bluuebunny/crossref_metadata_2025 huggingface dataset:
Temporal trends in small cell lung cancer: Analysis of the national Surveillance, Epidemiology, and End-Results (SEER) database
Authors: Navada S. , Lai P. , Schwartz A. G. , Kalemkerian G. P.
Published: March 2020

7082

Background: Research interest in small cell lung cancer (SCLC) has waned over the past 10 years due to the lack of significant therapeutic advances and a presumed decline in the incidence of SCLC. Methods: We analyzed data on all patients with primary bronchogenic carcinoma registered in the national SEER database from 1973–2002. To identify temporal trends, the study period was divided into three decades: 1973–1982 (D1), 1983–1992 (D2), and 1993–2002 (D3). Results: Of 318,584 eligible patients, 59,704 (18.7%) had SCLC. The proportional incidence of SCLC relative to non-SCLC was higher in Caucasians than African-Americans (19.6% vs 13.9%), women vs men (21% vs 17.4%), and patients ≥ 50 yrs old vs < 50 yrs old (18.9% vs 16%). By decade, the proportional incidence of SCLC was: D1, 18.4%; D2, 19.8%; D3, 17.9%. The overall incidence rates for both SCLC and non-SCLC initially rose and then declined during the study period. The incidence rates for SCLC were similar in both Caucasians and African-Americans throughout the study period, while those for non-SCLC were significantly higher in African-Americans. The gap between incidence rates in men and women has narrowed to a similar degree for both SCLC (M/F: D1, 2.6/1 to D3 1.4/1) and NSCLC (M/F: D1, 3.3/1 to D3, 1.7/1). Only 0.8% of SCLC patients underwent surgical resection from 1988–2002. The use of radiotherapy decreased during the study period (D1, 53% to D3, 43%) with greater use in younger patients and African-Americans. Stage-specific 2- and 5-year survival rates for SCLC improved over time (regional 2-yr/5-yr: D1, 15%/6.8% to D3, 22%/11%; distant 2-yr/5-yr: D1, 3.4%/1.3% to D3, 5.6%/1.9%). In multivariate analysis, significant favorable prognostic factors included: younger age, Caucasian race, female gender, limited stage, and later year of diagnosis. Conclusions: The proportional incidence of SCLC has declined only slightly over the past three decades. While overall survival has modestly improved, SCLC remains a major public health problem.

No significant financial relationships to disclose.
Targeting Lewis Y (LeY) in small cell lung cancer (SCLC) with a humanized monoclonal antibody, hu3S193
Authors: Krug L. M. , Milton D. , Chen L. , Jungbluth A. A. , Quaia E. , Nagel A. , Jones J. , Finn R. , Divgi C.
Published: March 2020

7086

Background: LeY is a blood group antigen with dominant expression on the surface of epithelial tumors, including SCLC, making it a potential target for antibody-based immunotherapy. 3S193, an IgG3 mAb, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-LeY antibodies. A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m2 demonstrated tumor targeting without serious toxicities or the development of human antihuman antibodies (Scott et al, ASCO, 2004). Methods: We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three prior chemotherapy regimens, measurable disease not previously irradiated, and tumor samples immunohistochemistry (IHC)-positive for 3S193. Patients received four weekly injections of hu3S193, 5 patients at 10mg/m2 and 5 patients at 20 mg/m2. The first and fourth injections were radiolabeled with 111Indium for gamma camera imaging. Results: Of 40 patients screened, 25/34 (74%) evaluable SCLC tumor samples were 3S193-positive by IHC: 1+ (n = 13), 2+ (n = 3), 3+ (n = 2), 4+ (n = 7). Ten patients were treated with hu3S193; eight completed all four injections (one had disease progression and one is still on treatment). At the lower dose, about 50% of lesions >2 cm diameter visualized on FDG-PET were also seen on 111In SPECT imaging. However, at the higher dose, essentially all FDG avid lesions showed targeting. The mean T1/2 for all infusions was 2.89 ± 0.84 days at 10 mg/m2 (n = 9) and 3.29 ± 0.66 days at 20 mg/m2 (n = 7). No difference was noted in imaging or pharmacokinetics between the first and fourth injections. At the 20 mg/m2 dose, patients experienced grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion. No other grade 2 or greater toxicities were observed. No objective responses were observed. Conclusions: SCLC has a high rate of Lewis Y expression. Given the strong tumor targeting, particularly at the higher dose, and the potential for immunomodulatory effects, administration of hu3S193 with chemotherapy would be warranted. Supported by the Ludwig Institute and the Experimental Therapeutics Committee of MSKCC.

No significant financial relationships to disclose.
High-dose ifosfamide, carboplatin and etoposide (HD-ICE) with peripheral blood stem cell transfusion (PBSCT) for limited stage small-cell lung cancer (LD-SCLC)
Authors: Katakami N. , Nishimura T. , Higashi Y. , Seo R. , Kubota M. , Naya R. , Hayashi M. , Ikeda A. , Tomii K. , Ishihara K.
Published: March 2020

7090

Background: Efficacy of high dose chemotherapy with autologous PBSCT has been demonstrated in the treatment of lymphoma. The purpose of this trial is to determine progression-free survival and long-term survival for LD-SCLC patients (pts) who responded to first-line concurrent chemo-radiotherapy followed by HD-ICE with PBSCT. Methods: Patients (pts) with pathologically proven SCLC without malignant pleural and pericardial effusion, stage II-IIIB, ECOG-PS 0–1 were eligible. All pts were treated with cisplatin (P) 60 mg/m2 day1 and etoposide (E) 100 mg/m2, days 1–3, with concurrent hyperfractionted radiotherapy initially (1.5Gy X 2/day X 15 days, total 45Gy) and then two or three cycles of chemotherapy consisted of P 60 mg/m2, day 1, and E 120 mg/m2, days 1–3, or APE (adriamycin 30 mg/m2, day 1, P 60 mg/m2, day1 and E 100 mg/m2, days 1–3) were repeated. Pts with tumor shrinkage more than 90% after initial therapy received HD-ICE (ifosfamide 3 g/m2, days 1–3, carboplatin 400 mg/m2, days 1–3, etoposide 400 mg/m2, days 1–3) followed by PBSCT. All pts received prophylactic cranial irradiation (1.5 Gy × 2/day × 9 days, total 27 Gy). Results: Between 1996 and 2001, 15 pts were eligible and all 15 pts received HD-ICE with PBSCT. Patient characteristics included M/F:14/1, median age: 55 (47–62), PS 0/1: 7/8 stage IIIA/IIIB: 7/8. Grade IV neutropenia and thorombocytopenia were observed in all pts and 93% of pts experienced neutropenic fever after HD-ICE. There was no toxic death. Median follow up time was 83.2 months. Median progression free survival time was 10. 7 months and overall median survival time (MST) was 30.9 months. Two, 3 and 5-year survival rates after initial chemoradiotherapy were 67%, 33%, 25%, respectively. Conclusion: HD-ICE with PBSCT for LD-SCLC revealed promising MST and a 5-year survival rate with manageable treatment-related toxicity. A randomized phase III study comparing chemo-radiotherapy followed by HD-ICE with PBSCT to standard chemo-radiotherapy for LD-SCLC is ongoing.

No significant financial relationships to disclose.
Pemetrexed (MTA) and carboplatin (CBDCA) in the treatment of advanced pleural mesothelioma (MPM)
Authors: Castagneto B. , Mencoboni M. , Degiovanni D. , Muzio A. , Giaretto L. , Rebella L. , Alabiso O. , Buosi R. , Cafferata M. , Botta M.
Published: March 2020

7093

Background: Aim of this study was to evaluate the activity and toxicity of MTA and CBDCA combination as first line chemotherapy in advanced MPM. Methods: Chemonaive patients (pts) with histologically proven, an ECOG performance status (PS) 0–2, and measurable advanced MPM were considered. The schedule of administration was: pemetrexed 500 mg/m2 in combination with CBDA AUC 5, once every 21 days for 8 cycles. Results: From July 2003 to March 2005 76 pts (54 male and 22 female) have been treated with this combination chemotherapy. Median age was 62.7 years (range 40–70); median PS 0 (range 0–3); epithelial histologic findings were in 57 (75%), mixed in 13 (17.1%), sarcomatous in 3 (3.9%), and unspecified in 3 (3.9%) pts. A total of 537 cycles was administered (median 7, range 1 to 13). Grade 3 hematologic toxicity according to WHO criteria was seen in 43 (56.6%) pts (neutropenia in 30, thrombocytopenia in 8, and anemia in 5); grade 4 hematologic toxicity in 5 (6.6%) pts. The most common nonhematologic events were grade 3 nausea/vomiting in 10 (13.1%), and fever in 4 (5.3%) pts. 74 pts were evaluable for clinical response. There were 16 (21.%) partial responses (PR) and 3 (3.9%) complete responses (CR), for an overall response rate of 23.9%. 29 (38.2%) pts reported stable disease (SD). The overall survival was considered from date of diagnosis to date of death from any cause or to date of last follow-up. The median survival time for the entire group was estimated at 23 months. Conclusions: The results of this phase II study indicate that, at this dose and schedule, the combination of CBDCA and MTA is moderately active and that the profile of toxicity is acceptable in pts with advanced MPM.

No significant financial relationships to disclose.
Cell cycle regulators and benefit of adjuvant chemotherapy in patients with non-small cell lung cancer
Authors: Pirker R. , Filipits M. , Dunant A. , Lantuejoul S. , Schmid K. , Huynh A. , Soria J. , Popper H. H. , Le Chevalier T. , Brambilla E.
Published: March 2020

7100

Background: The International Adjuvant Lung Cancer Trial (IALT) demonstrated that adjuvant cisplatin-based chemotherapy improves the 5-year survival rate of patients with completely resected non-small-cell lung cancer (NSCLC) by absolute 4.1% (N Engl J Med 350, 351–360, 2004). The purpose of our study was to determine whether cell cycle regulators are of prognostic and/or predictive value in NSCLC patients who were enrolled into IALT. Methods: Expression of cell cycle regulators and Ki-67 was immunohistochemically assessed in tumor specimens obtained from 778 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted on clinical and pathological parameters. Results: Expression of p16, p27, cyclin D1, cyclin D3, cyclin E and Ki-67 was considered as positive in 37%, 40%, 74%, 37%, 55% and 29% of tumor specimens, respectively. None of these biomarkers was significantly associated with overall survival of the patients. However, there was a relationship of borderline significance between p27 status and benefit of cisplatin-based chemotherapy (test for interaction, p = 0.04). Patients with p27-negative tumors who were treated with cisplatin-based chemotherapy had a longer overall survival than patients from the observation group (hazard ratio for death [95% CI]: 0.71 [0.55–0.93]), whereas in patients with p27-positive tumors overall survival was not different between the two groups (hazard ratio for death [95% CI]: 1.11 [0.81–1.51]). In contrast to p27, the other cell cycle regulators and Ki-67 did not predict benefit of adjuvant cisplatin-based chemotherapy. Conclusions: NSCLC patients with p27-negative tumors appear to benefit most from adjuvant cisplatin-based chemotherapy following complete tumor resection. Thus, the predictive value of p27 should be confirmed in prospective trials.

No significant financial relationships to disclose.
Phase Ib/II study of DMXAA combined with carboplatin and paclitaxel in non-small cell lung cancer (NSCLC)
Authors: McKeage M.
Published: March 2020

7102

Background: DMXAA (AS1404) is a small-molecule vascular disrupting agent, which in animal models shows additive or supra-additive effects with cytotoxics including taxanes and platinum agents. This phase Ib/II study evaluated DMXAA in combination with carboplatin (C) and paclitaxel (P) in NSCLC. Methods: Patients had histologically confirmed stage IIIb or IV NSCLC previously untreated with chemotherapy. Safety of the combination was initially assessed in 1 patient receiving C (AUC 6 mg/ml × min) + P (175 mg/m2) + 600 mg/m2 DMXAA. Seventy-seven patients were then randomised to receive up to 6 cycles of C + P with or without DMXAA (1,200 mg/m2 or 1,800 mg/m2). Safety assessments included EKG, adverse events, laboratory screens, pharmacokinetics and ophthalmic exams. Efficacy endpoints are objective response rates, time to progression, duration of response and stable disease, and median and 1-year survival. Results: 78 patients were enrolled. One received C + P + 600 mg/m2 DMXAA; no serious toxicities were observed; the patient had a partial response (PR, RECIST, investigator assessment). Randomisation was initiated: 35 patients received C + P, 36 C + P + 1200 mg/m2 DMXAA and 6 C + P + 1800 mg/m2 DMXAA. The safety profile in the control and DMXAA arms was comparable. No pharmacokinetic interactions were observed. Investigator-assessed RECIST data are available from 68 patients with at least one post-baseline CT scan. First post-baseline scans were taken after the defined stable disease interval (6 weeks), so patients without progressive disease (PD) at this point have confirmed disease control (best overall RECIST response of PR or stable disease (SD), with final disposition dependent on subsequent scans). Of 30 patients in the control arm 23 show disease control and 7 PD. Of 33 patients in the 1200 mg/m2 DMXAA arm 28 show disease control and 5 PD. Of 5 patients who received 1800 mg/m2 DMXAA, all show disease control, with 3 confirmed PRs. Conclusions: Addition of DMXAA to standard doses of C and P did not add significantly to toxicity. Initial response data suggest this combination could provide additional benefit compared with C and P alone.

No significant financial relationships to disclose.
A phase II study of a novel anti-tubulin, E7389, in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Das A. , Spira A. , Iannotti N. , Savin M. , Zang E. , Datta K. , Shapiro G. , Patturajan M. , Silberman S.
Published: March 2020

7106

Background: E7389, a synthetic analog of halichondrin B that was isolated from a marine sponge, has broad anti-proliferative activity at nanomolar levels and a unique profile of tubulin interactions. Methods: This is an open-label, single-arm, stratified phase II study of E7389 in patients with measurable, recurrent and/or metastatic NSCLC who progressed during or after platinum-based doublet chemotherapy. E7389 (1.4 mg/m2) was administered as a bolus IV on days 1, 8, and 15 of a 28-day cycle to 72 patients (cohort 1) in stratum I (55 taxane pretreated patients) and stratum II (17 taxane-naive patients) and on Days 1 and 8 of a 21-day cycle (cohort 2), providing an additional 22 patients in stratum I. The primary efficacy endpoint was objective response rate to E7389 monotherapy. Results: As of 9 December 2005, 94 evaluable patients received E7389. Nineteen tumors were classified as squamous cell carcinomas, 39 as adenocarcinomas, and 36 were large cell carcinomas or unclassified. The median number of cycles completed was 3. Fifteen patients completed 6 or more cycles and 75 patients underwent tumor assessments after cycle 2. Major toxicities related to study drug included myelosuppression, nausea, fatigue, dehydration, arthralgias, dyspnea, and peripheral neuropathy. Based on RECIST criteria, 6 partial responses (PR) were observed among 94 evaluable patients (PR rate = 6.4%, 95% CI: 2.8%, 12.8%). For 33 patients the best response was stable disease (SD rate = 35.1%, 95% CI: 25.5%, 45.1%). Disease control rate (PR + SD) was 41.5% (95% CI: 31.4%, 51.7%). For cohort 1, the 12-week progression free survival rate was 57.2%. As of 9 December 2005, median PFS time was 108 days (95% CI = 55, min-max = 1–239+). Cohort 2 is being followed to estimate their 12-week PFS. The correlation of beta tubulin isotype, stathmin, microtubule-associated protein 4 (MAP4) and tau protein mRNA expression with tumor responses is on-going. Conclusions: Based on this data, E7389 has been shown to be safe and effective in the treatment of NSCLC patients. Updated information and results of molecular correlations of responses will be presented.

[Table: see text]
EGFR, HER2, and phospho-Akt are not predictive factors for response to first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Toschi L. , Metro G. , Magrini E. , Bartolini S. , Ligorio C. , Finocchiaro G. , Pession A. , Cancellieri A. , Tallini G. , Cappuzzo F.
Published: March 2020

7111

Background: Response to Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is significantly associated with increased EGFR gene copy number, increased EGFR expression or presence of activating EGFR gene mutations. In presence of EGFR, increased HER2 gene copy number, as well as activation of the anti-apoptotic protein Akt demonstrated to increase EGFR-TKI sensitivity in both clinical and preclinical models. Aim of the present study was to assess whether these biomarkers also associate with response to first-line chemotherapy. Methods: Patients with advanced NSCLC with full clinical data and with tumor tissue available were selected for this analysis. Specimens were evaluated for EGFR and HER2 gene copy number by FISH, EGFR and p-AKT protein expression by immunohistochemistry. RECIST criteria were used to assess response to chemotherapy. Results: A total of 144 NSCLC were included in this analysis. Patient characteristics included: male/female: 95/49; PS 0/1/2: 112/29/3; stage III/IV: 44/100; adenocarcinomas plus bronchioloalveolar/squamous/other: 86/35/23; never/former/current smokers: 26/69/49. The majority of patients were treated with first-line platinum-based chemotherapy (115/79.9%). Response to chemotherapy was not associated with any clinical characteristic. A trend towards better response was observed in non-adenocarcinoma histologies (p = 0.08) and in smokers (p = 0.20). Response and time to disease progression (TTP) were not influenced by EGFR/HER2 FISH status, nor P-Akt/EGFR expression. In EGFR FISH positive response rate was 36.4% and TTP was 6.4 months, versus 28.7% and 7.3 months in EGFR FISH negative (p = 0.4 for both). Conclusions: Biomarkers useful for selection of patients candidate for TKI therapy are not predictive for response to first-line chemotherapy in NSCLC.

No significant financial relationships to disclose.
Trends in demographics and survival for patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Kubota K. , Masuhara H. , Hosoya K. , Yoh K. , Niho S. , Goto K. , Ohmatsu H. , Nishiwaki Y. , Saijo N.
Published: March 2020

7114

Background: In clinical trials, concurrent chemoradiotherapy improves survival of pts with inoperable stage III NSCLC compared with sequential chemoradiotherapy or radiotherapy alone, and platinum doublets with third-generation chemotherapy prolong survival of pts with stage IV NSCLC. Epidermal growth factor receptor antagonist is active as second-line chemotherapy. Few outcomes research regarding demographics and survival trends in advanced NSCLC has been conducted. Methods: The National Cancer Center Hospital East Database was searched for all pts with inoperable stage III and IV NSCLC. Data was recorded for histology, age, sex, smoking history, tumor location, stage, performance status (PS), and treatment modality. Pts were divided into two groups; group A: newly registered pts from July 1992 to December 1997, group B: from January 1998 to June 2004. Survival curves were evaluated using the Kaplan-Meier methods, and statistical significance was estimated by the log-rank test. Results: 2,135 pts (771 pts group A vs. 1364 pts group B) were identified. Pts demographics of each group (% group A/B) were as follows; male; 74/77, non-smoker; 19/19, PS 0–1; 79/85, squamous cell histology; 26/24, stage III; 45/44. Median age was 63 years old in group A and 64 in group B. Median survival (MS), 1-year survival rate (1ys), 2ys and 3ys were 8 months (M), 33%, 12% and 7% in group A, 10M, 42%, 23% and 14% in group B, respectively (P < .0001). In pts with stage III, MS, 1ys, 2ys, 3ys were 12M, 46%, 20%, 12% in group A and 15M, 56%, 34%, 20% in group B (P < .0001). In non-smoker, MS, 1 ys, 2 ys were 11 M, 46%, 19% in group A and 15 M, 56%, 30% in group B (P < .0001). In females, MS, 1 ys, 2 ys were 10 M, 39%, 16% in group A and 15 M, 55%, 31% in group B (P < .0001). Conclusion: Although there were no apparent differences in demographics between the two groups, survival was significantly improved chronologically. The improvement was prominent in stage III, non-smokers and females suggesting the benefit of chemoradiotherapy and tyrosine kinase inhibitors.

[Table: see text]
The Four-Arm Cooperative Study (FACS) for advanced non-small cell lung cancer (NSCLC): A subgroup analysis in elderly patients (pts)
Authors: Goto K. , Nishiwaki Y. , Saijo N. , Takeda K. , Katakami N. , Kudoh S. , Ichinose Y. , Ohashi Y. , Ariyoshi Y. , Fukuoka M.
Published: March 2020

7115

Background: Efficacy and safety in fit, elderly NSCLC pts receiving platinum-based treatment have been reported to be similar to those in younger pts. However, there is controversy about which platinum-based regimens are suitable for the elderly. To compare efficacy and safety of platinum-based chemotherapy regimens in the elderly, we conducted an age specific subgroup analysis on FACS, a phase III randomized trial comparing four platinum-based regimens for advanced NSCLC. Methods: FACS was designed to compare three platinum-based combination regimens to cisplatin (80 mg/m2, day 1) plus irinotecan (60 mg/m2, days 1, 8, 15) (IP) as the reference arm. The experimental regimens were: carboplatin (AUC 6, day 1) plus paclitaxel (200 mg/m2, day 1) (TC); cisplatin (80 mg/m2, day 1) plus gemcitabine (1000 mg/m2, days 1, 8) (GP); cisplatin (80 mg/m2, day 1) plus vinorelbine (25 mg/m2, days 1,8) (NP). Results: Of the 105 pts ≥ 70 years (17% of 602 enrolled pts), 27 were on the IP arm, 27 on TC, 28 on GP, and 22 on NP. Patient characteristics were similar in each arm. Response rates were 26% in IP, 20% in TC, 32% in GP, 50% in NP. Frequency of grade 3 or greater leukocytopenia (IP/TC/GP/NP: 52%/33%/36%/86%) was higher in NP, and thrombocytopenia (IP/TC/GP/NP: 11%/19%/43%/0%) was higher in GP, however anemia (IP/TC/GP/NP: 56%/19%/29%/55%) was lower in TC and GP. Frequency of grade 2 or greater vomiting (IP/TC/GP/NP: 52%/22%/39%/41%) was lower in TC, and diarrhea (IP/TC/GP/NP: 48%/7%/4%/14%) was lower in TC, GP and NP, however, grade 2 or greater sensory neuropathy (IP/TC/GP/NP: 0%/22%/0%/0%) was higher in TC. One year survival rates were 48% for the IP arm, 48% for TC, 61% for GP, and 46% for NP. There were no significant survival differences between IP and each experimental regimen. In addition, no significant differences between ≥ 70 and < 70 years were observed in each treatment regimen regarding hematological and non-hematological toxicities, response rates, and survival, except that grade 3 or greater anemia was significantly higher in ≥ 70 years pts in IP and NP arms. Conclusions: These platinum-based four regimens were similarly active and tolerable for fit, elderly NSCLC pts, and their efficacy and toxicity in the elderly were similar to those in younger pts.

No significant financial relationships to disclose.
Radiotherapy vs. temozolomide in the treatment of patients with lung cancer and brain metastases: A nordic randomized phase II study
Authors: Wagenius G. , Brodin O. , Nyman J. , Greim G. , Hillerdal G. , Riska H. , Sundström S. , Grönberg B. , Wang M. , Garmo H.
Published: March 2020

7136

Background: Metastasis to the brain is the most common intracranial tumour and 20–40% of all cancer patients will develop brain metastases. Lung cancer is the most common primary tumour and compose of 40%-50% of all brain metasases. As the survival in many malignancies increases, brain metastases will be an increasing problem. It is therefore important to find new treatment options. The aim of this study was primary to study quality of life and to compare radiotherapy and Themozolomide in that context. Methods: Inclusion criterias were confirmed small cell or non-small cell lung cancer, multiple brain metastases, PS 0–2, no previous radiotherapy to the brain. Previous chemotherapy was allowed. Patients were randomized to arm A (radiotherapy 30 Gy over 10 fractions) or arm B (Temozolomide 200 mg/m2 day 1–5, new cycle on day 29). Quality of life (QoL) was measured with a general cancer module, EORTC QLQ-C30, and a brain cancer specific module, BCM20. The primary end-point was the proportion of patients in each treatment arm with maintained or better QoL score at 8 weeks compared to the base line evaluation. In this first analysis exclusion rate from the study at 8 weeks was used as a surrogate end-point. Results: 208 patients were included, 104 in arm A and 104 in arm B. 36 (17%) squamous cell, 97 (47%) adenocarcinomas, 10 (5%) large cell, 23 (11%) undifferentiated and 42 (20%) small-cell lung cancer were included. 93 (45%) patients were chemonaive. At 8 weeks, 79 patients were excluded from the study, 51 (49%) from the temozolomide arm and 28 (27%) from the radiotherapy arm. 53% of the patients with squamous cell carcinoma were excluded compared to 40% of small cell lung cancer, 33% of adenocarcinomas and 27% of large cell carcinomas. The exclusion rate at 8 weeks was higher among patients with symptoms at randomization compared to patients without symptoms. There were no difference in exclusion rate when comparing number or size of the metastases. Conclusion: The exclusion rate at 8 weeks was higher in the temozolomide arm compared to the radiotherapy arm. Histopathology and symptoms at randomization seems to be factors influencing the exclusion rate whereas number or size of metastases does not. Survival and quality of life data will be presented at the meeting.

No significant financial relationships to disclose.
Phase II pharmacodynamic trial of erlotinib in advanced non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy: FISH results
Authors: Felip E. , Rojo F. , Reck M. , Heller A. , Klughammer B. , Maacke H. , Möcks J. , Brennscheidt U. , Gatzemeier U. , Baselga J.
Published: March 2020

7160

Background: The HER1/EGFR inhibitor erlotinib significantly prolongs survival of patients with previously-treated advanced NSCLC. Methods for selecting patients most likely to derive clinical benefit from erlotinib are not established. Increased HER1/EGFR gene copy number has been suggested as a potential predictive biomarker of clinical benefit, and was investigated in this phase II study. Methods: Advanced NSCLC patients who failed first line chemotherapy were treated with erlotinib monotherapy, 150 mg/d p.o. Each patient underwent tumor biopsy before start of treatment. Tumor HER1/EGFR gene amplification status was assessed using FISH, and classified as positive (amplification, polysomy, high polysomy) or negative (disomy, trisomy). Results: 83 patients were included: median age 56 (range 35–78); sex: male 72%, female 28%; histology: adenocarcinoma 43%, large cell 31%, squamous cell 19%, others 7%; smoking status: 44 current smokers, 28 former smokers, 11 never smokers. Of 73 evaluable patients, 7 (10%) achieved partial response (PR), 28 (38%) had stable disease (SD) and 38 (52%) had disease progression. PRs were observed in 4 males / 3 females; in 5 adenocarcinomas / 1 large cell/ 1 squamous cell; in 2 current / 3 former / 2 never smokers. Erlotinib was well tolerated and no unexpected toxicities were seen. HER1/EGFR gene copy number was evaluated in 53 patients. 15 patients were FISH +, 10 of whom achieved clinical benefit (PR, or SD for ≥12 weeks). Only 5 of 38 FISH - patients had clinical benefit. FISH + patients achieved a longer median time to progression (137 vs 43 days; p = 0.00011; HR 0.35) as well as overall survival (226 vs 115 days; p = 0.3221, HR 0.722). Conclusion: In this study, increased HER1/EGFR gene copy number was associated with a better outcome on erlotinib therapy.

[Table: see text]

[Table: see text]
Phase II trial of erlotinib in elderly patients (age > 70) with previously untreated advanced non-small cell lung cancer (NSCLC): An analysis of quality of life and symptom response
Authors: Jackman D. M. , Yeap B. , Lucca J. , Ostler P. A. , Morse L. K. , Fidias P. , Lynch T. J. , Temel J. , Johnson B. E. , Janne P. A.
Published: March 2020

7168

Background: Elderly patients derive survival benefit but significant toxicity from chemotherapy for NSCLC. Erlotinib is associated with reasonable toxicity and has a survival benefit for relapsed patients previously treated with 1–2 chemotherapy regimens. This targeted agent may prove an effective and well-tolerated first-line therapy in elderly patients with advanced disease. Methods: 80 patients (chemo-naïve, age ≥ 70, PS 0–2, stage IIIB/IV NSCLC) were treated with erlotinib 150 mg/d as part of a phase II study. Primary endpoint was survival. QoL was a secondary endpoint, as assessed by LCSS at baseline and q4 weeks until progression. The primary endpoint of QoL analysis was to determine changes from baseline in LCSS score. Patients were eligible for QoL analysis if they completed an LCSS questionnaire at baseline and ≥ 1 other monthly follow-up visit. Each of 9 items was assessed on a 100mm visual analog scale from 0 (best) to 100 (worst); symptom improvement or worsening was based on a change of ≥ 10mm, with decreased scores implying improvement. Score differences between the baseline and best follow-up response of each subscale and total LCSS are assessed by the signed rank test. Results: 64 patients (80%) were eligible for QoL analysis. There was a trend towards improvement in QoL, based on the total LCSS score. Statistically significant improvements in dyspnea, cough, fatigue, and pain were seen, both in terms of median changes from baseline and the proportion of patients improved (Table). No patients were symptomatic for hemoptysis at baseline, so improvement could not be calculated. Conclusions: Erlotinib in elderly patients with advanced NSCLC was associated with encouraging survival (10.9 mo), a trend towards improved QoL, and statistically significant improvements in key symptoms of dyspnea, cough, fatigue, and pain. Mixed effects longitudinal modeling showing changes in LCSS over time will be presented at the conference.

[Table: see text]

[Table: see text]
IFCT0401-bio trial: Pathological and EGF-r molecular analysis of tumor-biopsy samples from patients with non-resectable, pneumonic-type adenocarcinoma (P-ADC) treated by gefinitib. Preliminary results from surgical specimens
Authors: Cadranel J. , Wislez M. , Coulet F. , Poulot V. , Morã J. F. , Debove P. , Perol M. , Souquet P. J. , Soubrier F. , Antoine M.
Published: March 2020

7185

Background: P-ADC is often a bronchioloalveolar carcinoma (BAC) variant in the 2004 WHO pathological classification. A French prospective multicentric phase II trial (IFCT0401) evaluated gefitinib as first line treatment in non-resectable P-ADC. Tissue samples were collected for central pathological review and molecular analysis in attempt to determine if an association existed between disease control (DC) by gefitinib and biological markers. Methods: Histologic types were classified according to the 2004 WHO classification as BAC variants and ADC, other types and as non-mucinous or mucinous/mixed. Immunohistochemistry were performed using antibodies against the following proteins: TTF1, Ki67, phosphorylated AKT, erbB2, and EGFR. Polysomy/amplification was examined for erbB2 and EGFR. EGFR 18–21 and K-ras 1 exons were amplified and sequenced. Results: A tissue specimen was collected from 67 of the 88 eligible participants, among which 35 were from surgical resection. This subgroup did not differ from the overall trial population in terms of sex ratio (0.51 vs 0.56), proportion of non-smokers (34 vs 55%) and DC rate (34 vs 29%). Results described herein were obtained in 22 of the 35 surgical specimens collected. Sixteen were BAC variants (73%) and 6 ADC other types. Of the 22, 14 were non-mucinous and 8 mucinous. TTF1, Ki67, P-AKT, erbB2 as well as EGFR expression did not differ between BAC variants and ADC other types. TTF1 and EGFR scores of expression were higher in non-mucinous than in mucinous P-ADC. DC on gefitinib was significantly associated with non-mucinous subtype (p = 0.006), higher TTF1 (p = 0.06) and EGFR (p = 0.07) scores of expression, but not with other markers. K-ras exon-1 codon 12 mutation was found in 6 tumors of which 5 progressed on gefitinib. Polysomy of EGFR was seen in 2 tumors, 1 of which also contained EGFR mutation (exon-19 deletion); both were controlled by gefitinib. Conclusions: Among patients with P-ADC who received gefitinib, non-mucinous subtype, high TTF1 or EGFR score of expression, and EGFR polysomy and/or mutation may have improved DC, while K-ras mutation seems associated with disease progression.

[Table: see text]
Maintenance gefitinib (G) after chemoradiotherapy (CRT) in patients (pts) with unresectable stage IIIA/B non-small cell lung cancer (NSCLC): A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Gray J. R. , Spigel D. R. , Hainsworth J. D. , Vazquez E. , Peyton J. D. , Raefsky E. L. , Malik R. , Marsland T. , Waples J. , Greco F. A.
Published: March 2020

7188

Background: Concurrent CRT improves outcomes for pts with unresectable stage III NSCLC compared with radiation (RT) alone. The EGFR inhibitor G benefits select pts with advanced NSCLC. This multicenter community phase II trial examined the role of CRT followed by G for pts with unresectable stage III NSCLC. Methods: Theprimary endpoint was 2-year overall survival (OS) in pts with unresectable stage IIIA/B NSCLC (effusions, N3 mediastinal nodes >4 cm excluded) treated with CRT followed by G. Induction(I) treatment (tx): docetaxel (D) 40 mg/m2 IV and gemcitabine 800 mg/m2 IV D1, 8 Q 21D × 3 cycles. Pts without progressive disease (PD) began: D 20 mg/m2 IV and carboplatin (C) AUC = 1.5 IV weekly × 6 and RT 61.2 Gy, 1.8-Gy M-F weekly × 7 (starting 1 week prior to D/C). If no PD, pts received G 250 mg PO daily × 2 years or until PD. Eligibility:measurable disease, ECOG PS 0–1, informed consent. Intent to treat analysis. Results: One-hundred three pts were enrolled from 7/03 to 4/05. Baseline features: medianage 60 years (37–79); male/female 54%/46%; ECOG PS 0/1:26%/74%; adenocarcinoma (26%), squamous (32%), large cell (28%), mixed/not specified (14%); IIIA/B (46%/54%). Grade 3/4 toxicities were limited to ≤ 8% except for neutropenia (17%, during I) - with notx-related deaths. Complete/partial responses after I were seen in 1 pt/34 pts, respectively, for an overall response rate (RR) of 34% (95% CI 26%-44%). Forty-two pts (41%) had stable disease (SD) and 12% had PD (9 pts were unevaluable.) Seventy-four pts (72%) received D/C/RT which resulted in an overall RR of 44% (95% CI 35%-54%). Fifteen percent had SD. Fifty-six pts (54%) received G for a median of 28 weeks (1–107). Median PFS and OS are 9.9 and 15 months, respectively. After a median follow-up of 19 months, actuarial 1- and 2-year progression-free survival (PFS) is 41% and 12%, respectively. 1- and 2-year OS rates are 64% and 21%, respectively. Subset analyses by smoking, gender, histology, and stage are in progress. Conclusions: Maintenance G following CRT in unresectable NSCLC does not appear to improve survival. It is possible that further analysis may suggest a role for G in selected pts.

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The relationship between RASSF1A aberrant methylation and survival in small sized lung adenocarcinoma
Authors: Miyajima K. , Ohira T. , Usuda J. , Saji H. , Tsuboi M. , Hirano T. , Kato H. , Suzuki M. , Toyooka S. , Gazdar A. F.
Published: March 2020

7199

Background: Aberrant methylation of CpG islands in promoter regions of tumor cells is one of the major mechanisms for silencing of tumor suppressor genes. The RAS association domain family 1A (RASSF1A) gene was isolated from the 3p21.3 region homozygously deleted in lung cancer cell lines, and it was shown to be inactivated by hypermethylation of the promoter region in lung cancers. In this study, we investigated the clinicopathological significances of RASSF1A methylation in the development and/or progression of small-sized (less than 2.0cm) lung adenocarcinoma. It is important to identify a marker for high-risk early stage patients who should benefit from new investigational adjuvant therapies. Methods: Surgically resected specimens from 77 cases of small-sized primary lung adenocarcinoma. We determined the frequency of aberrant promoter methylation of the RASSF1A genes in small-sized adenocarcinoma. Aberrant promoter methylation was examined using methylation-specific PCR (MSP). Results: Twenty-five of 77 (32.5%) tumors showed RASSF1A methylation. RASSF1A methylation was dominantly detected in smoker (P < 0.03). There was no significant correlation of RASSF1A methylation with gender, age, T stage, N stage and pathological stage. RASSF1A methylation correlated with adverse survival by univariate analysis (P < 0.005) as well as multivariate analysis (P = 0.0062; RR 4.251; 95% C.I., 1.507–11.993). Furthermore, RASSF1A promoter hypermethylation in resected stage I small-sized lung adenocarcinoma was associated with impaired patient survival (P < 0.01). Conclusions: Aberrant promoter methylation of the RASSF1A was present in 25 of 77 (32.5%) of small-sized lung adenocarcinoma by MSP assay. These results indicated that epigenetic inactivation of RASSF1A plays an important role in the progression of small-sized lung adenocarcinoma, and that RASSF1A hypermethylation appears to be a useful molecular marker for the prognosis of patients with small-sized and stage I lung adenocarcinoma. RASSF1A is a potential tumor suppressor gene that undergoes epigenetic inactivation in lung adenocarcinoma through hypermethylation of its promoter region. RASSF1A methylation was significantly related to unfavorable prognosis in small-sized lung adenocarcinoma.

No significant financial relationships to disclose.
Chromosomal aneusomy in sputum predicts for lung cancer in nested case-control study
Authors: Franklin W. , Schulte A. P. , Zeng C. , Wolf H. J. , Yin X. , Hirsch F. R. , Byers T. , Miller Y. E. , Baron A. E. , Varella-Garcia M.
Published: March 2020

7201

Background: Lung cancer usually is disseminated at diagnosis and prognosis is poor for most patients. Heavy smokers are known to be at high risk factor for lung cancer and are target population for lung cancer prevention. Sputum has long been considered a potential source of material for biomarker based early detection but no tests have been validated. Methods: Chromosome aneusomy was sought in sputum of 114 cases and 110 controls from the Colorado Sputum Screening Cohort Study, which includes heavy smokers with airflow obstruction matched on age, gender, and date of sample collection. Subject characteristics were as follows: mean age 67 (± 8 years), 75% males, 36% current smokers, mean pack-year 71.2 (± 33.5). The FISH probe LAVysion (Vysis/Abbott) was used, including the DNA targets EGFR, MYCC, 5p15 and CEP6. Results: The multi-target set showed the highest sensitivity (0.78) and specificity (0.95) rates in specimens collected within 12 months of lung cancer diagnosis. The individual probes EGFR, MYCC, 5p15 and CEP6 showed, respectively, decreasing sensitivity rates (0.78, 0.67, 0.62, and 0.29) and increasing specificity rates (0.84, 0.91. 0.86, and 0.95). Combinations of two specific probes (AND) or of any of two probes (OR) have not favorably impacted these coefficients. Proportion of abnormal sputum specimens was higher in squamous cell carcinoma than in adenocarcinoma or small cell carcinoma, both considering the set of specimens collected 12 months prior to disease diagnosis (92%, 75%, 60%) and all specimens (80%, 58%, 44%). Conclusions: Chromosomal aneusomy in sputum was demonstrated in a nested case-control cohort to be a promising marker for prediction of lung cancer risk in heavy smokers with airflow obstruction. Evaluation of four DNA targets was more effective than any single marker or combination of markers, and the test had high sensitivity in patients with squamous cell carcinoma.

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Five-year results of a non-randomised study evaluating spiral computed tomography (sCT) for early detection of lung cancer (LC)
Authors: Novello S. , Giajlevra M. , Lausi P. , Brizzi M. , Selvaggi G. , Sardo D. , Borasio P. , Dogliotti L. , Fava C. , Scagliotti G. V.
Published: March 2020

7210

Background: In high-risk subjects low-dose sCT showed a 4-fold increase in the detection rate of neoplastic nodules in comparison with chest-X-ray. However, among studies there is a considerable discrepancy in the % of lung nodules, overall lung cancer and stage I detection rate as well as of the additional diagnostic work up. Subjects & Methods: From April to December 2001, 520 asymptomatic volunteers aged ≥ 55 years with a history of cigarette smoking ≥ 20 packs-year and of no previous cancer received annually chest sCT for 5 consecutive years. Results: At baseline 73% were male, median age was 59 years and 91% current smokers. At baseline sCT 127 subjects (24.5%) had nodules <5 mm while nodules ≥5 mm were detected in 114 (22%); the size of lung nodules ranged from 5 to 9.9 mm in 81.5% of the cases. The % of nodules worth of additional investigation varied over time (2 yr: 6%; 3 yr: 5%; 4 yr: 11%). Five (1%) cases of LC were detected during the 1st year (3 stage I) and in two additional resections an atypical adenomatous hyperplasia was found. Three new cases of thoracic cancers were detected in the 2nd, 3rd and 4th year of the study. Drop-out rate in the first year was 5% (2 yr 4,5%, 3 yr 2.3% and 4 yr 3%). One interval case was detected during the 3rd year. Subjects who quitted smoking in the 1st year were 13% and the % decreased over years (6% at the end of 3rd yr and 3% at 4th and 5th yr) and among quitters failure rate was 1–2%/year. In 3% of cases quitting was related to an acute cardiovascular or respiratory event. Fifty % of subjects showed some radiological signs of emphysema. Conclusions: Evidence from ongoing randomised trials is needed to support the routine use of sCT for early detection of LC. A program of smoking cessation is strongly recommended for further studies. Currently a conservative attitude should be encouraged.

No significant financial relationships to disclose.
Prognostic value of different standard uptake values (SUV) of primary tumor measured with FDG-PET in resectable non-small cell lung cancer
Authors: De Jong W. K. , Van der Heijden H. F. , Pruim J. , Oyen W. J. , Groen H. J.
Published: March 2020

7214

Background: The SUV is a measure for the preferential uptake of a radiopharmaceutical in a tumor compared with a homogenous distribution in a body. SUV can be based on the maximum value (SUVmax) or on the mean value in a region outlined by isodensity contours, e.g., 70% and 50%. The prognostic value of the different SUVs in non-small cell lung cancer (NSCLC) is not clear. We evaluated the prognostic value of SUVmax, SUV 70% and SUV 50% in patients (pts) with resectable NSCLC. Methods: All consecutive pts who underwent an attenuation corrected whole body FDG-PET scan were selected. All data were reconstructed iteratively. Only pts with stage I through IIIA NSCLC were included. By adjusting the isocontour in the region of interest, the SUVmax, SUV 70% and SUV 50% of the primary tumor were calculated. Cox regression analysis was used to calculate the relation between the different SUVs and survival. Results: Eighty-four pts (67 males, median age 64 years, range 38–86) were included. Histology was squamous cell carcinoma (n = 43), adenocarcinoma (n = 27), large cell carcinoma (n = 13), and 1 patient with bronchoalveolar carcinoma. Nineteen pts had stage IA, 28 stage IB, 4 stage IIA, 19 stage IIB, and 14 stage IIIA. Median (range) SUVmax, SUV 70%, and SUV 50% were 6.9 (1.6–32.5), 5.5 (1.0–23.2), and 4.5 (0.9–21.9), respectively. Analysis of residuals of SUVmax as a continuous variable suggests no cut-off point and no indication of time-dependency. By univariate analysis, all pts with a SUV higher than the median value had a worse survival than pts with a SUV lower than median (Hazard ratio’s for SUVmax, SUV70% and SUV 50% were 2.3 (p = 0.024), 2.5 (p = 0.015), and 2.7 (p = 0.010), respectively). Conclusions: SUVmax, SUV 70% and SUV 50% measured with FDG-PET have a similar prognostic impact. No cut-off point for SUVmax has been observed.

No significant financial relationships to disclose.
Analysis of single nucleotide polymorphisms (SNPs) of cytidine deaminase (CDA) and xeroderma pigmentosum group D (XPD) genes for the prediction of clinical response to gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC) patients
Authors: Vasile E. , Giovannetti E. , Tibaldi C. , Mey V. , Nannizzi S. , Landi L. , Stasi I. , Danesi R. , Del Tacca M. , Falcone A.
Published: March 2020

7219

Background: Detection of genomic differences predictive of drug response may allow to customize chemotherapy to the characteristics of individual patients. Gemcitabine alone or in combination with cisplatin are two of the most common regimens used in the treatment of advanced NSCLC. We investigated the correlation between selected SNPs of genes encoding enzymes involved in the activity of gemcitabine and cisplatin, including CDA, XPD and ERCC1, and the response to chemotherapy. Methods: Forty advanced NSCLC chemo-naïve patients were enrolled into the study; 16 patients, aged > 70 years, were treated with gemcitabine; 24 patients, aged < 70 years, were treated with cisplatin plus gemcitabine. SNPs CDA A79C, XPD A751C, XPD G312A and ERCC1 C118T were analyzed with the ABI PRISM 7900HT Sequence Detection System using TaqMan probe-based assay in DNA obtained from peripheral blood samples. Statistical analysis was performed using Pearson χ2 test, Kaplan-Meier curve and log rank test. Results: Up to now 31 patients, 11 treated with gemcitabine and 20 with cisplatin plus gemcitabine, are evaluable for response with RECIST criteria; correlation between response and genotype are showed in the table. Actuarial progression free survival (PFS) was longer in patients treated with gemcitabine ± cisplatin with CDA A79A genotype than in others (respectively 11.0 vs 2.5 months, p = 0.0092), while no correlation was found between the SNPs of XPD and ERCC1 and PFS in patients receiving cisplatin and gemcitabine. Conclusions: CDA A79A genotype resulted predictive of response and longer PFS in NSCLC patients treated with gemcitabine ± cisplatin. There was also a trend toward significant correlation between XPD A751A and better response in cisplatin-treated patients, while the SNPs in XPD 312 and ERCC1 118 were not associated with response to chemotherapy.

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No significant financial relationships to disclose.