer.
Authors: Zhong Wenzhao , Chen Zhi-yong , Xu Fangping , Yang Xue-Ning , Su Jian , Chen Zhihong , Zhang Xuchao , An Shejuan , Zhou Qing , Yang Jinji , Wu Yi Long
Published: March 2020

e18547

Background: The mixed subtype adenocarcinomas account for nearly 90%. The driving gene mutations are found with different frequency in various histological subtypes. The role of the intra-tumoral heterogeneity is still controversial. Methods: In order to compare the gene status of the area of different growth patterns, the representative morphologically different tumor areas within the same surgical resected primary tumour were extracted from tissue sections. Driver genes were detected by sequencing, ARMS and FISH methods. Results: During routine clinical genotyping, 79 consecutive surgical resected cases with mixed subtype adenocarcinoma harboring driving gene mutation were selected. The gene statuses of different growth patterns within the same primary tumor were compared. The discrepancies of EGFR mutation were 10 in 65 with direct sequencing, and 1 in 65 with ARMS, among which consistent EGFR mutations were found in all the 5 cases adenosquamous cell carcinoma. The discrepancy of KRAS mutation in direct sequencing was 2 in 10. No discrepancy of EML4-ALK rearrangement in FISH was found in 4 cases. Conclusions: Rare discrepancy of driving gene mutations within histologically heterogeneous primary lung adenocarcinoma was found. It indicated that the different components of the primary lung cancer may have originated from a common ancestor.
Genetic background and risk of lung adenocarcinoma in never smokers.
Authors: Takamochi Kazuya , Oh Shiaki , Suzuki Kenji
Published: March 2020

e18549

Background: The causative association between tobacco smoking and lung cancer is well-known. However, the mechanism underlying the pathogenesis of lung adenocarcinoma in never smokers remains unclear. Recently, several driver oncogenes, such as EGFR and EML4-ALK, have been identified in lung adenocarcinomas ofnever smokers. Methods: This was a retrospective review of 596 patients with surgically resected lung adenocarcinomas between February 2009 and October 2012. The clinicopathological factors (age, gender, and pathological stage), EGFR and KRASmutation status, past history of any cancer or benign tumor, family history of any cancer, and the presence of multiple primary lung cancers were compared between never smokers (n = 312) and smokers (n = 284). Results: Lung adenocarcinomas in never smokers were more frequently found in females (P < 0.001) and in patients with early stage disease (P = 0.01) than those in smokers. EGFR mutations were detected in 183 (59%) never smokers and in 89 (31%) smokers (P < 0.001). K-ras mutations were detected in nine (3%) never smokers and in 57 (20%) smokers (P < 0.001). The proportion of patients with a past history of any cancer was higher in smokers than in never smokers (28% vs 21%, P = 0.03). This may reflect the fact that tobacco smoking can cause various types of cancers. In contrast, the proportions of patients with any benign tumor and a family history of any cancer were higher in never smokers than in smokers (14% vs 4%, P < 0.001 and 20% vs 13%, P = 0.02). These findings may suggest that a certain genetic background is involved in the pathogenesis of lung adenocarcinoma in never smokers. The frequency of multiple primary lung cancers was not significantly different between never smokers and smokers (6% vs 5%, P = 0.6). In never smokers, the EGFR and KRASmutation status was not associated with the frequency of a past history of any cancer or benign tumor, a family history of any cancer or the presence of multiple primary lung cancers. Conclusions: A certain genetic predisposition is suspected to be involved in the pathogenesis of lung adenocarcinoma in never smokers. Further studies are thus needed to elucidate the genetic alterations associated with the susceptibility to lung adenocarcinoma in never smokers.
Is CT-based selective nodal irradiation safe for clinical stage N0-1 LD-SCLC patients?
Authors: Hu Man , Fan Bingjie , Kong Li , Yu Jinming
Published: March 2020

e18551

Background: Radiotherapy plays an important role in the management of limited-disease small-cell lung cancer (LD-SCLC). However, volume of irradiation remains unanswered as well as optimal total dose, timing and sequencing of radiation. In this study, we compared the clinical lymph node staging with pathological staging, with the aim of investigating the safety of CT-based selective nodal irradiation for clinical stage N0-1 LD-SCLC patients. Methods: From July 2004 to March 2012, 20 potentially operable patients with clinical stage N0-1 LD-SCLC underwent contrast-enhanced CT scans and other routine initial staging procedures followed by radical resection of primary tumor and systemic intra-thoracic lymph node dissection. The results of reviewing clinical staging for the mediastinal lymph node metastases were compared with pathologic findings. Results: Preoperative nodal staging was compared with postoperative pathological staging, 35% (7 of 20) of patients were under staged by clinical staging. Of all the 7 patients with mediastinal lymph node metastases, 4 patients (57.1%) had subcrinal nodes (station 7) metastases, 1 had right upper paratracheal nodes (station 2R) metastases, 1 had left lower paratracheal nodes (station 4L) metastases, 1 had aortopulmonary nodes (station 5) metastases. Conclusions: CT-based selective nodal irradiation for LD-SCLC may result in geographical miss in clinical stage N0-1 patients. Mediastinal lymph node regions especially the subcrinal nodes should be contained in the clinical target volume for radiotherapy.
Prognostic value of epidermal growth factor receptor gene amplification in surgically resected non-adenocarcinoma lung cancer patients.
Authors: Yang Yaewon , Chang Hyun , Lee Jong-Seok , Kim YuJung , Jheon Sang-hoon , Chung Jin-haeng
Published: March 2020

e18553

Background: The purpose of this study is to investigate the prognostic role of genomoic gain and expression for epidermal growth factor receptor (EGFR) gene in surgically resected non-adenocarcinoma of non-small-cell lung cancer (NA-NSCLC). Methods: This retrospective study included 115 NA-NSCLC consecutive patients with available tumor tissue and survival data, median follow up period of 6.4 years. EGFR gene copy number and protein expression was evaluated using by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) in tissue microarray sections, respectively. Results: Among 115 patients, 99 patients (86.1 %) were with squamous cell carcinoma histology. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 57 (49.6%) and 45 (39.1%) patients, respectively. Patients with EGFR FISH+ had significantly shorter overall survival [median, 41 months vs. not reached (>70 months), P = 0.011]. Multivariable model confirmed that patients with EGFR FISH+ had a significantly greater risk of death than those with EGFR FISH-negative after adjusting pathologic staging, presence of pleural invasion, venous invasion and adjuvant chemotherapy (hazard ratio = 2.11, 95% confidence interval 1.23-3.61, P = 0.006). EGFR IHC expression did not associate with overall survival in same group. Conclusions: EGFR increased gene copy number is an independent negative prognostic factor in surgically resected NA-NSCLC.
Combination efficacy of mTOR and MEK inhibitor in malignant pleural mesothelioma (MPM).
Authors: Matsumoto Seiji , Orui Hayato , Kuroda Ayumi , Hashimoto Masaki , Yoneda Kazue , Takuwa Teruhisa , Kondo Nobuyuki , Hasegawa Seiki
Published: March 2020

e18557

Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor and poor prognosis. Active new agents is an urgent priority for patients with MPM. PI3K/AKT/mTOR pathway inhibitors in MPM have reported, but, the results has limited. Because PI3K/AKT/mTOR pathway inhibitors will make signaling feedback loops and cross-talk between signaling pathways. Combining PI3K/AKT/mTOR pathway inhibitors with other inhibitors might improve efficacy. Activation of RTKs stimulates both the PI3K/AKT/mTOR and RAS/RAF/MEK signaling pathways, and some study shows that inhibition of both pathways may be more effective than targeting either alone. We speculated that simultaneous inhibition both of mTOR and MEK by everolimus and selumetinib might improve the treatment of MPM. Methods: At first, we examined the growth inhibitory effects of everolimus or selumetinib alone on MPM cell lines. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. We next confirmed the in vivo efficacy of everolimus or selumetinib alone, and the combination of both compounds in H226 MPM xenograft model. Results: Everolimus inhibited the growth of MPM cell lines with IC50 values 1.19-21.5 μM. Selumetinib also inhibited the growth of MPM cell lines with IC50 values 4.68-88.2μM. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. With H226, the combination index (CI) at fraction (Fa) 0.5 and 0.8 were (0.56 ± 0.30) and (0.76 ± 0.48), respectively, indicating everolimus and selumetinib act synergistic, respectively. Everolimus or selumetinib alone showed significant antitumor activity, and the combination of everolimus and selumetinib enhanced the individual antitumor activity in H226 MPM xenograft model. (p<0.05). Conclusions: These findings indicate that the combination of everolimus and selumetinib is effective in MPM growth inhibition not only in vitro but in vivo and chemotherapy regimens involving the combination of everolimus and selumetinib may be new molecular target therapy for MPM patients
Predictive factors of distant recurrence after surgery in patients with clinical stage IA lung adenocarcinoma.
Authors: Ibuki Yuta , Miyata Yoshihiro , Yoshiya Tomoharu , Mimae Takahiro , Tsutani Yasuhiro , Okada Morihito
Published: March 2020

e18563

Background:The tumor recurrence after complete surgical resection occurs even in patients with clinical stage IA lung adenocarcinoma. The predictive factors of the distant recurrence have not been determined yet in such early stage lung adenocarcinoma patients. Methods:A total of 610 patients with clinical stage IA lung adenocarcinoma who underwent complete resection in multi-institutions were retrospectively analyzed . The correlation between clinicopathological factors andthe incidence of distant recurrence was examined. Results:Thirty six patients with distant recurrence had significant inferior overall survival. In the multivariate Cox regression analysis, solid tumor size on high resolution computed tomography (HRCT) and maximum standardized uptake (SUVmax) on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) were found to be independent predictors of distant recurrence. According to receiver operating characteristic analysis, 1.6cm or more of solid tumor size and 3.3 or more of SUVmax were indicated to be an optimal criteria to detect a high risk group for distant recurrence. In fact, distant recurrence and local recurrence were more frequently observed in patients whose solid tumor size and SUVmax met the criteria than the unmet patients (24 of 104 (20.2%) patients v.s. 12 of 506 patients (2.4%)). Conclusions:Solid tumor size on HRCT and SUVmax on FDG-PET/CT were indicated to be predictive factors of distant recurrence for the patients with clinical stage IA lung adenocarcinoma. It is highly possible that neoadjuvant chemotherapy is useful for such a high risk group.
KRAS and EGFR status as predictive markers of response and time to progression in EGFR wild-type stage IV non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine-kinase inhibitors.
Authors: Domine Manuel , Rojo Federico , Hernandez Tatiana , Zazo Sandra , Serrano Gloria , Chamizo Cristina , Carames Cristina , Madoz Juan , Moreno Irene , Perez-Gonzalez Nuria , Ortega Carolina , Carvajal Nerea , Lobo Francisco , Auz Carmen Laura , Casado Victoria , Rubio Gustavo , Oruezabal Mauro , Lendinez Alberto , Leon Ana , Garcia-Foncillas Jesus
Published: March 2020

e19000

Background: KRAS mutations on codons 12, 13 and 61 result in the constitutive activation of protein, which may render tumor cells independent of epidermal growth factor receptor (EGFR) signalling and thereby resistant to tyrosine-kinase inhibitor (TKI) therapy in NSCLC patients. This study was aimed to evaluate the associations of KRAS and EGFR copy number alteration and mutations with response and time to progression (TTP) in EGFR TKI-treated patients. Methods: 84 samples from NSCLS patients treated with erlotinib or gefitinib were analyzed for KRAS and EGFR mutation status by cobas KRAS and EGFR Mutation Tests (Roche). EGFR copy number was determined by fluorescent in situ hybridization (FISH, Abbott Molecular) and amplification was defined with three or more gene copies in tumor. Results: KRAS mutation was detected in 15 (17.8%) cases, EGFR mutation in 27 (32.1%) and EGFR amplification in 8 (9.5%). Significant differences were detected in response rates for wild-type (0.2) and mutant KRAS (0.0) (p=0.023), for wild-type (0.12) and mutant EGFR (0.39) (p=0.007), and for non-amplified (0.18) and EGFR-amplified (0.71) patients (p=0.005). Additionally, significant benefit from TKI therapy was observed for KRAS wild-type compared with KRAS-mutated patients (median TTP 7 vs. 3 months, p=0.001), for EGFR-mutated compared with wild-type patients (14 vs. 4 months, p=0.004) and for EGFR-amplification in contrast to non-amplified cases (11 vs. 5 months, p=0.001). KRAS and EGFR mutations or EGFR amplification did not correlated with overall survival (18 vs. 19 months, p=0.406; 16 vs. 21 p=0.094; 25 vs. 17 months, p=0.103, respectively). Combined analysis of favourable status of three biomarkers strongly predicted benefit to TKI therapy (median TTP 15 vs. 3 months, p<0.001). Conclusions: Combined analysis ofKRAS mutation, EGFR mutation and EGFR amplification in EGFR TKI-treated NSCLC might provide superior predictive information than single biomarker study in these patients.
Impact of concomitant use of anti-acid agents on efficacy of gefitinib in EGFR-mutant non-small-cell lung cancer (NSCLC).
Authors: Chikamori Kenichi , Aoe Keisuke , Maeda Tadashi , Kishino Daizo , Oishi Keiji , Hotta Katsuyuki , Matsumoto Tsuneo , Ueoka Hiroshi
Published: March 2020

e19008

Background: Gefitinib, an EGFR-tyrosine kinase inhibitor, is an essential agent for EGFR-mutant NSCLC. The preclinical studies revealed its reduced area under the curve (AUC) by elevation of pH in GI tract, potentially leading to alteration in the absorption of gefitinib. It, however, has been controversial as to whether and how simultaneous use of anti-acid agents, commonly used in clinical practices, could alter the sensitivity of gefitinib, especially in EGFR-mutant NSCLC. Thus, we conducted a retrospective cohort study to clarify this issue. Methods: We evaluated progression-free survival (PFS) and overall survival (OS) from the medical charts of chemotherapy-naïve patients with EGFR-mutant NSCLC treated with gefitinib monotherapy in our institution. We also identified history of concomitant use of anti-acid agents (proton pomp inhibitors and histamine type 2 receptor blockers) at the time of initiation of gefitinib therapy and assessed its impact on the efficacy of gefitinib using Cox’s proportional hazard model. Results: Between 2006 and 2012, consecutive 83 patients received gefitinib therapy, of whom 29 (34.9%) used anti-acid agents simultaneously. Baseline clinical characteristics between the two groups (use and non-use of anti-acid agents) were well balanced except performance status (PS) of 0: 17.2% vs. 37.0% respectively. Neither PFS nor OS were influenced by concomitant use of anti-acid agents in univariate analysis (hazard ratio: 1.12; 95% confidence interval: 0.66-1.92 and 1.67; 0.86-3.44, respectively). Multivariate analysis also showed no significant effect of anti-acid agent use on PFS and OS (1.18; 0.67-2.06 and 1.66; 0.81-3.38, respectively), whilst poor PS affected OS (2.03; 1.27-3.26). Additionally, no difference in the impact of use of anti-acid agents on the gefitinib sensitivity was observed when stratified by the type of EGFR mutations. Conclusions: Concomitant use of anti-acid agents does not seem to affect efficacy of gefitinib in EGFR-mutant NSCLC. It is unlikely that physicians need to keep in mind the drug interaction of gefitinib and anti-acid agents in daily clinical practices, although further extensive cohort studies are warranted.
A pemetrexed-based genetic study of Chinese Han patients with advanced non-small cell lung cancer (NSCLC).
Authors: Lu Shun , Niu Xiaomin , Li Ziming , Yu Yongfeng , Ye Xiangyun , Liu Yun , Chen Zhiwei , Kan Mengyuan
Published: March 2020

e19014

Background: Pemetrexed has been approved for ﬁrst- and second-line treatment in patients with non-small cell lung cancer (NSCLC). Two studies have confirmed the role of polymorphisms (SNPs) in reduced folate carrier (SLC19A1) is related with the survival differences in pemetrexed-treated NSCLC in Caucasian population. Considering different genetic backgrounds in different populations, our study was aimed to identify candidate SNPs for pemetrexed-treated NSCLC in Chinese Han population. Methods: Fifty-seven patients with previously treated NSCLC received pemetrexed-based third-line treatment from Shanghai Chest Hospital from Nov 2006 to Jul 2011. Four genes, SLC19A1, gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), and methionine synthase (MTR), responsible for pemetrexed transport and activation were evaluated. The five SNPs (rs4819128, rs914232, rs4818789, rs3788189, rs1051298) in SLC19A1, two SNPs (rs3780130, rs3780126) in GGH, two SNPs (rs1801133, rs180131) in MTHER, and one SNP (rs1805087) in MTR were selected based on the HapMap Chinese Han databases. All SNP genotyping was performed by TaqMan PCR using the ABI Prism 7900HT Sequence Detection System. Kaplan-Meier cumulative probability and Cox multivariate analyses were used to evaluate the relationship between genetic variations with survival outcome. Results: Fifty-seven patients received a median of three cycles (range, 1-16 cycles) of pemetrexed-based treatment. Median overall survival (OS) and progression-free survival (PFS) times were 23.0 and 3.2 months, respectively. Patients with AA/AG genotype of SLC19A1 rs1051298 had the better PFS and OS compared with GG genotype (5.5m vs 1.9m for PFS, P=0.047; 45.5m vs 17m for OS, P=0.001). The TT/TA genotype of novel GGH rs3780130 was correlated with better PFS compared with AA genotype (5.8m vs 2.5m, P=0.029). Conclusions: This study in Chinese Han NSCLC patients identified the unique result that novel TT/TA genotype of GGH rs3780130 was related with better PFS for pemetrexed-based treatment. Meanwhile, we obtained the same result with that in Caucasian study, AA/AG genotype of SLC19A1 rs1051298 was related with better PFS and OS.
Clinical observation of next-generation photodynamic therapy (NGPDT) for advanced non-small cell lung cancer.
Authors: Li Li Jun
Published: March 2020

e19028

Background: Clinical observation of next-generation photodynamic therapy (NGPDT) for advanced non-small cell lung cancer (NSCLC). Methods: Through pathology or cytology diagnosis, 66 cases of advanced non-small cell lung cancer patients were selected and randomly divided into two groups. The Next Generation Photodynamic Therapy (NGPDT) group had 32 patients. Photosensitizer was administered on a dosage of 2 mg per kilogram of body weight, wherein two-thirds via ultrasonic atomization inhalation and one-third via oral intake. After the irradiation target(s) were determined, optical fiber for laser treatment purposes was guided into lung tumor(s) via interstitial procedure, percutaneous puncture under precious laser navigation, irradiation light intensity was 200 J/cm2, irradiation power was 1,000 mw, activation was then started and lasted for eight to ten minutes, laser irradiation into tumor was two to five centimeters in length, irradiation could be performed phase by phase (sub-paragraph treatment) based on tumor size or irradiations could be performed repeatedly. While in the mean time in the chemotherapy/radiotherapy group (external beam radiotherapy + whole body chemotherapy) 34 cases were observed, 15 MV X ray radiation therapy irradiation field covers primary lung tumor lesion(s) and mediastinal lymphatic drainage area, dosage was 65-70 Gy, on every first day in a week of radiotherapy, 20 mg cisplatin was administered via intravenous application. Results: In the NGPDT group and simultaneous radiotherapy/chemotherapy group, one and two years survival rate were 93.75%, 70.60% and 68.75, 32.35% respectively (P <0.05). The complete remission rate and partial remission rate were 56.20% and 21.30%, rate of the NGPDT group was significantly higher than that of the corresponding radiotherapy and chemotherapy group, the difference was statistically significant (P <0.05). Conclusions: NGPDT can prolong survival in patients with advanced NSCLC, improving their quality of life; it is one of the most effective measures for advanced non-small cell lung cancer treatment.
Economic analysis of TORCH: Erlotinib versus cisplatin and gemcitabine as first-line therapy for advanced non-small cell lung cancer (NSCLC).
Authors: Chung Carmen , Isaranuwatchai Wanrudee , Di Maio Massimo , Jiang Haiyan , Lau Anthea , Hoch Jeffrey S. , Feld Ronald , Tsao Ming Sound , Gridelli Cesare , Ciardiello Fortunato , Butts Charles Andrew , Gallo Ciro , Perrone Francesco , Leighl Natasha B.
Published: March 2020

e19031

Background: The TORCH (“Tarceva or Chemotherapy”) randomized phase III trial demonstrated that first-line erlotinib compared to cisplatin/gemcitabine in unselected advanced NSCLC patients yielded inferior survival, but no major differences in global quality of life. We determined the incremental costs and utility between arms, including in the EGFR mutation positive subgroup. Methods: Direct medical resource utilization data and EQ5D scores were collected prospectively during the trial. Costs for medications, outpatient visits, investigations and toxicity management including hospitalization were determined, and presented in 2012 Canadian dollars (CAD). The outcome of the analysis was the incremental cost per life year and quality-adjusted life-years (QALYs) gained. Results: The incremental mean cost per patient in the chemotherapy arm was $4,163CAD, largely related to drug and outpatient visit costs, while higher costs from hospitalization and adverse events were seen in the erlotinib arm. Mean overall and quality-adjusted survival times were longer in the chemotherapy arm. In the subset of patients with EGFR mutations (n=39), mean survival was not significantly different between arms (1.35 years for chemotherapy versus 1.29 years for erlotinib, p-value=0.86), but quality-adjusted survival favoured erlotinib treatment (i.e. mean QALYs were 1.04 for chemotherapy, and 1.40 for erlotinib). The incremental cost-effectiveness ratio for initial erlotinib in the EGFR mutation positive subgroup was $30,301 CAD per QALY. Conclusions: Initial chemotherapy in unselected advanced NSCLC yields better survival at minimal increased cost compared to erlotinib. In the EGFR mutation positive subgroup, first-line erlotinib is cost effective compared to first-line platinum doublet therapy, supporting routine EGFR genotyping to select first-line therapy in advanced NSCLC.
Reduced folate carrier (RFC) as a predictive marker for response to pemetrexed in advanced non-small cell lung cancer (NSCLC).
Authors: Alvarez Fernandez Carlos , Pérez Arnillas Quionia , Ruiz Ana Lucrecia , Rodriguez Rubi David Jose , Sánchez Lorenzo Luisa , Li Torres Walter Antonio , Izquierdo Manuel Marta , Berros Fombella Jose Pablo , Luque Cabal Maria , Jiménez Paula , Villanueva Palicio Noemi , Esteban Emilio
Published: March 2020

e19034

Background: RFC is the major transport system in mammalian cells for folate cofactors and antifolate therapeutics. The aim of this study was to assess the predictive value of RFC expression in patients receiving pemetrexed for advanced NSCLC. Methods: The study was carried out in a population of 48 patients with advanced NSCLC which have received pemetrexed monotherapy in second and third line. RFC expression was assessed using a two-step model of immunohistochemical staining in paraffin-embedded tissue samples. Results: RFC expression was detected in 16 (33%) patients. In the global population, the median progression free survival (PFS) and the median overall survival (OS) were 3.3 and 6.5 months respectively. The subgroup of patients with expression of RFC had a tendency to better median PFS (4.5 vs 2.8 months; p=0.926) and median OS (11.7 vs 4.8; p=0.150). In patients with adenocarcinoma histology and RFC expression median OS after treatment with pemetrexed was 14.4 months versus 5.0 in those with adenocarcinoma but without RFC expression (p=0.039). Conclusions: These results suggest the possible relation between RFC expression and response to treatment with antifolates (pemetrexed) independently of the tumor histology. Further studies are required to confirm these results.
Benefits of a centralized cancer control program on outcomes: Evaluation of wait times for diagnosis and management of advanced non-small cell lung cancer (NSCLC).
Authors: Noonan Krista , Laskin Janessa J. , Tong King Mong , Ramsden Katherine , Zhai Yongliang , Ho Cheryl
Published: March 2020

e19039

Background: Canada has a national cancer registry that tracks patterns across the population; British Columbia (BC) has the lowest lung cancer mortality in the country. The BC Cancer Agency (BCCA) operates five regional cancer centres and community outreach sites that deliver cancer care using evidence-based standards and guidelines established by the BCCA. The province is 945,000 km2; the population is distributed 85% urban and 15% rural. We hypothesize that adherence to provincial cancer control programs results in equitable services in all geographic locations. Methods: A retrospective population-based review of stage IIIb/IV NSCLC patients (pts) diagnosed from Jan 2008 to Dec 2010 referred to the BCCA was done. Pt characteristics and time intervals between diagnosis, referral, oncology consultation and palliative therapy were extracted. The Kruskal-Wallis test was used to compare wait times (WT). The Kaplan-Meier method and log rank test was used for OS. Results: 1,431 pts were identified. Median time from diagnosis (DX) to referral (RF) was similar across all geographic regions (11-13 days). Median time from RF to oncology consultation ranged from 7-16 d. Table 1 describes medical oncology (MO) WT to chemotherapy (CT) and radiation oncology (RO) WT to radiotherapy (RT). Conclusions: While WT varied between key events in the pts’ lung cancer trajectory by geographic location, the overall survival from diagnosis was similar in all groups. Provision of provincially mandated guidelines and care conferred equitable outcomes in advanced NSCLC across BC. [Table: see text]
Survival analysis of induction cisplatin (CDDP)-docetaxel (DOC)-bevacizumab (BEV) chemotherapy followed by maintenance BEV-pemetrexed (PEM) therapy in advanced nonsquamous non-small cell lung cancer (NonSq NSCLC): A phase II trial from Okayama Lung Cancer Study Group 0903.
Authors: Nogami Naoyuki , Hotta Katsuyuki , Kozuki Toshiyuki , Yoshioka Hiroshige , Nishiyama Akihiro , Fukuda Yasushi , Tabata Masahiro , Shinkai Tetsu , Tanimoto Mitsune , Kiura Katsuyuki ,   Okayama Lung Cancer Study Group
Published: March 2020

e19040

Background: BEV maintenance therapy and PEM maintenance therapy in platinum-based chemotherapy yield a significant survival advantage in CALGB and PARAMUNT trials, respectively, but each agent gave only modest impact on survival. We conducted a phase II trial of CDDP-DOC-BEV therapy followed by maintenance BEV-PEM therapy inchemo-naïve advanced NonSq NSCLC. Methods: Forty-one patients (pts) participated in the induction phase, specified as four cycles of induction CDDP (80 mg/m2), DOC (60 mg/m2) and BEV (15 mg/kg) on day 1 of a 21-day cycle. Pts who had not progressed during CDDP-DOC-BEV received maintenance BEV (15 mg/kg) and PEM (500 mg/m2) on day 1 of a 21-day cycle until disease progression. The primary endpoint was PFS, and the secondary endpoints included OS, toxicity, and response. Survival time was calculated from the date of registration. Results: Pt characteristics were as follows: median age: 62 yrs; 76% male; 32% PS 0; 73% stage IV; 93% Ad; 5% EGFR-mutant and 2% ALK-mutant. At the time of this analysis, 34 pts (83%) discontinued the treatment, mainly due to progressive disease (53%). The principal toxicity was myelosuppression (gr. 4 hematological: 21 pts [51%]), and grs. 3/4 febrile neutropenia was observed in 10 (24%) despite no treatment-related deaths. The objective response rate and disease control rate (DCR, % pts with CR/PR/SD) was 82.9% and 97.6%, respectively. Median follow-up time was 15.6 months, and 1-yr PFS rate was 34.2% with 95% confidence interval (CI) of 20.3-48.5%, which met the primary endpoint. Also, 1-yr OS rate was 75.6% (95%CI: 59.4-86.1%). Exploratory analysis for pts with both EGFR- and ALK-wild-typed NonSq NSCLC (n = 16) demonstrated 1-yr PFS and OS rates of 50.0% (24.5-71.1%) and 87.5% (58.6-96.7%), respectively. Also, pts with maintenance therapy (n = 34) had 1-yr PFS and OS rates of 41.2% (24.8-56.9%) and 82.4% (64.9-91.7%), respectively. Conclusions: CDDP-DOC-BEV followed by BEV-PEM maintenance seems highly effective despite moderately toxic profiles in chemo-naïve pts with advanced NonSq NSCLC. Clinical trial information: UMIN000004127.
Phase I study of the safety and pharmacokinetics of epitinib, an oral EGFR tyrosine kinase inhibitor, in patients with advanced solid tumors.
Authors: Zhou Qing , Wu Yi Long , Yu Xiyong , Yang Jinji , Wen Limin , Sai Yang , MU Hua
Published: March 2020

e19042

Background: Epitinib is an oral small molecule compound selectively inhibits epidermal growth factor receptor (EGFR). It has demonstrated potent inhibitory effects on multiple human tumor xenografts with a large safety window and broad tissue distribution including high drug contribution in brain. This first-in-human study is being conducted to assess the safety and tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of Epitinib. Methods: This phase I study uses a 3+3 design for dose-escalation of Epitinib given once daily (QD) in 28-day treatment cycles in patients with solid tumors who failed or have no access to standard therapies. Safety and tumor response are assessed according to NCI CTCAE 4.0 and RECIST 1.1, respectively. Results: By Dec 31, 2012, 19 pts aged 40-66 yr old (ECOG PS 1) with NSCLC (n=16) or breast cancer (n=3) were enrolled in 5 dose cohorts of 20-160 mg. Six NSCLC pts had EGFR mutations (3 with T790M). All pts had ≥2 lines of prior systemic treatments (7 pts with gefitinib or elotinib). Most AEs were mild (Gr1). Treatment-related AEs included skin rash (36.8%), abnormal liver function tests (42.1%), diarrhea (10.5%), vomiting (5.3%), paronychia (5.3%), decreased neutrophil count (5.3%) and increased creatinine (5.3%). Three SAEs were reported as possibly unrelated to the study drug. No DLT was observed and MTD has not been reached yet. PK analysis showed that the mean elimination half-life of Epitinib was approximately 40 hours and Tmax was around 2 h. Both Cmaxand AUC exhibited good dose proportionality over the studied dose range with low inter-patient variability following single and multiple doses. Among 15 evaluable pts, 1 EGFR mutation+ NSCLC pt achieved confirmed partial response (66.7% tumor reduction) for more than 6 months and the treatment is ongoing; 8 pts had stable disease, including 1 with T790M for 6 months and 1 with brain metastasis for 12 months who is still on treatment. Conclusions: Epitinib was well tolerated at doses up to 160mg QD to date with manageable adverse events and excellent pharmacokinetic properties. Encouraging clinical activity was observed, including durable SD in NSCLC patients with T790M or brain mets.
Hydration with magnesium and mannitol without furosemide prevents the nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced non-small cell lung cancer.
Authors: Muraki Keiko , Koyama Ryo , Suina Kentaro , Asao Tetsuhiko , Honma Yuichiro , Shukuya Takehito , Ohashi Rina , Shimada Naoko , Takahashi Fumiyuki , Takahashi Kazuhisa
Published: March 2020

e19043

Background: The aim of this study was to examine the effect of hydration with magnesium and mannitol without furosemide on the nephrotoxocity accompanying combination chemotherapy using cisplatin and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). Methods: Fifty patients with NSCLC who received cisplatin plus pemetrexed, using either old hydration protocol including normal saline with mannitol and furosemide, or a new one including normal saline with magnesium and mannitol without furosemide were retrospectively analyzed. Nephrotoxicity was compared between patients treated using the old protocol and those treated with the new protocol. Univariate and multivariate analyses were performed to identify the independent factors associated with protection against nephrotoxicity in patients with NSCLC who received cisplatin plus pemetrexed. Results: Thirty patients received the old hydration protocol, while 20 patients were treated using the new hydration protocol. The patients treated using the new hydration protocol showed a significantly greater increase in creatinine clearance (p=0.0004) and a decrease in the serum creatinine level (p=0.0148) after one course of chemotherapy compared with those treated using the old hydration protocol. There were no differences in the chemotherapeutic response or overall survival between the groups (p=0.572). The new hydration protocol with supplemented magnesium with mannitol without furosemide was an independent factor for the protection against nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced NSCLC (HR 0.232 (95% CI: 0.055-0.986), p=0.039). Conclusions: These results demonstrate that the new hydration protocol comprising supplementation with magnesium without furosemide could prevent the nephrotoxicity induced by cisplatin and pemetrexed without affecting the treatment outcome.
EGFR mutation rate in liquid-based cytology compared with biopsies from primary and metastatic lung cancer using real-time PCR.
Authors: Buglioni Simonetta , D'Alicandro Valerio , Melucci Elisa , Ercolani Cristiana , Visca Paolo , Fabi Alessandra , Filippetti Massimo , Milella Michele , Mottolese Marcella
Published: March 2020

e19052

Background: Specific EGFR tyrosine kinase inhibitors (TKIs) are recommended as first-line therapy in patients with non-small cell lung cancer (NSCLC) that have active EGFR mutations. Although cytology and tumor biopsy are a very common approaches to evaluate patient eligibility to TKIs, the limited number of tumor cells present in these samples may often constitute a bias for molecular analysis. In this context, the use of sensitive methods to detect EGFR mutations may be of pivotal clinical importance. The aim of this study was two-fold: 1) to determine the accuracy and sensitivity in detecting EGFR mutations between liquid-based cytology (LBC) and bioptic specimens, 2) to compare the performance of direct DNA sequencing and real-time PCR (qPCR) in two different series of cytologic and histologic primary and metastatic NSCLC. Methods: DNA wasextracted from 537 specimens of NSCLC patients including 422 biopsies and 115 ThinPrep (TP) collected samples respectively. EGFR mutations were analyzed by direct sequencing (exons 19 and 21) in 284 biopsies and 68 TP samples and by qPCR (exons 18, 19, 20, 21) in 138 biopsies and 47 LBC samples. Results: The overall specimen insufficiency rate between LBC and biopsies was significantly higher by direct sequencing compared to qPCR (biopsies: 11.6% vs 7.2%) and (LBC: 14.7% vs 2.3%). In the series of 309 valuable cases analyzed by direct sequencing (251 bioptic and 58 LBC), we found 34 (11%) EGFR mutations (11.2% biopsies and 10.3% LBC ). Of interest, a higher percentage of EGFR mutant cases (18.1%) was observed in the 170 valuable cases analyzed by qPCR (11.1% biopsies and 21.4% LBC). Conclusions: Our data indicate that TP collected specimens seem to be more reliable than formalin fixed biopsies for molecular analysis, probably due to the better quality of the extracted DNA. Furthermore, qPCR enabled detection of EGFR mutations in samples with low tumor content for which conventional Sanger sequencing was not informative.
Clinical characterics of mixed neuroendocrine cancer of lung: Retrospective analysis of 20 cases from 2,501 lung cancer.
Authors: Li Dong-Hai , Zhou Lin , Ding Zhenyu
Published: March 2020

e19055

Background: The mixed neuroendocirne cancer of the lung consists endocrine cancer and other pathological types of cancer, and is generally overlooked in daily practice. The current study to explore the clinical characteristics of mixed neuroendocirne cancer of the lung. Methods: Totally 2,501 cases with primary lung cancer were retrieved from the archive of the Cancer Center, West China Medical School. And the relevant medical records including diagnosis, histology, therapy, and outcome were collected. Results: Among the 2, 501 cases, 20 were found to have mixed neuroendocrine cancer with morbidity rate 0.01% (19 male, 1 female). The median age was 60 years. The surgery (13 cases, 65%) and chemotherapy (19 cases, 95%) were the mainstay of therapy. 2 cases (10%) received thoracic radiation, and 3 cases (15%) received whole brain radiation. Chemotherapy regimens included etoposide-based doublets (A) or the third-generation agent-based (B) regimens. The long-term follow-up data were available for 18 cases (90%) with the median follow-up duration of 20.5 months. The overall survival of the stage IV patients was 18.2 months, while that of the stage I-III was not reached (P=0.325). The chemotherapy regimens (A or B) did not exert impact on survival (P=0.535). Patients received operation (11 cases) had less mortality compared with those without operation (7 cases) (P<0.001). Conclusions: The mixed neuroendocrine cancer of lung is a rare disease. Male takes a predominant part. Stage and histology are important for the prognosis. The chemotherapy seems to have less impact on the prognosis, but the surgery is critical for the long survival.
Association of clinical and nutritional factors with treatment related toxicity of “fixed standard dose” of afatinib in patients with advanced NSCLC.
Authors: Arrieta Oscar , de la Torre Martha , Pérez Dana , Turcott Jenny , Juárez Eva , Sanchez-Lara Karla , López Diego
Published: March 2020

e19068

Background: Afatinib, an irreversible tyrosine kinase inhibitor of ErbB-family, has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. Adverse effects related to afatinib such as diarrhea, stomatitis and rash can negatively impact on QoL and survival by interrupting treatment. Dose of TKI´s of EGFR are fixed regardless of weight or body surface (BS), which could affect the severity of treatment related toxicity. Methods: We prospectively studied patients with advanced NSCLC treated with afatinib in order to determine if malnutrition and clinical factors are associated to higher incidence of severe toxicity. Prior treatments with afatinib 40mg, 78 patients were assessed. Nutritional status was assessed by Subjective Global Assessment (SGA), and toxicity was obtained during 2 cycles by CTCAE 4.0, severe toxicity is defined as grades 3 and 4. Results: Mean age was 59.2 years, 71.8% were women, 89.7% had adenocarcinoma, 76.9% had a good performance status (ECOG 0-1), and median weight and BS were 59.9kg and 1.58m2. Sixty percent of patients had some grade of malnutrition (SGA B+C). Factors associated to severe diarrhea, mucositis and other gastrointestinal toxicity are shown in Table 1, no factors were found to be associated with the development of severe rash. Conclusions: The performance status, malnutrition and body surface are independent factors related to severe gastrointestinal toxicity to Afatinib. This study suggests that for the initial dose selection of TKI´s of the EGFR these factors should be considered in order to reduce the risk of severe toxicity.
Epidermal growth factor +61 a/g polymorphisms as predictors for survival in advanced lung adenocarcinoma and squamous cell carcinoma.
Authors: De Mello Ramon Andrade , Ferreira Monica , Soares-Pires Filipa , Costa Sandra , Oliveira Pedro , Hespanhol Venceslau , Reis Rui M
Published: March 2020

e19069

Background: Our purpose was to evaluate epidermal growth factor (EGF) +61 A/G polymorphisms as prognostic marker for progression free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC). Methods: 148 Portuguese Caucasian, medically treated for NSCLC between February 2010 and April 2011, were included in this study. DNA was extracted from peripheral blood leucocytes. Genotyping was performed by PCR-RFLP. Chi-square test, Kaplan-Meier estimator and cox regression hazard model were used to assess the prognostic value of selected polymorphisms. Results: Genotype frequency was A/A (25.3%), A/G (55.6%), G/G (19.2%). We found no differences in PFS among EGF+61 A/G polymorphisms and NSCLC (p = 0.339). However in G/G+A/G genotype patients group showed a trend to higher OS than A/A genotype (p = 0.055). Moreover, adenocarcinoma and squamous cell (SC) lung cancers patients harboring in A/G+G/G genotype group showed a trend to higher OS than those harboring A/A genotype (p = 0.074). Furthermore, patients in advanced stages carrying G/G genotype presented higher OS than those carrying A/A genotype: 13 months versus 3 months (adenocarcinoma); and 6 months versus 1 month (SC lung cancer), respectively, p = 0.043. Conclusions: We were able to observe the G/G genotype of EGF+61 A/G polymorphisms as a positive predictor for survival in medically treated advanced adenocarcinoma and squamous cell lung carcinoma patients. In future, our findings could be used as a biological marker in order to identify eligible NSCLC subgroups with potential improved response to EGFR tyrosine-kinase-inhibitors.
Phase Ib study of chidamide (CS055), a new subtype-selective oral histone deacetylase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer.
Authors: Hu Xing-Sheng , Shi Yuan-Kai , Wang Lin , Lin Lin , Han Xiao-Hong , Meng Zhi-Yun , Dou Gui-Fang , Sun Yan
Published: March 2020

e19075

Background: Chidamide (CS055) is a new benzamide type of histone deacetylase (HDAC) inhibitor with subtype selective activity against HDAC1, 2, 3 and 10. Synergistic effect of chidamide combined with paclitaxel and carboplatin (PC) have been demonstrated in various in vitro studies. Chidamide has shown well-tolerated and favorable PK profiles in patients (pts) with advanced solid tumors and lymphomas.This phase Ib study was designed to assess the safety and pharmacokinetics of chidamide plus PC in pts with advanced non-small cell lung cancer (NSCLC). Methods: Chemonaive pts with stage IIIb or IV NSCLC were treated with the escalating doses of chidamide (20, 25, and 30mg) plus PC. Chidamide was oral administered twice per week. Paclitaxel (175 mg/m2) and carboplatin (AUC 5 mg·min/mL) were given both on day 1 every 3 weeks. Pts with response or stable disease after four cycles maintained single chidamide therapy until disease progression or unacceptable toxicity. Results: No DLT was observed in the 20 mg (n=3) and 25 mg (n=3) cohorts. 2 DLTs occurred in the 30 mg cohort (n=4), where 1 pt experienced grade 4 thrombocytopenia at the end of the first cycle, and the other developed grade 3 neutropenia and grade 2 thrombocytopenia resulting in the delay of the 2nd treatment cycle for > 14 days. Therefore, chidamide in 25 mg was determined to be the MTD with this combination regimen. ≥ Grade 3 toxicities were thrombocytopenia (n=3) and neutropenia (n=1). 1 pt experienced grade 1 prolonged QTc. Co-administration had no significant effect on clearance of either chidamide or paclitaxel. 1 pt in the 20 mg cohort had confirmed partial response. Of 5 pts with brain metastases, 2 of them had complete disappearance of brain tumors after 4-cycle treatment. Conclusions: Chidamide plus PC was safe and well tolerated, with no apparent chidamide-paclitaxel pharmacokinetic interaction. Preliminary efficacy results suggest that chidamide combined with PC could provide benefit to NSCLC pts, with a potential interest of further observation of brain metastasis control in NSCLC with this regimen. Clinical trial information: ChiCTR-ONC-12002283.
Impact of erlotinib activity on overall survival in non small cell lung cancer patients: Is the post progression survival a new paradigm?
Authors: Franchina Tindara , Russo Alessandro , Proto Claudia , Chiofalo Giuseppe , Picciotto Maria , Scimone Antonino , Toscano Giuseppe , Berenato Rosa , Noto Laura , Adamo Vincenzo
Published: March 2020

e19086

Background: In the last few years, the treatment of non-small cell lung cancer (NSCLC) has been dramatically changed with the introduction of EGFR TK (Epidermal Growth Factor Tyrosine Kinase) inhibitors. Given its objectivity and the benefits derived by patients, overall survival (OS) has been historically considered the most important therapeutic objective in advanced NSCLC. However, little is known about postprogression survival (PPS) in NSCLC. This study evaluates the correlation between response to erlotinib and post progression survival (i.e. the time between disease progression and death) to estimate the impact of this drug on overall survival. Methods: We retrospectively analyzed 68 NSCLC unselected patients consecutively treated with second or third line erlotinib at our institution from 2007 to 2010, including in the responder group patients who progressed after stable disease on erlotinib for at least six months (n=20). The relationship between OS and PPS was evaluated by standard statistical tests. P-values <0.05 were considered statistically significant. Results: Survival was significantly prolonged in responders patients (18.6 vs 11.3) suggesting the important role of EGFR TK inhibitors in NSCLC management. In addition a significant increase of PPS was recorded in these patients (9.1 vs 4.6 p=0.02), allowing to perform further therapy lines to better control cancer evolution. Conclusions: These data underline the key role of EGFR in NSCLC growth and progression and the impact of erlotinib in cancer control evolution. Post progression therapy influence the effect on overall survival. This analysis suggests that a treatment strategy incorporating all active agents over the course of disease optimizes OS. Further investigations will be needed in selected patients harboring EGFR-activating mutations to better define the role of PPS as new indicator of erlotinib efficacy.