bluuebunny/crossref_metadata_2025_split huggingface dataset:
Serum-free estradiol (E2) levels are prognostic in men with chemotherapy-naive advanced non-small cell lung cancer (NSCLC) and performance status (PS) 2
Authors: Ross H. , Oldham F. B. , Bandstra B. , Sandalic L. , Bianco J. , Bonomi P. , Singer J. W. 
Published: March 2020

7683 Background: In women with advanced NSCLC, premenopausal estradiol levels are associated with a worse survival than postmenopausal levels, suggesting an adverse effect of estradiol on prognosis in NSCLC (JCO 2006, 24(18S):7038; JCO 2006, 24:59–63). Levels of E2, produced from testosterone by aromatase, are often higher in men than in postmenopausal women (Ann Intern Med. 2000, 133:951–63). To investigate the effect of E2 on prognosis in male patients (pts) with advanced NSCLC, total and free E2 levels were assayed in pretreatment samples from men participating in 2 randomized phase III studies, STELLAR 3 and 4. Methods: Free serum E2 levels were measured prior to chemotherapy using a radioimmuno-assay in samples from 289/307 male pts with advanced NSCLC and PS2 enrolled in STELLAR 3 (paclitaxel + carboplatin (C) v. paclitaxel poliglumex (PPX) + C) and STELLAR 4 (vinorelbine or gemcitabine v. PPX). The effect of free E2 levels on survival was evaluated by log rank test. Male pts were categorized as high or low E2 based on values above or below the median (0.42 pg/ml; range: 0.1–2.95).The assay range for normal men is 0.2 - 0.5 pg/ml; in pre- and postmenopausal women, the range is 0.80- 3.45 and 0.12 - 0.39 pg/ml, respectively. Results: Hazard ratio's (HR), median, and 1-yr survival are summarized in the table . Survival was worse for male pts with E2 values higher than the median compared to those below the median (HR 1.56, p = .0008). This difference in survival was not dependent on treatment arm as survival was similar for male pts > 0.42 pg/ml receiving either PPX or control. Conclusions: High serum free E2 levels are associated with shorter survival in men with advanced NSCLC, consistent with the shorter survival noted in NSCLC in premenopausal compared to older women. While PPX is associated with improved survival in women with premenopausal E2 levels (JCO 2006, 24(18S):7039), the relatively low levels of E2 in men may be insufficient to affect survival in male pts receiving PPX. [Table: see text] [Table: see text]
Integrated genomic analysis of lung adenocarcinomas identifies loss of the MAPK phosphatase gene DUSP4 in most EGFR mutant tumors
Authors: Broderick S. R. , Chitale D. , Motoi N. , Gong Y. , Pao W. , Venkatraman E. , Rusch V. , Brennan C. , Gerald W. , Ladanyi M. 
Published: March 2020

7686 Background: Genomic analyses of lung adenocarcinoma have yielded striking advances that are already impacting on clinical management. Further advances in understanding the biological heterogeneity of this disease will require integration of multiple types of genomic data. To this end, we have assembled a large integrated genomics dataset of lung adenocarcinomas. Here, we highlight one of the novel findings emerging from its initial analysis. Methods: 173 primary lung adenocarcinomas were included in this analysis. Profiling of genomic gains and losses was done by array comparative genomic hybridization (aCGH) on Agilent 44K arrays. Expression profiling was based on Affymetrix U133A arrays. The dataset was annotated for EGFR mutations (exon 19 deletion and L858R) by sensitive PCR-based assays and for KRAS mutations by sequencing. Results: By unsupervised analysis of the aCGH data, the 173 tumors clustered robustly into two or three patterns of co-occurring gains and losses. One aCGH cluster was strongly associated with EGFR mutation (p<10−4) and was characterized by 7p gains (in the EGFR region) and 8p losses. Remarkably, by expression profiling the most consistently underexpressed gene (p<10−9) in EGFR mutant cases compared to EGFR wild type cases was a MAPK phosphatase gene at 8p12, DUSP4 (MKP-2). The DUSP4 region showed genomic loss in 27/35 EGFR mutant cases vs 47/138 non-mutated cases (p<10−4). A limited screen (n=11) has so far revealed no DUSP4 mutations. Western blotting shows low DUSP4 in most EGFR mutant lines, compared to KRAS mutant lines. Conclusions: EGFR mutations in lung adenocarcinomas are strongly associated with genomic loss and low expression of DUSP4. DUSPs are known to be transcriptionally upregulated by MAPK signaling as a negative feedback mechanism and DUSP family members are emerging as putative tumor suppressors in other cancers. We hypothesize that DUSP4 loss cooperates with EGFR mutation to allow full oncogenic activation of the MAPK pathway. Functional studies of DUSP4 in lung adenocarcinoma cell lines are in progress. Our data highlight the value of large, integrated, highly annotated genomic datasets in generating novel insights and hypotheses. No significant financial relationships to disclose.
Phase II trial of docetaxel (D) plus gefitinib (G) in elderly (≥70 years) patients with advanced stage non-small cell lung cancer (ANSCLC)
Authors: Williams C. , Bepler G. , Begum M. , Chiappori A. , Arora R. , Haura E. , Antonia S. , Extermann M. , Simon G. 
Published: March 2020

7690 Background: Adding G to first-line doublet chemotherapy did not improve survival in comparison to doublet chemotherapy alone in phase III trials (INTACT 1 and INTACT2). We hypothesized that therapy with D and G will yield similar efficacy to doublet chemotherapy but with improved toxicity profile that would be especially meaningful for elderly patients. We report here the results of a completed phase II trial. Methods: Previously untreated elderly patients with ANSCLC with ECOG performance status (PS) of 0 or 1, were eligible. D was given at 75 mg/m2 IV on day1, Q 21 days. G given orally daily; starting day 1, at a dose of 250mg. D-G was given for 2 cycles beyond maximal response. G was continued until progression. Tumors were assessed every two cycles while on D-G and every two months while on G. The RECIST criteria were used to measure responses. Results: Forty-four eligible patients were enrolled from 07/2003 to 11/2005. Demographic characteristics were M/F = 25/19; Median age 75 years (range; 70 to 84 years); ECOG PS 0/1= 27/16; Stage IV/IIIB = 38/6; Never-smoker/smoker 8/36; Adenocarcinoma/non-adeno-NSCLC 30/14; Median number of D-G cycles administered is 4 (range; 1 to 6). Median duration on maintenance D was 5 months (range; 1 to 36) Overall response rate was 29% (CR- 2%; PR- 27%) with 48% stable disease. Median progression free survival (PFS) was 8 months (95% CI: 6.2–10.6), PFS at 12 months was 34%, and 24 months was 19%. Median Overall Survival (OS) was 12 months (95% CI: 5.6–17.5). OS at 12 months was 52% and 24 months was 20%. The most common hematologic and non- hematologic adverse events were lymphopenia/anemia, and fatigue/hyperglycemia (steroid-induced)/dyspnea, respectively. Three patients had febrile neutropenia (6.8%). Detailed toxicity analyses will be reported at the meeting. Conclusion: The combination of D and G demonstrates comparable efficacy to conventionally used doublet chemotherapy regimens. The relatively favorable toxicity profile warrants further development of this approach, especially in clinical situations or special populations where toxicities are an impediment to treatment. No significant financial relationships to disclose.
Cisplatin (CDDP) plus vinorelbine (VRB) as first-line treatment for patients with advanced non-small cell lung cancer (NSCLC): Molecular correlates
Authors: de las Peñas R. , Provencio M. , Camps C. , Cobo M. , Massuti B. , Jimenez U. , Artal A. , Cardenal F. , Taron M. , Rosell R. 
Published: March 2020

7692 Background: The combination of cisplatin plus vinorelbine is a reference regimen as first-line therapy in advanced NSCLC. The correlation between predictive genetic markers and clinical endpoints may improve the prediction of treatment success and thereby the tailoring of chemotherapy. In this trial, predictive genetic markers of response to CDDP/VRB were examined in genomic DNA and cDNA derived from tumors and circulating tumors. Methods: 238 chemonaive p with stage IIIB (pleural effusion or supraclavicular lymph nodes)- IV or recurrent NSCLC were accrued at 35 sites between April 2004 and January 2006. Treatment consisted of CDDP 75 mg/m2 IV day 1 plus VRB 25 mg/m2 IV or 60–80 mg/m2 oral, days 1, 8 every 21 days. DNA samples were collected from primary tumors for the assessment of microtubule associated protein 4 (MAP4) and from serum for the checkpoint forkhead-associated and ring finger (CHFR) methylation. Results: Data on 198 p is available. Median age 62 years (38–80); males: 83.8%; smokers: 77.8%; PS 0–1: 95.3%; adenocarcinoma, 48.9% / squamous, 32.8%; stage IIIB: 16.7%, IV: 83.3%. Median cycles: 4 (1–12). Hematological toxicities (%p): grade 3/4 neutropenia, 9.6%/7.6%; grade 3/4 thrombocytopenia, 0.5%/0.5%; grade 3 anemia, 2%. Febrile neutropenia appeared in 14 cycles / 10 p (1.8%/5,1%). Non-hematological toxicities (%p): pulmonary grade 3/4, 3.0%/2.5%; nausea/vomiting grade 3/4, 7.6%/0.5%; asthenia grade 3, 13.2%; pain grade 3, 6.6%; infection grade 3, 4.1%; neurotoxicity grade 3, 0.5%. Efficacy in evaluable population: CR, 2.3%; PR, 30.8%; ORR, 33.1% (95% CI, 26.1% to 40.2%); SD, 39.7%. With a median follow up of 6.7 months, median survival for the whole population was 9 months (m), progression free survival 5.07 m, event free survival 4.8 m, 1-year survival 39.9%. Conclusions: The tolerability, efficacy and survival results of this trial confirm that CDDP/VRB is effective as first-line therapy, presenting a favorable toxicity profile in p with advanced NSCLC. Complete data on genetic markers will be presented. No significant financial relationships to disclose.
Prognostic implication of smoking history in patients with non-small cell lung cancer (NSCLC)
Authors: Oze I. , Segawa Y. , Nogami N. , Komori E. , Sawada S. , Yamashita M. , Shinkai T. 
Published: March 2020

7699 Background: The AJCC disease stage, performance status (PS), and weight loss are established and important prognostic factors in patients with NSCLC. However, it is controversial whether smoking history affects the prognosis or not. We therefore assessed prognostic implication of smoking in patients with NSCLC. Methods: This retrospective study was performed using an institutional database for 1,440 NSCLC patients between 1995 and 2005. The characteristics of these patients were as follows: median age, 68 years (range,19–93); male/female, 947/493 patients; smokers/never-smokers, 897/543 patients; ECOG PS 0–1/2–4, 1319/121 patients; AJCC disease stage I-II/III-IV, 715/725 patients; squamous cell/non-squamous cell histologies, 391/1,049 patients; and weight loss > 5%/0–5%, 229/1,211 patients. Results: At a median follow-up time of 17 months (range, 1–59.7 months), the median survival time in smokers was 25 months, and significantly shorter than that in never-smokers (52 months, P < 0.0001). In a multivariate analysis using a Cox regression model, significance of the risk of death in smoking was confirmed when adjusted for age, sex, AJCC disease stage, ECOG PS, weight loss, and histologic subtypes (HR = 1.227, 95% CI 1.018–1.478, P = 0.032). Conclusions: Smoking history was considered to be a possible prognostic factor in patients with NSCLC. No significant financial relationships to disclose.
Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib
Authors: Uramoto H. , Sugio K. , Oyama T. , Iwata T. , Onizuka T. , Yasuda M. , Sugaya M. , Nozoe T. , Takenoyama M. , Hanagiri T. , Yasumoto K. 
Published: March 2020

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.
A randomized trial of intrapericardial (ip) bleomycin (BLM) after drainage for management of malignant pericardial effusion (MPE) in lung cancer patients (pts): Report of a Japan Clinical Oncology Group trial (JCOG 9811)
Authors: Kunitoh H. , Tamura T. , Shibata T. , Imai M. , Nishiwaki Y. , Nishio M. , Yokoyama A. , Watanabe K. , Noda K. , Saijo N. 
Published: March 2020

7710 Background: This trial was aimed to evaluate the safety and efficacy of ip BLM instillation as compared to pericardial drainage alone in pts with MPE. Methods: Pts ≤ 75 y.o. with pathologically documented lung cancer, who had received pericardial drainage for clinical MPE within 72 hours of the enrollment, were eligible. Pts with chemo-naïve small cell cancer, major organ failure, or severe co-morbidity were excluded. Signed consent form was obtained. Pts were randomized to either Arm A: observation alone after drainage, or Arm B: ip BLM of 15mg, followed by additional ip BLM 10mg q48hours. Drainage tube was removed when daily drainage was ≤20mL; the protocol therapy was judged as primary failure, with no regulations on post-therapy, if this criteria could not be met after 7 days from enrollment. MPE was followed at 1,2,4,6 and 12 months by echocardiography. The primary endpoint was survival with MPE control (effusion failure-free survival, EFFS) at 2 months, assumed to be 60% vs. 30%. The trial was designed to provide 80% power with 5% one-sided alpha, with 80 cases. Results: From Aug./99 to Jan./06, 80 pts were enrolled, with 79 eligible. M:F=51:29, median age 60 y.o. (range: 39–75), 75 nonsmall histology, 53 with prior chemotherapy, and 20 with prior radiotherapy. Median drainage volume was 600 mL (range: 130–1930). Cytology of the effusion was positive in 58/76 examined. EFFS ( table ) tended to favor Arm B, with hazard ratio of 0.64 (one-sided p=0.030 by logrank test, 95% C.I. 0.40–1.03). No additional acute toxicities or complications were observed for Arm B. There were 2 cases with late constrictive complications in Arm B, but none was severe. The median survival was 79 days (A) and 119 days (B) (not significant). Conclusions: Although the difference of EFFS at 2 months was not statistically significant, BLM ip after pericardial drainage appears to be safe and effective in allover for management of MPE. No significant financial relationships to disclose. [Table: see text]
Toxicities in a phase II study of accelerated high dose thoracic radiation therapy (TRT) with concurrent chemotherapy for limited small cell lung cancer (LSCLC) (RTOG 0239)
Authors: Komaki R. , Moughan J. , Ettinger D. , Videtic G. , Bradley J. , Glisson B. , Choy H. 
Published: March 2020

7717 Background: Accelerated fractionation proved beneficial in INT0096, but the total dose was low and local recurrence was high with higher acute grade (Gr.) 3+ esophagitis. RTOG 0239 was a phase II trial to improve local control and survival with LSCLC with acceptable acute Gr. 3+ esophagitis using accelerated high dose TRT and concurrent cisplatin/etoposide. This is the first report of acute Gr.3+ esophagitis and Gr.5 toxicities. Methods: Patients (pts) with LSCLC without pleural effusion, contralateral hilar or contralateral supraclavicular nodes and PS 0–1 were enrolled. TRT was given to large fields to 28.8 Gy at 1.8 Gy per fraction, 5 days per week for 16 fractions followed by BID with large field in AM, boost in PM, then off-cord boost BID for last 5 days, all at 1.8 Gy per fx for a total dose of 61.2 Gy in 34 fx in 5 weeks. Concurrent chemotherapy was started with TRT with cisplatin, 60 mg/m2 i.v. day 1; etoposide, 120 mg/m2 i.v. day 1; etoposide, 240 mg/m2 p.o. per day or 120 mg/m2 i.v. per day on days 2 or 3. Cycles were repeated q.3 wks during and for 2 cycles after TRT. Pts who have achieved complete response one month after completion of 4 cycles of chemotherapy were asked to participate in a prophylactic cranial irradiation (PCI) study. Common toxicity criteria (CTC) 2.0 was used for acute toxicity. Results: From 10/2003 to 5/2006, 72 pts were accrued. Median age was 63 yrs with 52% females. Survival data is still maturing. Acute toxicity information is available for 68 pts. Eleven pts (16%) experienced acute Gr. 3 and 1 pt (1%) had acute Gr. 4 esophagitis. 47 pts (69%) had grade 4 blood/bone marrow toxicities. There were 2 (3%) Gr. 5 toxicities reported [1 infection with neutropenia; 1 pulmonary (pneumonia)]. Conclusions: This accelerated high dose TRT with concurrent chemotherapy for LSCLC resulted in 17% acute Gr.3+ esophagitis compared to 27% with BID TRT with 45Gy in 3 weeks by INT0096. There were 3% grade 5 toxicities. This preliminary report suggests that RTOG-0239 has tolerable toxicity. The acute Gr3+ esophageal toxicity correlated with V20 and V40 will be presented. Pts continue to be followed for the primary endpoint of 2-year survival. No significant financial relationships to disclose.
Phase II trial of gemcitabine and irinotecan in previously treated patients with small-cell lung cancer
Authors: Nishio M. , Ohyanagi F. , Horikike A. , Okano Y. , Satoh Y. , Sakae O. , Ishikawa Y. , Nakagawa K. , Nakagawa K. , Horai T. 
Published: March 2020

7718 Background: Gemcitabine and irinotecan has been shown to have an antitumor activity as a single agent against previously treated SCLC. The objective of this study was to assess the efficacy and safety of gemcitabine combined with irinotecan in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving one platinum-based chemotherapy were eligible for the study. Treatment consisted of gemcitabine (1,000 mg/m2) and irinotecan (150 mg/m2) on days 1 and 15 of a 28-day cycle.The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 30 patients (Simon's two-stage minimax design). Results: Thirty-one patients were enrolled and 30 patients (24 males/6 females, 10 refractory/20 sensitive, median age, 65 years) receive protocol treatment in this phase II trial. The median treatment cycles were 3 (1–10). The overall response rates was obtained in 39.3% (95% CI: 18.1% to 60.5%) of the patients, including two patients with refractory disease and 9 patients with sensitive disease. The median overall survival time was 14.4 months, and the 1-year survival rate was 51%. The median survival time of the patients with refractory disease was 7.4 months, compared with 14.4 months for patients with sensitive disease. The chief grade 3/4 toxicities included neutropenia (42%), thrombocytopenia (3%), diarrhea (9%), and liver dysfunction (3%). The only grade 4 toxicities were one case of grade 4 neutropenia (3.3%) and one case of grade 4 thrombocytopenia (3.3%). Conclusion: Gemcitabine plus irinotecan is an active regimen that seems to be well- tolerated by patients with previously treated SCLC. No significant financial relationships to disclose.
Phase I evaluation of carfilzomib (PR-171) in hematological malignancies: Responses in multiple myeloma and Waldenstrom’s macroglobulinemia at well-tolerated doses
Authors: Stewart K. A. , O’Connor O. A. , Alsina M. , Trudel S. , Urquilla P. R. , Vallone M. K. , Molineaux C. J. , Goy A. , Orlowski R. Z. 
Published: March 2020

8003 Background: Carfilzomib is a novel, irreversible tetrapeptide proteasome inhibitor derived from the natural product epoxomicin. Carfilzomib was well tolerated in preclinical animal studies when administered on a two-week cycle, QDx5; proteasome inhibition one hour after dosing at the MTD was >80%. Two Phase I dose-escalation studies are ongoing, aimed at determining the safety, tolerability, and biological response to carfilzomib. Methods: Carfilzomib was administered according to two different dose-intensive schedules. In PX-171–001, carfilzomib was administered on a two week cycle, QDx5 with nine days rest; in PX-171–002, carfilzomib was administered on a four week cycle, QDx2 weekly for three weeks with 12 days rest. Eligible patients have multiple myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Hodgkin's Disease (HD), or Waldenström's Macroglobulinemia (WM). Results: Thus far, a total of 54 subjects have been enrolled. Although the maximum tolerated dose (MTD) has not yet been identified on either study, responses seen on both protocols have established 11 and 15 mg/m2 as the minimal effective doses (MEDs) on PX-171–001 and 002, respectively. Of 3 patients with MM or WM treated on the 001 protocol, one MM patient has had a Partial Response (PR) and one WM patient had a Minimal Response (MR). Of 8 patients with MM treated on the 002 protocol, 3 patients have had PRs. 6 additional patients have had Stable Disease lasting longer than 6 months and symptomatic improvement has been seen in patients on both protocols. 11 subjects remain on study with stable disease or better. Proteasome inhibition in whole blood at the highest dose levels exceeded 80% one hour after the first dose. Carfilzomib has been well tolerated at doses at and above the MED thus far. There has been no incidence of painful peripheral neuropathy on either study. No dose-limiting toxicities (DLTs) have occurred on PX-171–001; one DLT (Gr 4 anemia and thrombocytopenia) was observed at 27 mg/m2 on PX-171–002. Conclusions: Thus far, intensive dosing with carfilzomib is well-tolerated at proteasome inhibition levels of more than 80%. Five responses have been observed, and several subjects have achieved long lasting SD and/or symptomatic improvement. No significant financial relationships to disclose.