bluuebunny/crossref_metadata_2025 huggingface dataset:
E2F1 overexpression associated with TS and survivin gene expressions in non-small cell lung cancer
Authors: Huang C. , Liu D. , Nakano J. , Ishikawa S. , Yokomise H. , Ueno M.
Published: March 2020

7669

Background: The thymidylate synthase (TS) expression is related to 5-FU sensitivity. The survivin expression is associated with tumor apoptosis, an indicator to predict the efficacy of chemotherapy. Recently, TS and Survivin have been reported to be E2F1 target genes. We investigate the clinical significance of the E2F1 gene expression in relation to gene expressions of TS and Survivin among non-small cell lung cancer (NSCLC). Methods: One hundred and twenty-seven NSCLC patients were investigated. Quantitative RT-PCR was performed to evaluate gene expressions of E2F1, TS, and survivin. The Ki-67 proliferation index and the apoptotic index using TUNEL method were also evaluated. Results: The E2F1 gene expression was significantly higher in stage II to III tumors than in stage I tumors (p=0.006). The E2F1 gene expression significantly correlated with the Ki-67 proliferation index (p<0.001), while no correlation was observed between the E2F1 gene expression and the apoptotic index. Regarding E2F1-target genes, the E2F1 gene expression significantly correlated with the TS gene expression (p<0.001). The E2F1 gene expression also significantly correlated with the survivin gene expression (p<0.001). The TS expression and the survivin expression significantly correlated with the Ki-67 proliferation index (p<0.001 and p<0.001, respectively). There was a significant inverse relationship between the survivin expression and the apoptotic index (p<0.001). The overall survival was significantly lower in patients with high-E2F1 tumors than in those with low-E2F1 tumors (p=0.002), especially among patients with stage II to III NSCLCs (p=0.018). The Cox regression analysis demonstrated that the E2F1 status was a significant prognostic factor for NSCLC patients (p=0.026). Conclusions: The present study revealed the E2F1 gene expression to correlate with TS and survivin gene expressions, and tumor proliferation. E2F1 overexpression could occur to produce more aggressive tumors with high proliferation rate and chemo-resistance during progression of NSCLCs. The suppression of E2F1 by RNA interference would be a useful strategy for cancer gene therapy.

No significant financial relationships to disclose.
Clinical significance of epidermal growth factor receptor gene mutations on treatment outcome after cytotoxic chemotherapy in Japanese patients with non-small cell lung cancer (NSCLC)
Authors: Hotta K. , Kiura K. , Toyooka S. , Takigawa N. , Soh J. , Fujiwara Y. , Tabata M. , Uno M. , Date H. , Tanimoto M.
Published: March 2020

7670

Background: The relationship between EGFR mutation status and clinical outcome has not fully been assessed in NSCLC patients receiving cytotoxic agents. The aim of this study was to clarify its association. We also examined if this association could be affected by the prior gefitinib treatment or not. Methods: Patients with advanced or postoperative recurrent NSCLC who received both cytotoxic chemotherapy and gefitinib monotherapy through their treatment course and whose tumors were assessable for EGFR mutation analysis were included in this study. EGFR mutation was determined in exons 19 and 21 by direct sequencing. Results: Sixty patients were included in the study, including 6 (10%) patients who received the first-line gefitinib monotherapy followed by cytotoxic chemotherapy in the second-line or later settings. Of the 54 (90%) patients, 22 also underwent subsequent cytotoxic chemotherapy after the relapse to gefitinib monotherapy. EGFR mutations were detected in 17 (28%) patients. In the first-line cytotoxic chemotherapy setting (n=54), EGFR mutations significantly affected progression-free survival (PFS) with 6-month PFS rates of 45.8 vs. 21.9% (p=0.05). This was also observed in the multivariate analysis (HR=0.42, p=0.04). EGFR mutation was also significantly correlated with overall survival (OS) in the multivariate analysis (HR=0.26, p <0.01). Contrary, in the 28 (47%) of 60 patients who received cytotoxic chemotherapy after gefitinib monotherapy, there were no differences in PFS stratified by EGFR mutation status. The sensitivity to gefitinib was, however, correlated with EGFR mutation status and its sensitivity was retained even in the second-line setting in patients with EGFR mutations. Conclusion: EGFR mutation was significantly associated with better PFS in the first-line cytotoxic chemotherapy regimens. However, its association was not observed in the cytotoxic regimens administered after the relapse to gefitinib monotherapy, while the sensitivity to gefitinib was associated with EGFR mutation even in the second-line or later setting.

No significant financial relationships to disclose.
Predictors and impacts of second-line chemotherapy on survival after progression in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Teramukai S. , Nishimura T. , Nakagawa M. , Kawahara M. , Kubota K. , Furuse K. , Fukushima M.
Published: March 2020

7675

Background: Survival after progression (SAP) was longer (median: 8 months) than progression-free survival (median: 6 months) in a phase III randomized trial in patients with stage IIIB or IV NSCLC (SWOG-Japan Common Arm Trial, the Japan Multinational Trial Organization LC00–03, Kawahara, PASCO 2006, #7013). The overall survival in the trial was longer than that in the US populations (median: 14 months vs. 9 months in the paclitaxel/carboplatin arms, Crowley, PASCO 2006, #7050). The aims of this study were to identify predictors and to assess impacts of second-line chemotherapy on SAP of advanced NSCLC. Methods: To identify independent predictors and to estimate hazard ratios (HR) for SAP, we used the Cox proportional hazards model. We evaluated survival benefit of second-line chemotherapies after adjustment for baseline factors and regimens of first-line therapy, types of progression, and time to progression. Results: Out of 393 patients in the LC00–03 trial, 340 patients had progressive disease during the follow-up period. The identified independent significant predictors for SAP were PS (HR: 2.19, p<0.001), weight loss (HR: 1.48, p=0.020), smoking (HR: 1.36, p=0.025), and LDH (HR: 1.37, p=0.032) as baseline factors. Lymph node metastases (HR: 2.17, p<0.001) and bone metastases (HR: 1.75, p=0.004) were poor predictors and relapse in primary lesion was a good predictor (HR: 0.74, p=0.027). Time to progression was correlated with SAP (p=0.008). The median SAP according to second-line treatments were 13 months in gefitinib treatment (response rate: 23%, n=67) and 9 months in other chemotherapies (n=174). The difference is not statistically significant after adjustment for the confounding factors (HR: 0.96, 95%CI: 0.65–1.41), although gefitinib was used after third-line at a constant proportion. Conclusions: Our study shows that baseline factors (PS, weight loss, smoking, LDH) and types of metastases at progression (lymph node, bone) are important prognostic factors for SAP, suggesting minimal effect of selecting gefitinib as a second-line treatment on SAP.

[Table: see text]
A surgical predictive risk model of in-hospital mortality for primary resectable lung cancer: Statistical analysis of 8,796 patients from a nationally representative database
Authors: Falcoz P. , Brouchet L. , Conti M. , Chocron S. , Puyraveau M. , Mercier M. , Etievent J. , Dahan M.
Published: March 2020

7677

Background: The aim of this study was twofold: to identify factors associated with in-hospital mortality among patients operated on for primary resectable lung cancer and to construct a risk model that could be used prospectively to inform decisions and retrospectively to enable comparisons and outcomes. Methods: Data from a nationally representative thoracic surgery database were collected prospectively in 59 hospitals between June 1, 2002 and December 1, 2006. Only adult patients with more than 95% of completed data were selected for the final analysis (n = 8,796 patients). Logistic regression analysis was used to predict the risk of in-hospital mortality. A risk model was developed with a training set of data (50% of patients) and validated on an independent test set (50% of patients). Its fit was assessed by the Hosmer-Lemeshow test (larger p value signifies greater reliability), and predictive accuracy was indicated by the area under the receiver operating characteristic curve (c-index). Results: Of the 8,796 original patients, 255 (2.9%) died during the same hospital admission. Within the data used to develop the model, the factors found to be significantly associated with the occurrence of in-hospital mortality in a multivariate analysis were: age, gender, performance status (World Health Organization) classification, side, class of procedure (lobectomy or wedge resection versus pneumonectomy), tumor histology, TNM stages and presence of co-morbid disease. The model was reliable (Hosmer-Lemeshow test = 8.94; p = 0.35) and accurate: the c-index (95% confidence interval) = 0.83 (0.81 to 0.85) for the training set and 0.82 (0.79 to 0.85) for the test set of data. The correlation between the expected and observed number of deaths was 0.99. Conclusions: The validated multivariate model for risk of in-hospital mortality among adult patients requiring surgery for primary resectable lung cancer described in this report was developed with national data, uses only 8 variables and has good performance characteristics. It would be useful both for calculating the mortality risk of an individual patient and contrasting expected and observed mortality rates for an institution or independent clinician.

No significant financial relationships to disclose.
Prognostic value of preoperative serum tumor markers, including CEA, Cyfra21–1, SCC, CA19–9, SCC, CA125, TPA, NSE, and SLX, in patients with completely resected pathological stage I non-small cell lung cancer
Authors: Matsuguma H. , Suzuki H. , Ishikawa Y. , Kondo T. , Nakahara R. , Kamiyama Y. , Mori K. , Kodama T. , Honjo S.
Published: March 2020

7681

Background: Recent randomized control trials have shown a survival benefit of adjuvant chemotherapy in patients with stage II or more advanced NSCLC, while surgery alone is still the standard therapy for stage I patients. There is, however, a subgroup of patients among the stage I patients who have a poor prognosis, for whom adjuvant chemotherapy can be as effective as has been observed for the patients with more advanced disease. Preoperative serum CEA level has been reported to be an independent prognostic factor for stage I NSCLC. However, many other tumor markers have also been reported as prognostic indicators in different studies using different tumor markers. It is unknown which tumor marker is the most effective for selecting poor prognostic subgroup of patients with stage I NSCLC for which adjuvant chemotherapy can be applied. Methods: A total of 355 patients underwent complete resection, and were diagnosed as having stage I NSCLC from 1995 to 2003. Analyzed tumor markers included CEA, Cyfra21–1, SCC, CA19–9, SCC, CA125, TPA, NSE, and SLX. Cut-off values for each tumor marker are listed in the table . Clinicopathologic factors including age, gender, histology, vessel invasion, pleural invasion, and pathologic T indicator are also analyzed in the multivariate analysis. Results: Among the 355 patients, 211 patients were male, 249 had adenocarcinoma, 82 had squamous cell carcinoma, and 253 had pathologic T1 tumors. Percentages of elevated value for each tumor marker are listed in the table in combination with related survival data. Cox proportional hazard model demonstrated age, pleural invasion, histology, and CEA were significantly independent prognostic factors. Conclusions: CEA is thought to be the best tumor marker for selecting the poor prognostic subgroup of patients with resected stage I NSCLC because of its high percentage of abnormal value and high ability to differentiate prognostic subgroups.

No significant financial relationships to disclose.

[Table: see text]
Nadaplatin or cisplatin combined with paclitaxol in treating non-small cell lung cancer: A randomized controlled study
Authors: Chen L. , Xu G. , Guan Z.
Published: March 2020

7689

Background: Nadaplatin is a 2nd generation platinum compound created in Japan. It also has been used in China for recent years and shown treatment effect in several kinds of cancer including lung cancer. However, no randomized clinical trial has been done compared with cisplatin when combined with paclitaxol in treating non-small cell lung cancer. This prospective clinical study is to investigate the treatment effect, long term survival, side effect and quality of life (QOL) of NSCLC patients treated with nadaplatin combined with paclitaxol controlled with cisplatin combined with paclitaxol. Methods: NSCLC patients with stage IIIB or IV were randomized into two groups: TN group- nadaplatin 30 mg/m2 d1–3, paclitaxol 175 mg/m2 d1, repeated every 4 weeks; TP group- DDP30 mg/m2 d1–3, paclitaxol 175 mg/m2 d1, repeated every 4 weeks. The treatment effect, 1 and 2 year survival and the side effect were observed. The functional assessment of cancer therapy-lung (FACT-L) was used to evaluate the quality of life (QOL). Results: Sixty patients were enrolled and 57 were assessable with 30 in TN group and 27 in TP group. The overall response rate were 43.3% vs 48.1% (P=0.716), and the disease control rate were 86.7% vs 88.8% in TN and TP group (P=0.799), respectively. The median survival time were 14.3 vs 13.0 months, and the 1 and 2 year survival were 62.5% vs 59.1%, 0% vs 5.8% in TN and TP group (P=0.839), respectively. Neutropenia and thrombocytopenia were similar in TN and TP group whereas more patients in TP group suffered from anemia (38.5% vs 17.5%, P=0.001), nausea and vomiting (68.0% vs 34.7% with grade 1 and 2, 14.6% vs 0.9% with grade 3 and 4, P=0.000), fatigue (35.9% vs 14.1% P=0.000) and peripheral neurotoxicity (50.0% vs 21.9%, calculated by case, p=0.023). In the FACT-L assessment, the relationship with doctor, the emotional well-being and the lung cancer related symptom were similarly improved in both TN and TP group whereas physical well-being was improved only in TN group. Conclusions: Nadaplatin combined with paclitaxol is an effective treatment regimen for NSCLC patients. When compared with similar regimen using cisplatin, the response rate and survival were similar; however, nadaplatin regimen shows superiority in some aspects of side effects and QOL.

No significant financial relationships to disclose.
Genomic copy number alterations in non-small cell lung cancers identified using CBS and MSA
Authors: Park M. S. , Ma C. , Aziz M. U. , Rao S. , Gold K. , Samanta M. , Guttman M. , Grant G. R. , Vachani A. , Brose M. S.
Published: March 2020

7695

Background: Lung cancer is the leading cause of cancer death in both men and women with a 5-yr survival rate of 15.5%. Previous studies have begun to characterized genomic copy number alterations of non-small-cell lung CA using array CGH and SNP arrays. We have used aCGH using our 1MB BAC arrays and two algorthims for making copy number alteration (CNA) determinations. We have also pursued the exact copy number gains and losses of several genes using Q-PCR. Methods: Genomic DNA from fresh frozen tumors of 27 patients with NSCLC. We performed aCGH using 1MB Arrays. We used CBS, and MSA to identify regions of CNA. We further pursued several genes of interest (including HRAS, CRK, and CDC42) identified using Q-PCR. Unsupervised hierarchical clustering was performed to look for distinct subgroups. Significant Analysis of Microarrays (SAM) was applied to identify the association between CNAs clinical parameters including tumor subtype, gender, lymph node involvement, tumor stage, and overall survival. Results: 240 regions of amplification and 181 regions of deletions were found, and included all previously published regions implicated in lung cancer. CNAs in > 70% of tumors included amplifications in 1q, 3q, 5p, 6p, 11p, 16q, 20q, and Xq, and deletions in 1p, 8p and 13q. We verified CNAs of HRAS, CRK and CDC42 using Q-PCR. Hierarchical clustering revealed 2 subgroups: one with amplifications in 2q, 4p, 4q, 8q, 21q, 15q, and 16p, and the other with amplifications in 3q, and 5q. These were confirmed by supervised SAM analysis. Using SAM we found that gain of 2q, 4p and 10q, and loss of 16p and 19q were significantly present in adenocarcinomas. (q = 0, FDR = 0%). Gain of 10q, and loss of 6p and 14q were associated with female gender. (q = 0, FDR = 0%). Conclusions: We used aCGH to identify CNAs that characterize non-small cell lung CA tumors with the aim of finding key regions which may harbor important oncogenes and tumor suppressors. Several regions of CNA have been identified, several of which have been associated with clinical parameters. Because much heterogeneity exists in non-small-cell lung tumors, we have demonstrated that clustering analysis is useful in identifying subtypes which may possess prognostic and therapeutic significance.

No significant financial relationships to disclose.
Pemetrexed plus cetuximab in patients (pts) with recurrent non-small cell lung cancer (NSCLC): A phase I-IIa dose-ranging study from the Hoosier Oncology Group
Authors: Jalal S. I. , Waterhouse D. , Edelman M. , Nattam S. , Ansari R. , Koneru K. , Yu M. , Shen J. , Breen T. , Hanna N.
Published: March 2020

7698

Background: Both pemetrexed (P) and cetuximab (C) have single agent activity in NSCLC, non-overlapping toxicities and different mechanisms of action, making the combination of P and C an attractive option to evaluate. This study evaluates the feasibility of combining these agents, and tests the activity and toxicity of this regimen in pts with recurrent NSCLC. Methods: Eligible pts had stage IIIB/IV NSCLC, previously treated ≥ 1 prior platinum containing regimen, PS 0–1. Prior use of EGFR tyrosine kinase inhibitors was permitted. The phase I portion determined the MTD (Bedano Proc ASCO et al., 2006). The primary endpoint of the phase II portion was to estimate TTP using Kaplan-Meier analysis (5% alpha, 80% beta), requiring 25 pts to demonstrate a TTP of ≥ 24 weeks vs. historical control of 12 weeks. Following a loading dose of C at 400 mg/m2 on week 1, pts received P at 750 mg/m2 iv q3wks and C at 250 mg/m2 iv weekly. Cycles were repeated every 21 days. After completing at least 4 cycles, pts with non-progressive disease (PD) were allowed to continue C alone until PD. Results: Eligible and treated phase II pts (n=23) received a median of 4 cycles (range 1–12). Pt characteristics: M:F 57%:43%; median age 64 (range 43–80), stage IIIB: IV 17%:83%; adeno:squamous cell 61%:30%; smoking status: current/former/never: 29%/62%/10%. Prior regimens, median 2 (range 1–6). G3/4/5 toxicities included: 4.3% neutropenia, 13% infection, 4.3% hemorrhage, 22% skin. There were no G3/4 episodes of anemia, TCP, febrile neutropenia, liver toxicity or diarrhea. Response data was available for 18 patients. Partial responses were seen in 2 pts (8.7 %), SD in 8 patients (34.8%). Median TTP was 25 weeks. Conclusion: It is feasible and safe to combine P at 750 mg/m2 every 21 days and C at 400 mg/m2 week 1 and 250 mg/m2 weekly thereafter. This combination resulted in longer TTP when compared with historical controls of P at 500 mg/m2 alone.

No significant financial relationships to disclose.
Sorafenib in malignant mesothelioma (MM): A phase II trial of the Cancer and Leukemia Group B (CALGB 30307)
Authors: Janne P. A. , Wang X. F. , Krug L. M. , Hodgson L. , Vokes E. E. , Kindler H. L.
Published: March 2020

7707

Background: Systemic chemotherapy with cisplatin/pemetrexed is the approved first line treatment regimen for patients with MM. There is no approved second line therapy. In addition, many patients, especially those >70, cannot tolerate combination chemotherapy. Angiogenesis inhibitors have emerged as attractive potential therapies for MM and SU5416 and PTK787 have previously demonstrated single agent activity. We examined the efficacy of sorafenib, an inhibitor of VEGFR2 and PDGFR-b, in chemotherapy naïve and previously treated patients with MM. Methods: This was an open label single arm phase II study of sorafenib in chemotherapy naïve and previously pemetrexed treated patients with MM. Primary end point was response rate (RR). Secondary objectives were 3-month failure free and overall survival (FFS and OS). Forty-four (44) eligible patients were expected to enroll to differentiate a RR of <5% versus >20%, with a Type I error of 0.0675 and a power of 0.955 Results: Between 10/04 and 8/05, 51 patients were enrolled and treated with sorafenib 400 mg bid. One cycle was defined as 28 days; restaging occurred every 2 cycles. Baseline demographics: M/F (36/15); Median age (69; range 36–88; 45% >70); Histology (epithelial/sarcomatoid/mixed/unknown: 37/4/8/2); pleural/peritoneal MM (46/5); ECOG PS 0/1 (11/40); chemo-naive/prior chemo (20/31). Grade 3/4 toxicities occurring in >10% of patients: Fatigue (12 (25%); 11/1) and hand-foot reaction (6 (13%); 6/0). No study related deaths occurred. Estimates of RR and FFS are based on 47 patients with available follow-up data. Response: CR: 0; PR 2: 4% (95% CI; 1- 14%); SD 28 (60%); PD 11 (23%); unevaluable 6 (14%). Three month FFS was 78%; median FFS was 3.7 months and median OS was 10.7 months. The median FFS were 3.6 and 3.6 months and the median OS were 4.9 and 14.6 months in chemo naïve and previously treated patients, respectively. Conclusions: Sorafenib demonstrated modest activity in this phase II trial but did not meet its primary endpoint. The improved outcome in previously treated patients likely reflects patient selection. Ongoing correlative science studies including expression of p-ERK 1/2, baseline VEGF and PDGF levels, are being performed to help identify patient subsets who may benefit (PR or SD) from sorafenib.

No significant financial relationships to disclose.
DNA methylation profile predicts survival of patients with resected malignant pleural mesothelioma (MPM)
Authors: Ceresoli G. L. , Destro A. , Baryshnikova E. , Garassino I. , Zucali P. A. , Morenghi E. , Testori A. , Alloisio M. , Roncalli M. , Santoro A.
Published: March 2020

7712

Background: Methylation in different tumor suppressor genes is among the most frequent alterations reported in MPM patients (pts). DNA methylation increases upon immortalization and transformation of human mesothelial cells, and demethylating agents were found to have some activity in MPM. In this study we analysed the methylation status of the promoter region of four candidate genes in MPM: p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A. Methods: Samples of 79 consecutive MPM pts who underwent surgical procedures (41 extrapleural pneumonectomy (EPP), 32 partial pleurectomy, 6 diagnostic biopsy) at our Institution from 1997 to 2005 were analyzed. DNA was isolated from each paraffin-embedded MPM; the methylation status of the four genes was evaluated by a methylation-specific PCR method (MSP). Correlations between methylation status, clinico-pathological parameters (including proliferation index) and overall survival (OS) were examined in all pts and in the EPP subgroup. Proliferation index was evaluated as percentage of nuclear immunoreactivity/10 high-power field using a mouse monoclonal antibody anti-human Ki-67, clone MIB-1 (DAKO Corporation, Carpinteria, CA). Results: The MSP analysis documented gene promoter methylation in at least one gene in 30 cases (38%). The methylation frequency of each gene was: p15INK4B 15 cases (19%), p16INK4A 9 (11.4%), RASSF1A 16 (20.2%), Nore1A 4 (5.1%). Of the 30 methylated MPMs, 18 (60%) showed only one methylated gene, 10 (33.3%) were methylated in two genes and 2 (6.7%) in three. Methylation in at least one gene was associated to a higher proliferation index (P=0.058, ANOVA), but not to OS, in the whole study population. In pts treated with EPP, the 22 methylated cases showed a trend to a worst OS in comparison to 19 unmethylated cases (median OS 16 months vs 35 months, P=0.066, HR=2.01, 95% CI 0.94–4.30, Cox regression), independently by histology and nodal status. Conclusions: In pts treated with EPP, the methylation profile of p15INK4BINK4B, p16INK4AINK4A, RASSF1A and NORE1A appeared to be an independent prognostic factor for OS. The methylation status was correlated to proliferation rate, indicating a potential role of these oncosuppressor genes in the neoplastic progression of MPM.

No significant financial relationships to disclose.
Surgery as primary treatment for limited disease small cell lung cancer: Time to re-evaluate
Authors: Lim E. , Goldstraw P.
Published: March 2020

7719

Background: Chemoradiation is considered the gold standard for the management of limited disease (LD) small cell lung cancer (SCLC). Surgery has been abandoned due to poor overall survival, but many small series report good results with selected extremely limited disease (in one study without adjuvant treatment). Controversy remains if and when surgery should be considered as a primary modality. We sought to determine the survival and impact of pathologic staging in patients after complete resection of SCLC and the prognostic impact of pathologic stage. Methods: A retrospective review was undertaken of patients who underwent surgery between 1980 and 2003. Patients were staged according to the 6th UICC revision, actuarial survival estimated with Kaplan Meier methods and comparisons were undertaken using Cox regression. Results: We identified 51 patients who underwent complete resection with systematic nodal dissection for SCLC. The mean age (SD) was 61 (11) years and 37 (73%) were men. Complete staging information was available in 47, listed by stage with IA (n=6), IB (n=10), IIA (n=5), IIB (n=15), IIIA (n=10), IIIB (n=1). The median time to follow up (1st to 3rd quartile) was 4.5 (1.3 to 11.9) years with an overall survival (95% CI) at 1 and 5 years of 82% (72, 93) and 61% (48, 76). There were no clear differences in the outcome of patients in T categories 1 and 2 (P=0.411) with good overall results in patients across the spectrum of nodal disease from N0 to N2 (P=0.281). Conclusions: This study shows excellent survival for stage I to III patients who underwent lung resection with complete nodal resection for SCLC. These results, in an era of improved pre-operative and intra-operative staging, suggests that TNM staging is relevant in extremely limited disease SCLC and suggest that the role of surgery in such cases should be re- evaluated.

No significant financial relationships to disclose.
A phase II study of picoplatin (pico) as second-line therapy for patients (pts) with small cell lung cancer (SCLC) who have resistant or refractory disease or have relapsed within 180 days of completing first-line, platinum (plat)-containing chemotherapy
Authors: Bentzion D. , Lipatov O. , Polyakov I. , MacKintosh R. , Eckardt J. , Breitz H.
Published: March 2020

7722

Background: Pico is a sterically hindered plat analogue designed to overcome plat resistance with improved safety and efficacy. In >600 pts pico had single-agent activity in lung, prostate, ovarian and other malignancies with rare significant nephro-, oto-, or neurotoxicity (∼2% grade 3 and 0% grade 4). In a previous phase 2 study of single agent pico as 2nd line therapy in SCLC, 4 of 48 pts (8%) had a partial response and 21 (44%) stable disease. Median survival was 27.0 (95% CI = 16–35) wks. This multi-center phase 2 trial was designed to confirm the activity of pico as 2nd line monotherapy for plat-resistant SCLC. Methods: Pts with SCLC who either 1) failed or progressed through 1st line plat-containing chemo (refractory disease), or 2) initially responded to 1st line plat-containing chemo and then relapsed/ progressed within 3 months (resistant disease), or 3) initially responded and then relapsed/progressed between 90 to 180 days (sensitive, relapsed 90 to 180 days), had measurable disease and ECOG PS 0–2 were treated with pico, 150 mg/m2 iv over1–2 hrs, q 21 days. Tumor response was assessed q 6 wks. Adverse events (AEs) were graded using the NCI CTCAE. Results: 77 pts received pico (45 refractory, 27 resistant, 5 sensitive). The median number of cycles received was 2 (mean = 2.9). The most frequently reported AEs of any severity were thrombocytopenia (39% of pts), anemia (35%), neutropenia (22%), nausea (20%), emesis (14%) and dyspnea (25%). Neutropenic fever occurred in 1 pt; there were no treatment related deaths. One pt had grade 3 neuropathy; there was no grade 3 or 4 ototoxicity or nephrotoxicity. Median overall survival is 28.1 (95% CI = 26–37) wks. Median progression free survival is 9.3 (95% CI = 7–12) wks. Of 63 pts with at least 1 post-treatment assessment of disease status, 33 (52%) had stable disease. Conclusion: Median survival compares favorably with other therapeutic options and toxicity is reduced in pico treated SCLC pts who have failed prior plat-containing first-line chemo or who have progressed within 180 days of first-line chemo. A phase III trial to confirm these results has been initiated.

No significant financial relationships to disclose.
Age, gender, performance status and stage outperformed stage alone in predicting overall survival (OS) in patients with small cell lung cancer: A pooled analysis of 1,623 patients from the North Central Cancer Treatment Group
Authors: Foster N. R. , Mandrekar S. J. , Schild S. E. , Nelson G. D. , Jett J. R. , Adjei A. A.
Published: March 2020

7723

Background: It is critical that we understand the impact of patient, tumor, and treatment-related factors on patient prognosis for the proper design and analysis of Small Cell Lung Cancer (SCLC) trials. An analysis of 15 SCLC trials was performed to investigate and improve our understanding of several factors on OS. Methods: Data from 1623 patients (pts) were used. Age, gender, performance status (PS), tumor stage, body mass index (BMI), creatinine levels, hemoglobin levels, white blood cell counts (WBC), platelet counts, and bilirubin levels were tested for prognostic significance for OS both univariately and multivariately using a Cox Proportional Hazards Model. Models were stratified by protocol, and analyses carried out on the complete data available based on the selected covariates. Model discrimination (i.e., ability to discriminate patients with different survival times) was evaluated using the concordance index (COI). Results: Median follow-up was 63.1 months (range: 1.9 to 155.7). 58% and 42% of pts had extensive-stage or limited-stage SCLC, respectively. Patients with extensive-stage disease, PS>0, increased age, and male gender had significantly worse OS both univariately and multivariately. Patients with increased WBC had significantly worse OS univariately, however, WBC was not a significant predictor when adjusted for other factors. None of the other factors were prognostic for OS. Model discrimination improved by 6.3% when age, gender, PS, and stage were included in a model compared to a model with stage alone (COI improved from 0.63 to 0.67). Conclusions: Age, gender, PS and stage did better at predicting OS than stage alone. Further refinement of this model, including the addition of number of metastatic sites at baseline and treatment related factors, is currently underway.

No significant financial relationships to disclose.

[Table: see text]
A phase II trial of VNP40101M in patients with relapsed or refractory small cell lung cancer (SCLC) with or without brain metastases
Authors: Mekhail T. , Gettinger S. , Blumenschein G. , Axelrod R. , Haigentz M. , Guarino M. J. , Cahill A. L. , Spigel D. , Greco F. A.
Published: March 2020

7724

Background: Relapsed or refractory SCLC patients (pts) have a poor prognosis. Median survival at relapse is 2–3 months; brain metastases (mets) are common. Alkylating agents have demonstrated activity in SCLC. Cloretazine is a new alkylator that is active against selected alkylating agent resistant tumor cell lines. Xenograft models show distribution across the blood-brain barrier. This study investigates VNP40101M safety and activity in SCLC patients who have relapsed or are refractory to standard 1st line chemotherapy. Methods: Pts are entered in 2 groups based on response to prior chemotherapy: sensitive relapse (chemotherapy-free interval >3 months); or resistant/refractory (chemotherapy-free interval ≤3 months). Eligibility criteria include: measurable or evaluable disease; life expectancy of ≥2 months; and ECOG PS of 0–2. Pts with brain mets are eligible. 31 pts received VNP40101M IV at a starting dose of 125 mg/m2/wk × 3, every 6 weeks. Due to a high incidence of grade 3–4 thrombocytopenia (34%), an amended protocol reduced the dose of VNP40101M to 100 mg/m2 at the same schedule. 13 pts received the reduced dose. Pts are evaluated by RECIST criteria after each 6-week cycle. Results: 44 of 87 planned pts have been treated at 7 sites. Of 41 evaluable pts, 21 patients have sensitive relapse disease, and 20 have resistant/refractory disease. Median age is 64 years (44–86). Median number of cycles received is 1 (1–3). Grade 3–4 thrombocytopenia was seen in 11/31 pts at the 125 mg/m2 dose and 3/13 pts at the 100 mg/m2 dose. Gr 3–4 non-hematologic toxicity is rare, except for fatigue (10%) and GI effects (10%). The response rate (PR) is 6/21 (29%) in the sensitive relapse group, and 1/20 (5%) in the resistant/refractory group. 2/6 PRs, in the sensitive relapse group, occurred at the reduced dose level. 16 pts had brain mets at study entry. Of these, there were 3 PRs (2 with measurable regression of brain mets) and 3 stable diseases. Conclusions: The study is ongoing to confirm efficacy and safety. VNP40101M has activity against SCLC in the 2nd line setting including pts with brain metastases; further study is warranted.

No significant financial relationships to disclose.
The impact of shortened vitamin supplementation lead-in time before pemetrexed (P) in patients with relapsed small cell lung cancer (SCLC)
Authors: Richards D. A. , Socinski M. , Raju R. N. , Coke K. , Reynolds C. , Chen R. , Cunneen J. L. , Tai D. F. , Treat J. A. , Obasaju C. K.
Published: March 2020

7726

Background: Clinical studies of P have shown less overall toxicity and reductions in Grades 3–4 hematologic and nonhematologic toxicities when pts are pretreated with folic acid and vitamin B12. Current recommendations are to give folic acid 350 μg - 1,000 μg by mouth for at least 5 of 7 days prior to the 1st dose of P, and 1 injection of vitamin B12 1000 μg during the week preceding the 1st P dose. Treatment delay to allow this supplementation may be clinically undesirable, particularly in pts with aggressive malignancies. A trial evaluating single-agent P for the treatment of relapsed SCLC gave us opportunity to observe the effects of a shortened lead-in time for vitamin supplementation. Methods: We reviewed data from a U.S. trial designed to assess the safety and efficacy of single-agent P in chemosensitive and chemorefractory relapsed SCLC pts. Eligible pts had limited or extensive-stage SCLC, PS 0 to 2, and 1 prior chemo regimen. Pts received P doses of 500 mg/m2 or 900 mg/m2 q 21 d. The protocol required the administration of folic acid for at least 5 of 7 days prior to the 1st P dose, and vitamin B12 administration on Day 1, Cycle 1, or up to 14 days prior to the 1st P dose. Included in the analysis were pts who received at least 1 dose of folic acid prior to 1st P dose. We then analyzed preliminary toxicity results for pts receiving vitamin B12 for 0–3, 4–6 and =7 days prior to 1st P dose. Results: From 7/2004 to 3/2006, 116 pts were treated with P. At baseline M/F 57%/59%; median age 64.5 years (range 35–85); PS 0/1/2 was 39%/57%/20%. Cycle 1 vitamin administration timing data is available for 109 pts. Data for all 116 pts will be reported at time of meeting. Because toxicities observed between the 2 P doses were not significantly different, the combined toxicities for both dosing groups are reported here. Conclusions: Based on this data, Vitamin B12 given less than 7 days prior to P does not appear to be associated with increased serious toxicities.

No significant financial relationships to disclose.

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A phase II study of a novel oral isotype-selective histone deacetylase (HDAC) inhibitor in patients with relapsed or refractory Hodgkin lymphoma
Authors: Younes A. , Fanale M. , Pro B. , McLaughlin P. , Neelapu S. , Fayad L. , Wedgwood A. , Dubay M. , Backstrom J. , Martell R. E.
Published: March 2020

8000

Background: MGCD0103 is a non-hydroxamate, isotype-selective, inhibitor of human HDACs. Abnormal regulation of HDAC activity is associated with malignant disease in humans, and small molecule HDAC inhibitors are a novel drug class with anticancer potential. Their proposed anti-Hodgkin activity is through regulation of aberrant gene expression at the transcriptional level by inhibiting proliferation, inducing apoptosis, and/or initiating differentiation in cancer cells. Methods: A phase II trial of MGCD0103 (110 mg 3x/week in 4- week cycles) is ongoing in patients (pts) with relapsed/refractory Hodgkin Lymphoma (RRHL). The primary endpoint is a composite of objective response and stable disease. Results: As of Dec 15th, 2006, 18 pts out of a planned 12–35 have been enrolled; median age 28 (range: 21–62). All pts were previously treated with autologous and/or allogeneic stem cell transplant. The median number of cycles received to date is 2 (range: 1–4). Seven pts have completed =8 weeks (2 cycles) of therapy and are evaluable for response analysis; 5 of these had tumor reduction ranging between 21% and 70% by CT, which is associated with a significant reduction in FDG-PET activity in 4 pts. Of the 18 pts, 5 have had dose reductions/discontinuations due to: mucositis (n=1); fatigue/nausea/diarrhea (n=1); nausea/vomiting (n=1); fatigue (n=1) and pancreatitis/hypotension (n=1). Significant HDAC inhibition (>20% of total activity), was seen in PBMCs from 7/9 pts with samples. Treatment is ongoing in 14 pts; including those with tumor reduction. Criteria have been met to expand to the second stage of the study (>1 response demonstrated in the first 12 patients). Conclusions: Preliminary results suggest that single-agent MGCD0103 demonstrates significant anti-tumor activity in RRHL and is well tolerated at a Phase II dose of 110mg in this ongoing trial.

No significant financial relationships to disclose.
Prospective, multicenter, randomized GITMO-IIL trial comparing intensive (R-HDS) to conventional chemoimmunotherapy (CHOP-R) in high-risk follicular lymphoma (FL) at diagnosis
Authors: Ladetto M. , De Marco F. , Benedetti F. , Vitolo U. , Patti C. , Passera R. , Rambaldi A. , Gianni A. M. , Corradini P. , Tarella C.
Published: March 2020

8006

Background: The GITMO-IIL trial evaluated if an intensified treatment with ASCT is better than conventional chemotherapy (both supplemented with Rituximab) in high-risk FL at diagnosis. Methods: Eligibility required a FL with aaIPI>1 or IIL>2 score and an age of 18–60. Primary endpoint was EFS. The analysis was intention to treat. Secondary endpoints were PFS, DFS, OS, rate and prognostic value of MR. R-HDS and CHOP-R have been already described (Ladetto et al ASH 2005, Rambaldi et al Blood 2002). Planned sample size was 240 to detect a 20% absolute increase in the 3-years EFS. However the trial was stopped at 136 pts due to R-HDS superiority in EFS at a planned interim analysis. Cross-over was allowed after CHOP-R failure. Centralized PCR-based molecular analysis was planned on BM cells. Results: Age, stage, LDH, bulky disease, B-symptoms ECOG PS, extranodal disease aaIPI, IIL and retrospectively assigned FLIPI were similar in the two arms. CRs were 59% with CHOP-R and 85% with R-HDS (p<0.001). At a median follow-up of 39 months EFS and PFS are 36% and 38% for CHOP-R and 66% and 72% for R-HDS. OS is 83% in each arm. 67% of relapsed R-CHOP pts underwent R- HDS. MRs were 44% after CHOP-R and 80% after R-HDS (p<0.001). MR was associated to a better PFS (p<0.001). Of note, 3yrs PFS of pts with or without MR was similar in the two arms (MR: 67% with CHOP-R and 76% with R-HDS) (no MR: 25% for CHOP-R and 32% for R-HDS). MR was the strongest independent prognostic factor for PFS, EFS and DFS by multivariate analysis. Conclusions: This is the first phase III trial including MR analysis in a high proportion of pts and comparing intensified versus conventional therapy in the rituximab age. This trial indicates that: a) R-HDS has a better EFS and PFS in truly high-risk FL patients; b) MR is the strongest outcome predictor available in FL; c) the similar outcome in pts achieving (or not achieving) MR, regardless of treatment received, indicates that the superior performance of R-HDS is mostly due to its superior MR rate.

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Rituximab compared to observation after high-dose consolidative first-line chemotherapy (HDC) with autologous stem cell transplantation in poor-risk diffuse large B-cell lymphoma: Updated results of the LNH98-B3 GELA study
Authors: Haioun C. , Mounier N. , Emile J. F. , Bologna S. , Coiffier B. , Tilly H. , Recher C. , Fermé C. , Morschhauser F. , Gisselbrecht C.
Published: March 2020

8012

Background: Rituximab has been evaluated as a single agent and also in combination with chemotherapy in aggressive and indolent lymphomas with evidence of efficacy. More recently, rituximab maintenance therapy has been successfully used to keep responding patients in remission. We have shown that consolidative HDC improves outcome of poor risk responder-patients (pts) with aggressive lymphoma. Methods: The aim of the present study was to evaluate the potential benefit, as randomly compared to observation, rituximab - 375 mg/m2/week for 4 weeks - 2 months after HDC, in decreasing the relapse rate (second randomization: R2). A secondary objective was to improve the response rate before HDC using the intensified ACE chemotherapy regimen (doxorubicin 75mg/m2 d1, cyclophosphamide 1g/m2 d1-d2, etoposide 150mg/m2 d1-d3) as compared to the standard ACVBP induction regimen (R1). Four cycles were delivered every 15 days. In responding pts, HDC (mitoxantrone 45 mg/m2, cyclophosphamide 1500 mg/m2 × 4d, etoposide 250 mg/m2 × 4d and carmustine 300 mg/m2) was started between d80 and d90. Results: From 10/99 to 05/03 (closing date), 476 pts younger than 60 years with diffuse large B-cell lymphoma and aa-IPI 2 or 3 (aa-IPI 3: 29%). were enrolled. 237 pts were assigned to ACE and 239 to ACVBP. Complete response (CR+CRu) rates to induction treatment did not significantly differ between the 2 regimens (65% and 63%, respectively). Death rate during induction phase was 4% in both arms. Among the 331 pts who received HDC, 269 were randomized (R2) to receive either rituximab (n=139) or observation (n=130). 545 infusions of rituximab were administered with no clinically relevant infectious toxicity except two severe VZV infections. With a median follow-up of 4 years after R2, a trend toward a better 4y-EFS was observed in the rituximab group (80% vs 71%, p=0.098). In addition, a two-sided log-rank test stratified by aa-IPI, induction treatment and response after HDC was performed and confirmed the results of the unstratified analysis. Conclusions: We conclude that early and brief rituximab maintenance is feasible after HDC and may prolong remission status.

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Late treatment mortality and secondary cancers after autologous stem cell transplant for relapsed or refractory Hodgkin lymphoma (HL)
Authors: Dhani N. C. , Roberts T. , Pintilie M. , Kuruvilla J. , Franke N. , Nagy T. , Tsang R. , Keating A. , Crump M.
Published: March 2020

8016

Background: Late treatment-related mortality and second cancers have an important influence on the long-term outcome of patients (pts) with HL. The incidence of treatment failure and causes of death were evaluated in pts with advanced HL receiving high-dose therapy and ASCT, to understand the impact of late events on overall survival (OS). Methods: From Dec 1986 to Nov 2005, 323 pts with relapsed/refractory HL after primary chemotherapy (plus radiation [RT]: 32%) received salvage chemotherapy to best response, followed by etoposide 60 mg/kg day -4 and melphalan 160–180 mg/m2 day -3 supported by autologous bone marrow (46%), mobilized peripheral blood stem cells (49%) or both (5%)on day 0; 24% received involved field RT post-ASCT. Risk of treatment failure and second cancer was estimated using competing risks methods. Results: Patient Characteristics: male: 61%; median age 33 years (range16–67). Number of salvage regimens pre-ASCT: 1: 72%; 2: 25%. Disease status post-salvage chemotherapy: CR 28%, PR 66%. After a median follow-up of 4.7 years post-ASCT (range 1–17), 174 pts (54%) have experienced treatment failure (relapse or treatment related death) and 154 pts (48%) have died, 75% following relapse and 20% from toxicity without relapse. Of the 30 deaths without relapse, 30% occured >5 years post-ASCT. Failure free survival at 3 and 10 years is 50% (95% CI, 44–55%) and 40% (33–46), and overall survival is 68% (63–73) and 39% (33- 46), respectively. There have been 29 second cancers (17 AML/MDS, 12 solid tumors) in pts alive without relapsed HL. The probability of a second cancer is 4.9% (2.8–7.8) at 3 years and 12% (8–17%) at 10 years. The hazard rates for second malignancy, leukemia and solid tumors for each 10-year age increment are 1.9 (p=0.0001), 1.9 (0.001) and 1.8 (0.03), respectively. Only 4 pts have relapsed beyond 5 years post- ASCT but the cumulative incidence of treatment-related death (from toxicity or second cancers) continues to increase from 9% (6–13) at 3 years to 15% (11–20) 10 yrs post-ASCT. Conclusions: In this single-institution series of uniformly treated patients with relapsed/refractory HL, late relapse of disease is uncommon, but late toxicities have a significant and ongoing impact on failure-free survival.

No significant financial relationships to disclose.