bluuebunny/crossref_metadata_2025_split huggingface dataset:
EGFR mutations detected by high-resolution melting analysis (HRMA) as a predictor of response and survival in non-small cell lung cancer (NSCLC) patients treated with gefitinib
Authors: Takano T. , Ohe Y. , Furuta K. , Tsuta K. , Nomoto K. , Matsuno Y. , Fukui T. , Sekine I. , Kunitoh H. , Tamura T. 
Published: March 2020

7075 Background: Recent studies have shown that EGFR mutations, mainly deletions in exon 19 (DEL) and L858R, are associated with gefitinib sensitivity in patients (pts) with NSCLC. We established a new easy method, using high-resolution melting analysis (HRMA), for detecting DEL and L858R mutations even from small biopsy or cytology samples, and evaluated the significance of EGFR mutations in NSCLC on a larger scale. Methods: Among 364 advanced or recurrent NSCLC pts treated with gefitinib between Jul 2002 and Dec 2004, HRMA was performed in 207 pts from whom specimens were available. DNA extracted from the archival tissue or cytology samples not subjected to microdissection was analyzed to detect DEL and L858R using HR-1 (Idaho Technology), an HRMA device. To validate this method, the results were compared with direct sequencing data obtained from microdissected tumor cells from surgical specimens in 66 pts. Results: Tissue/cytology/both samples were analyzed in 91/77/39 pts. EGFR mutations were detected in 85 (41%; DEL/L858R: 49/36) of the 207 pts. In the comparison with direct sequencing, consistent results were obtained from all of the 66 tissue samples, while false negative results were obtained in 2 of the 28 cytology samples. EGFR mutations were seen more frequently in women (54% vs. 31%; P = .001), never-smokers (53% vs. 32%; P = .002), and pts with adenocarcinoma (44% vs. 11%; P = .007). CR/PR/SD/PD was observed in 2/64/11/8 pts with EGFR mutations and in 0/10/23/89 pts with wild-type EGFR. The response rate (78% vs. 8%), time to progression (median, 9.1 vs. 1.6 months) and overall survival (median, 19.9 vs. 9.1 months) were all significantly superior in pts with EGFR mutations (P < .0001). Minor response and/or long SD (>6 months) was observed more frequently in SD pts with EGFR mutations than in those with wild-type EGFR (91% vs. 26%; P < .001). Among the pts with EGFR mutations, the response rate was significantly higher in the pts with DEL than in those with L858R (86% vs. 67%; P = .037). Conclusions: HRMA is a practical and precise method to detect DEL and L858R mutations. EGFR mutations strongly predict a better response and longer survival in NSCLC pts treated with gefitinib. No significant financial relationships to disclose.
Topotecan: Weekly intravenous (IV) schedule similar to standard 5-day IV schedule as second-line therapy for relapsed small cell lung cancer (SCLC)—A Minnie Pearl Cancer Research Network phase II trial
Authors: Shipley D. L. , Hainsworth J. D. , Spigel D. R. , Gray J. R. , Barton J. H. , Switzer A. , Nicolau M. , Marsland T. , Joseph G. , Greco F. A. 
Published: March 2020

7083 Background: Topotecan IV weekly produces significantly less myelotoxicity than the standard 5-day IV schedule and appears as active as the 5-day schedule in patients (pts) with relapsed ovarian cancer. Topotecan 5-day IV schedule is the standard for second-line therapy for sensitive relapse SCLC. Methods: The primary endpoints of this phase II trial were to determine the response rate and toxicity of topotecan IV weekly as second-line therapy in patients with sensitive relapse (SR) and resistant relapse (RR) SCLC. Topotecan 4mg/m2 IV over 30 minutes for 12 consecutive weeks was planned. Dose modifications were made based on toxicity. Pts were evaluated for response after 4 weeks; at least 3 weekly treatments were required to be evaluable. Results: A total of 103 pts (59 SR; 44 RR) were enrolled: 56 men, 48 women; age range 42–86 (median 65); performance status 0=18, 1=69, 2=16, 3=1. 47 pts with SR and 34 pts with RR were evaluable for response by WHO criteria. For SR, 3 pts had partial response (6.4%, 95% CI 1.3%-17.5%), 17 pts had stable disease (7 had minor responses with tumor shrinkage of 39%, 27%, 21%, 20%, 20%, 7%, and 3%, respectively). Using RECIST criteria 5 pts had PR (13%, 95% CI 6%-25%). For RR, 1 pt had a CR (3%, 95% CI 0.1%-15.3%), 6 pts had stable disease (2 had minor responses with 36%, 5% tumor shrinkage). Grade 3/4 neutropenia/thrombocytopenia was seen in 17 and 22pts, grade 3 infection 6 pts; grade 3/4 fatigue 16 pts. There was 1 treatment-related death. Median and 1-year survival for all patients was 4.5 months (SR = 5.6 months; RR 3.2 months, p = 0.05) and 19% (SR = 22%; RR = 10%). There was no difference in survival for PR versus stable pts, and PR/stable had 1-year survival of 46% compared to PD of 9% (p < 0.0001). Conclusions: Topotecan IV weekly has similar activity to the standard 5-day IV schedule in SR SCLC, and considerably less myelotoxicity. These data support the weekly schedule for standard therapy of SR SCLC, and further study of weekly topotecan as a component of combination therapy for SCLC. [Table: see text]
Safety and pharmacokinetics (PK) of AMG 706, panitumumab, and carboplatin/paclitaxel (CP) for the treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Blumenschein G. , Sandler A. , O’Rourke T. , Eschenberg M. , Sun Y. , Gladish G. , Salgia R. , Alden C. , Herbst R. S. , Reckamp K. 
Published: March 2020

7119 Introduction: AMG 706 is an investigational, oral, multi-kinase inhibitor with both antiangiogenic and direct antitumor activity targeting VEGF, PDGF, and Kit receptors. Panitumumab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFr), has shown antitumor activity and acceptable safety in pts with solid tumors. Methods: This is an ongoing, multicenter, dose finding, phase 1b study of AMG 706 with panitumumab and CP in pts with advanced NSCLC. Primary objectives were to assess the safety and PK of AMG 706; secondary objectives included drug exposure and objective response rates. Pts had stage IIIB/IV NSCLC, ECOG score of 0–1, no symptomatic or untreated CNS metastases, and no prior chemotherapy for NSCLC (segments A&C) or ≤ 1 regimen for NSCLC (segment B). AMG 706 was given orally either QD (50 mg or 125 mg) or BID (75 mg) with CP Q3W (P:200 mg/m2; C: AUC = 6 mg/mL · min; Segment A), with panitumumab (9.0 mg/kg Q3W; Segment B), or with CP+ panitumumab (Segment C). AMG 706 was dosed continuously in 21-day cycles (days 3–21 in cycle 1; days 1–21 in cycle 2 and beyond); pts were sequentially enrolled into escalating AMG 706 dose cohorts. Results: As of 9/05, 22 pts were enrolled (10 in A, 12 in B) into AMG 706 dose cohorts of 50 mg and 125 mg QD. In A and B, respectively, 7 and 6 pts were men; median (range) age was 60.5 (60, 74) and 60.5 (55.7, 71.0). One pt in the 125 mg QD cohort in Segment B had grade (gr) 5 pneumonia. Treatment-related adverse events occurring in >5% of all patients are summarized ( table ). Preliminary data showed that AMG 706 PK profiles were similar when administered with CP either 30 min or 48 hrs apart. At 50 mg QD, there was no effect of AMG 706 on the PK of P. Conclusions: Preliminary data indicate that AMG 706 can be combined safely with CP or panitumumab in pts with advanced NSCLC and that there is no effect on the PK of AMG 706 or P. Updated data will be presented. [Table: see text] [Table: see text]
Survival update for the phase III study of pemetrexed vs docetaxel in non-small cell lung cancer (NSCLC)
Authors: Demarinis F. , Paul S. , Hanna N. , Chang Yao Tsao T. , Adachi S. , Lim H. L. 
Published: March 2020

7133 Background: Results from a large, randomized, phase III study of pemetrexed vs docetaxel as second-line treatment for advanced NSCLC indicated that pemetrexed, a novel multitargeted antifolate, has a median survival time (8.3 months) similar to that of docetaxel (7.9 months) with a more favorable safety profile [JCO 2004;22:1589–97]. This updated analysis reflects data available 23 months after the original analysis, which was performed Jan 2003 (after 519 deaths). Methods: Pts (n = 571) were randomized from March 2001 to Feb 2002 to receive either pemetrexed (500 mg/m2 IV infusion), supplemented with vitamin B12 injections and folic acid, or docetaxel (75 mg/m2 IV infusion) on day 1 of a 21-day cycle. An unadjusted survival analysis was performed and a Cox multiple regression analysis (n = 532) was done to adjust for factors (other than treatment intervention) that affected survival including ECOG performance status (PS), disease stage, and time since last chemotherapy. Percent retention was performed using the Rothmann method. Results: The updated survival analysis (performed after 519 deaths) indicated similar median survival times for pemetrexed (8.3 months; 95% CI: 7.0–9.4) and docetaxel (8.0 months; 95% CI: 6.6–9.3), and comparable hazard ratios (HR) (original 0.99 [95% CI: .82–1.20] vs updated 0.97 [95% CI: .81–1.15]). Percent of docetaxel benefit over best supportive care retained by pemetrexed was similar in both analyses: original 102% (95% CI: 52%-157%) vs updated 106% (95% CI: 68%-163%). Cox multiple regression analysis again showed that the two drugs were similar in survival after adjusting for factors significantly associated with increased survival. Conclusions: These updated survival analyses consistently demonstrate that second-line pemetrexed has similar survival to docetaxel in pts with NSCLC. Given the continued finding of comparable therapeutic efficacy, pemetrexed may be considered a standard second line therapy. [Table: see text] [Table: see text]
Circulating molecular markers in predicting radiation-induced lung damage
Authors: Zhao L. , Kong F. , Hayman J. , Kalemkarian G. , Arenberg D. , Lysons S. , Curtis J. , Cease K. , Brenner D. , Lawrence T. 
Published: March 2020

7144 Background: We hypothesized that circulating molecular markers such as transforming growth factor-beta1 (TGF-β1), interleukin-6 (IL-6), and angiotensin-converting enzyme (ACE) change early during the course of radiotherapy (RT), and that such changes precede RILD after completion of the therapy. Methods and Materials: Patients with stage I-III NSCLC treated with RT (11) or chemoRT (15) (enrolled onto two prospective clinical trials) were included in this study. Serum and platelet poor plasma were obtained prior to (Pre-RT), at 40–50 Gy (during-RT), and at the end of RT (end-RT). The plasma TGF-β1 and IL-6 and serum ACE levels were measured using molecule specific enzyme-linked immunosorbent assays. The endpoints for RILD were ≥ grade 2 radiation pneumonitis (RP) and measures of pulmonary function tests such as forced vital capacity (FVC), forced expiratory volume in the 1st second (FEV1), and diffusing capacity for carbon monoxide (DLCO). The minimal follow-up duration was 3 months. Data is presented as mean ± standard deviation; student t-test was used for significant analysis. Results: Plasma TGF-β1 and IL-6 levels changed remarkably after 40–50 Gy of RT. The mean relative TGF-β1 levels (during-RT over pre-RT) were 1.9 ± 0.9 and 0.9 ± 0.6 in patients with and without RP (p = 0.010), respectively. There were no significant associations between changes of plasma IL-6 and ACE levels and the occurrence of RP. Significant DLCO reduction was observed at 3 months after RT in almost every patient, and such reduction was significantly more remarkable in those who had radiation induced elevation in plasma IL-6 levels (34.8 ± 15.9% versus 15.6 ± 14.5%, p = 0.045). Interestingly, the pre-RT ACE level was significantly associated with changes of FEV1 (p = 0.037) and FVC (p = 0.014): improvement of 13.2 ± 12.0% and 11.0 ± 9.0% versus reduction of 7.6 ± 17.0% and 10.8 ± 17.7% for patients with high versus low levels, respectively. Conclusion: Radiation induced elevation in circulating TGF-β1 and IL-6 levels may be predictive of RILD, while serum ACE level may be associated with decreased risk of RILD. No significant financial relationships to disclose.
Prevalence of pre-existing conditions and incidence of new medical conditions after diagnosis of non-small cell lung cancer
Authors: Koo L. C. , De Lissovoy G. , Hanna N. L. , Lyidick E. , Lambe M. , Higenbottam T. , Steinberg M. H. , Langmuir P. 
Published: March 2020

7152 Background: Patients with non-small cell lung cancer (NSCLC) are likely to have concurrent disease that affects treatment/prognosis. Estimates on the: 1) prevalence of pre-existing co-morbidities provides background information for clinical trials and patients, and 2) incidence of new conditions post diagnosis improves understanding of disease progression, treatment effects, and adverse event reports. Methods: Patients aged ≥66 with a primary diagnosis of NSCLC from 1991–1999 were identified in the SEER- Medicare linked database. ICD-9 codes from medical service claims (≥2) were analyzed to estimate comorbidity rates. Results: In the 12 months prior to NSCLC diagnosis, the prevalence for ischemic heart disease, cardiac dysrhythmias, and heart failure were 14%, 9%, and 8% respectively– indicating a substantial proportion of patients who might be poor candidates for surgery or cardio-toxic treatments. These prevalence estimates are likely to underestimate true prevalence due to the 1-year window of observation. For all 9 medical conditions, the incidence rates for new conditions were as much as 2 to 3 times higher than the prevalence rates for the same comorbidity before diagnosis. Conclusions: NSCLC patients have high prevalence of cardio-vascular conditions prior to diagnosis and many new medical conditions are detected post diagnosis as a result of increased detection, disease progression, and treatment. [Table: see text] [Table: see text]
A phase II study of gefitinib as first line treatment for good performance advanced or metastatic non-small cell lung cancer in East Asian patients
Authors: Yang C. , Yu C. , Chen K. , Lin Z. , Kuo S. , Hwang T. , Cheng A. , Yang P. 
Published: March 2020

7167 Background: Gefitinib is an effective treatment for chemotherapy-treated nonsmall cell lung cancer (NSCLC) in East Asian patients. There were only limited prospective studies on the use of gefitinib in chemonaive advanced or metastatic NSCLC patients. Methods: Eligibility included histological or cytological proven chemonaive stage IIIB/IV NSCLC, measurable disease, ECOG performance status of 0–2, good organ functions and candidate for platinum-based chemotherapy. Patients were treated with 250mg gefitinib per day. Tumor assessments were performed every two months by RECIST criteria. Responding patients were treated until progression. Patients with stable disease more than 2 months may continue treatment or shift to chemotherapy. The primary objective of this study was overall response rate of patients. Secondary objectives included 1-year progression-free survival, overall survival, and ancillary biomarker studies. Simon’s two-stage design was used to aim at a response rate more than 20%. Forty-four patients were planned in stage one and the study will be terminated if 5 or less patients responded to the treatment. A total of 106 patients are planned. Results: The planned interim analysis on the first 44 patients is reported here. There were 13 male and 31 female, median age was 63 (range 39–86), ECOG performance status of 0/1/2 were 0/40/4. 33 patients were nonsmokers. 39 patients had adenocarcinoma. The side effects of the treatment were mild and well accepted by patients. There were 24/9/10/1 patients with PR/SD/PD/NE. Overall response rate was 54.5% and disease control rate was 75%. The response rates for female / adenocarcinoma / nonsmoker were 58%/59%/61% respectively. The response rates for male / non-adenocarcinoma / smoker patients were 46%/20%/36%. The median time to progression for all patients was 6.3 months. Conclusions: Gefitinib is a very effective treatment for East Asian chemonaive advanced or metastatic NSCLC patients. Although the patients’ number was small, the response rates for patients with one unfavorable predictive factor were comparable to the response rates of patients receiving combination chemotherapy. The response rates and duration for 106 patients will be presented in the meeting. [Table: see text]
Final survival and safety results from a multicenter, open-label, phase IIIb trial of erlotinib in patients with advanced non-small cell lung cancer
Authors: O’Neill V. , Hainsworth J. , Spigel D. , Bloss J. D. 
Published: March 2020

7169 Background: Erlotinib is an orally available, reversible inhibitor of the EGFR tyrosine kinase with a proven survival advantage for patients with locally advanced or metastatic NSCLC who have failed one prior chemotherapy regimen. Preliminary data suggest that never smokers respond particularly well, as assessed by both response and survival. Method: This is a phase IIIb, multicenter, open-label trial of erlotinib in patients with advanced NSCLC who have progressed following standard chemotherapy treatment. The trial allowed patients access to erlotinib therapy prior to FDA approval; patients could remain on study up to 9 months following approval. The co-primary objectives were best ORR (as assessed by investigator) and OS associated with erlotinib therapy in this group, and in patient subsets defined by tobacco history. Secondary objectives include evaluating safety; characterization of OS and RR in sub-populations, including histology, sex, ethnicity; duration of time on treatment. Patients and Treatment: Between August and November 2004, 229 patients were enrolled and treated. Erlotinib was given at the standard dose of 150mg once daily. Demographics are as follows: M/F% 60/40; median age 68 (27–90); ECOG PS% 0/1/2/3 25/44/23/7; squamous histology 34%, adenocarcinoma 45%; >1 prior regimen 47%; prior platinum 83%; never smoked 9%. Results: At the time of the final analysis (August 2005), 60% of subjects had died; data are therefore mature. Among the 229 treated subjects, the best ORR was 8.3% (CI: 5.2% - 12.4%). The ORR in never-smokers, previous smokers and current smokers was 28.6% (CI: 13.2% - 50.6%), 6.0% (CI: 3.0% - 10.4%) and 7.3% (CI: 2.0% - 19.0%), respectively. Median overall survival for all patients was 6.3 months (CI: 4.7 - 8.0). Median survival was 5.2 (CI: 4.2 - 7.3) and 6.3 months (CI: 3.6 - 9.2) in previous smokers and current smokers, respectively; and was not reached in never-smokers. Median duration of treatment was 10.6 weeks. One ILD-like event was reported (0.4%). Conclusions: No unexpected safety signals were seen. The observed ORR and survival data are consistent with the findings from the pivotal phase III randomized trial. [Table: see text]
Prognostic significance of EGFR FISH and IHC in non small-cell lung cancer patients treated with chemotherapy alone
Authors: Dziadziuszko R. , Holm B. , Skov B. G. , Osterlind K. , Franklin W. A. , Varella-Garcia M. , Bunn P. A. , Hirsch F. R. 
Published: March 2020

7193 Background: High EGFR gene copy number by fluorescence in situ hybridization (FISH) predicts response and survival benefit in non small-cell lung cancer (NSCLC) patients (pts) treated with EGFR tyrosine-kinase inhibitors, but its prognostic value remains debated. We aimed to evaluate the association of EGFR FISH, EGFR immunohistochemistry (IHC) and prognosis in NSCLC pts treated with chemotherapy alone. Methods: 85 pts treated with platinum-containing chemotherapy (median follow up of 15 months [range: 2–29 months]) were included in the study. There were 47% females, 35% of pts with performance status (PS) 0, 53% PS = 1 and 12% PS = 2, 6% of never-smokers. Median age was 62 years (range: 41–80 years). Stage I-IIIA was diagnosed in 7%, stage IIIB - 44% and stage IV - 48% pts. Adenocarcinoma was the most common histology (51% pts). EGFR FISH was performed using LSI EGFR SpectrumOrange/CEP 7 SpectrumGreen probe and IHC using DAKO PharmDx kit. Results: FISH results were available in 79 pts (93%), and EGFR FISH-positive tumors (high polysomy or gene amplification) were found in 28 pts (35%). IHC results were available in 81 pts (95%) and 25 pts (31%) were scored as positive (staining index ≥200). Distribution of clinical characteristics did not differ according to either FISH or IHC result. FISH-positive pts had higher EGFR IHC staining indices as compared with FISH-negative pts (median 160 vs. 60, p = 0.005, Mann-Whitney U test). Median survival of FISH-positive pts was 12.6 months vs. 8.1 months in FISH-negative pts (log-rank p = 0.68; HR = 0.88 [95% CI: 0.49–1.59]) and the respective figures for progression-free survival (PFS) were 7.5 vs. 4.9 months, log-rank p = 0.72; HR = 0.91 [95% CI: 0.55–1.51]. Median survival in IHC-positive vs. IHC-negative pts was 6.6 months vs. 9.2 months (log-rank p = 0.44; HR = 1.27 [95% CI: 0.69–2.36]). There was no significant difference in PFS (median of 4.8 vs. 5.3 months, respectively; log-rank p = 0.71; HR = 1.11 [95% CI: 0.64–1.92]). FISH and IHC remained insignificant in a Cox regression survival analysis. Conclusion: In this cohort of NSCLC patients treated with chemotherapy alone, EGFR FISH was associated with EGFR IHC and both features had no statistically significant influence on prognosis. [Table: see text]
Extrapulmonary findings detected in a low-dose spiral computed tomography (sCT) early detection study for lung cancer (LC)
Authors: Ricardi U. , Novello S. , Cardinale L. , Crida B. , Perotto F. , Sperone P. , Borasio P. , Giajlevra M. , Selvaggi G. , Scagliotti G. V. 
Published: March 2020

7206 Background: In 2001 a feasibility study testing low-dose sCT as an early diagnosis tool in asymptomatic volunteers at high risk for lung cancer was planned and initiated at our institution with an evaluation at baseline and then annually for 5 years. Subjects & Methods: We enrolled 520 asymptomatic volunteers, 73% males, aged 55 years or older (median age 60 yrs), with at least 20 pack-years of cigarette smoking and no previous cancer. Results: At baseline, one hundred forty-four extra-pulmonary findings (28%) were detected. The more common findings were: radiologically-detected adrenal enlargements (19%); thyroid struma (8%); hepatic abnormalities, like angiomas, cysts, calcifications, steatosis (29%); renal alterations, like cysts, lithiasis, vascular calcifications and one case of stage I renal carcinoma (21%); spleen abnormalities, like cysts, calcifications, accessory spleen (5%); cholelithiasis (4%); pancreatic alterations (1%); thymic nodules (1%); axillary adenopathy (5%); aortic ectasia or aneurysm (5%) and one breast nodule. In 2 cases (renal carcinoma and breast nodule) a surgical resection was performed. All these findings were followed up through a letter to the general practitioner. In 62 subjects the initial findings were considered worth of further imaging investigations or were suggestive for a clinically definite disease (e.g. renal carcinoma). In the remaining 82, mainly based on personal history data, the abnormalities were already known and previously diagnosed. Globally, the cumulative number of extrapulmonary findings from 2nd to 5th year was 275 and the more common findings were: cysts (hepatic 9%, renal 13%), lithiasis (renal 1%, hepatic 5%), thyroid struma 4%, adrenal adenomas 3%, vascular calcifications 37%, aneurysm 3%, vertebral artropathy 2%. Conclusions: Even if early detection of lung cancer will result in a survival benefit, in the cost-effectiveness analyses the additional costs from the detection of extra-pulmonary findings should also be carefully considered because in many cases they may request substantial outpatient clinic admissions and further diagnostic investigations. No significant financial relationships to disclose.