bluuebunny/crossref_metadata_2025 huggingface dataset:
Irinotecan (I), carboplatin (C), and radiotherapy (RT) followed by maintenance bevacizumab (B) in the treatment (tx) of limited-stage small cell lung cancer (LS-SCLC): Update of a phase II trial of the Minnie Pearl Cancer Research Network
Authors: Patton J. F. , Spigel D. R. , Greco F. A. , Liggett W. H. , Zubkus J. D. , Baskette M. , Schreeder M. , Woytowitz D. , Nelson E. , Hainsworth J. D.
Published: March 2020

7085

Background: Targeting VEGF has proven to be an effective tx strategy in many solid tumors including non-small cell lung cancer. VEGF expression in SCLC provides rationale for studying B in addition to chemoradiotherapy. Methods: The endpoints of this multicenter community-based study were to assess the safety, response rate (RR), and progression-free survival (PFS) of I/C/RT followed by B in patients (pts) with LS-SCLC. Tx included: C AUC = 5 IV D1, I 50mg/m2 IV D1,8 Q 21D x 4 cycles, and RT 1.8 Gy daily to a total of 61.2 Gy, beginning with the 3rd cycle. 3rd and 4th cycles were 28D each. Pts were restaged after 4 cycles. If no progressive disease (PD) pts received B 10 mg/kg IV Q 14D x 10 doses. Eligibility included: measurable disease, ECOG PS 0–1, informed consent, and no new brain metastases or bleeding. Results: Fifty-seven pts were enrolled from 8/03 to 10/04. Forty-five pts (79%) and 41 pts (72%) received planned tx with I/C/RT and B, respectively. The range of follow-up is 14–28 months. Baseline features: median age 65 years (42–80); male/female, 37%/63%; ECOG PS 0,1: 26%/74%. Grade (G) 3/4 non-hematologic toxicity: diarrhea (9%), DVT (4%), vomiting (11%), and fatigue (9%). G3/4 hematologic toxicity: neutropenia (37%), anemia (5%), and thrombocytopenia (13%). Only 9% of pts experienced G3/4 toxicity during B tx (1 pt each: DVT, hypokalemia, depression, pain, and colon perforation). There were 2 tx-related deaths (both from respiratory failure; 1 and 2 doses of B had been administered). Complete/partial responses were observed in 15 pts (26%)/31 pts (54%), respectively, for an overall RR of 80% (95% CI 70%-90%). Four pts had stable disease, and 5% had PD (4 pts were unevaluable.) 1- and 2-year PFS rates were 63% and 54%, respectively. 1- and 2- year overall survival (OS) rates were 71% and 29%, respectively. Median OS was 15 months. Conclusions: The safety, RR, and 1- and 2-year survival results of I/C/RT followed by B compare favorably with standard tx for LS-SCLC; and B may improve PFS. Assessing the role of B as maintenance tx in improving OS in this setting will require randomized trials.

[Table: see text]
Randomized phase II trial of irinotecan plus cisplatin (IP) versus irinotecan, cisplatin plus etoposide (IPE) every three weeks in patients with extensive disease small cell lung cancer (ED-SCLC)
Authors: Sekine I. , Nokihara H. , Takeda K. , Nishiwaki Y. , Nakagawa K. , Isobe H. , Mori K. , Matsui K. , Saijo N. , Tamura T.
Published: March 2020

7087

Background: A promising complete response rate and median survival time were obtained in our previous phase II study of IPE chemotherapy repeated every 4 weeks in patients with ED-SCLC, but the infusion of irinotecan on day 15 was omitted in 77% of patients. Methods: The objective was to evaluate toxicities and antitumor effects of IP and IPE regimens every 3 weeks and to select the arm for subsequent phase III trials. The primary endpoint was overall survival. Previously untreated ED-SCLC patients aged between 20 and 70 years old with a performance status (PS) of 0–2 were randomized to receive either IP (I 60 mg/m2 days 1, 8 and P 60 mg/m2 day 1) or IPE (the same dose of IP and E 50 mg/m2 days 1–3 with G-CSF support) every 3 weeks for 4 cycles. The projected sample size was 110 patients (Liu’s Selection design for pilot studies on survival). Results: From March 2003 to May 2005, 53 patients (43 males/10 females, median age 63) were randomized to IP and 57 patients (48 males/9 females, median age 62) to IPE. Body weight loss and PS were well balanced between the arms. Full cycles were administered in 75% of patients in the IP and in 67% in the IPE arm. Dose reduction was required in 17% of patients in the IP and 28% in the IPE arm. Grade 3–4 neutropenia, anemia and thrombocytopenia were observed in 53%, 34% and 4% of patients in the IP, and 93%, 45%, and 23% of patients in the IPE arm, respectively. Grade 3–4 infection, malaise, anorexia, and diarrhea were noted in 15%, 2%, 0%, and 15% of patients in the IP, and 30%, 11%, 15%, and 24% of patients in the IPE arm, respectively. No treatment related death occurred. Complete and partial responses were noted in 8% and 68% of patients in the IP, and 11% and 75% of patients in the IPE arm, respectively. Conclusion: Toxicity was more severe, but tumor responses seemed better in the IPE arm. The survival analysis will be carried out in April 2006.

No significant financial relationships to disclose.
The occurrence of hyponatriemia in SCLC and the influence on prognosis. A retrospective study of 468 patients treated in single institution in a 10-year period
Authors: Hansen O. , Sorensen P. , Hansen K. H. , Holtved E.
Published: March 2020

7091

Background: Hyponatriemia is very often seen in SCLC due to the paraneoplastic syndrome SIADH. Hyponatriemia has been found to be associated with poorer outcome in some but not in the majority of published studies. This study was performed to investigate the prognostic value of hyponatriemia in SCLC. Methods: Data from the patient files from 468 patients diagnosed with SCLC and treated at Odense University Hospital 1995 to 2005. In the 444 cases data on the initial S-Na was available. A Cox multivariate analysis was performed including possible prognostic factors. Results: Stage: Extensive disease (ED) 283 (64%), limited disease (LD) 161 (36%). The standard chemotherapy was 6 cycles of carboplatin-etoposide. 70% of the patients with LD received thoracic radiotherapy, usually in a dose of 45 Gy/22–30 F and 49% received PCI usually as 25 Gy/11F. Median survival in ED 7.2 months with a 1 and 2-year survival rate of 21% and 6%. In LD the figures was 15.2 months, 65%, 31% and a 5-year survival rate of 16%. S-Na was <125 mEq/L in 36 patients (8%), between 126–135 mEq/L in 158 (36%). 250 patients (56%) showed normal values of S-Na. In a Cox multivariate analysis, hyponatriemia was associated with poor prognosis. Other independent prognostic factors included LDH, gender, age, performance status and stage. Among non-significant factors were hemoglobin, WBC, and alkaline phosphatase. Conclusions: Hyponatriemia was a significant prognostic factor associated with poor prognosis with an odds ratio of 1.5 (p = 0.0013) if S-Na was 1.25–1.35 mEq/L and an odds ratio of 1.9 (p = 0.0008) if S-Na was <1.25 mEq/L.

[Table: see text]

No significant financial relationships to disclose.
The influence of radiotherapy technique and dose on the patterns of failure for mesothelioma patients following extrapleural pneumonectomy
Authors: Allen A. M. , Den R. , Wong J. S. , Janne P. A. , Zurakowski D. , Soto R. , Bueno R. , Sugarbaker D. J. , Baldini E. H.
Published: March 2020

7094

Background: Extrapleural pneumonectomy (EPP) is an effective treatment of pleural mesothelioma(MPM). We present a comparison of moderate-dose hemithoracic radiation (MDRT) to high-dose hemithoracic radiation (HDRT) following EPP for MPM. Methods: From 7/94 to 4/04, 39 pts underwent EPP and adjuvant radiotherapy (RT) at DFCI/BWH. From 1994–2002, MDRT, 30Gy to the hemithorax with boosts to the mediastinum or chest wall to 40–54 Gy was given, generally with concurrent chemotherapy (CT). Beginning in 2003, HDRT to 54 Gy as published by Yajnik et al (IJROBP 03’) was given with sequential CT. Results: Thirty-nine pts received RT following EPP. Median age was 59 yrs (range 44–77). Histology was epithelial in 25 (64%) pts and mixed/sarcomatoid in 14 (46%) pts. Twenty-four pts were treated with MDRT. 19 pts received concurrent platinum-based CT with MDRT. Three received cyclophosphomide, adriamycin and cisplatin (CDDP) CT prior to radiotherapy and 2 did not receive CT. 14 pts (39%) were treated with HDRT. 10/14 received sequential CDDP/gemcitabine, 4 received CDDP/pemetrexed and 1 patient received intraoperative CDDP. The median follow-up was 20 mos (range, 6–73 mos). Overall survival (OS) was 19 mos (95% CI, 14–24 mos). The median times to distant failure (DF) and local recurrence (LR) were 20 mos (95% CI, 14–26 mos) and 26 mos (95% CI, 16–36 mos), respectively. No significant differences in outcome between the two radiotherapy regimens were seen. One patient died of radiation-induced liver disease, one of pneumonitis and one of an MI. Four pts who received HDRT are alive and NED. On univariate and multivariate analysis mixed histology was predictive of DF and OS (p < .006; p < .004). Neither RT technique nor type of CT were predictive of LF, DF, or OS. The patterns of failure are in the table below. Conclusions: HDRT appears to limit in field local failures as compared to MDRT. Distant failure remains a significant challenge, with half of the patients experiencing distant failure.

[Table: see text]

No significant financial relationships to disclose.
A phase II study of intravenous (IV) milataxel (M) for the treatment of non-small cell lung cancer (NSCLC) refractory to platinum-based therapy
Authors: Mekhail T. , Serwatowski P. , Dudek A. , Belani C. , Jankowska R. , Pandya K. J. , Arnold S. , Brahmer J. , Gitlitz B. , Govindan R.
Published: March 2020

7098

Background: M (TL139, MAC-321) is a novel taxane that has shown activity when administered IV or orally in both taxane-resistant and susceptible nude mouse xenograft models. The current study is an open-label study in previously treated patients (pts) with locally advanced, metastatic, or recurrent NSCLC to determine response rate. Methods: Pts with cytologically or histologically confirmed NSCLC must have received 1 or 2 prior regimens including prior platinum, and may have received prior paclitaxel or docetaxel. Good performance status (ECOG 0 or 1), and adequate hematologic, hepatic and renal function were required. Pts with clinically active brain metastases were excluded. Pts were treated with M 35 mg/m2 as a 4 hr IV infusion every 3 weeks. The primary end point was objective response rate. Results: A total of 46 pts were treated: 21 (46%) female pts and 25 (54%) male pts. Mean age was 59 (range 41–85), ECOG was PS 0 in 13 (28%) pts, PS 1 in 31 (67%) pts and unknown in 2 (4%) pts. The number of prior chemotherapy regimens was > 1 in 21 (46%) pts. Twenty-five (54%) pts had one prior taxane and 7 (15%) pts had both paclitaxel and docetaxel previously. The median number of cycles was 3 (range 1–14). Nine (20%) pts required dose reduction. Five (11%) pts discontinued treatment due to adverse events. A total of 25 (54%) pts reported drug related grade 3 or 4 adverse events. Non-hematologic grade 3 or 4 drug-related events occurring in more than 1 pt included: neuropathy 4 (9%) pts, neutropenic fever 3 (7%) pts, arthralgia 2 (4%) pts. There was no treatment related mortality. Objective responses were confirmed in 4 (9%) pts (3 PR, 1 CR). Three pts with response (including pt with CR) had received prior docetaxel. PR duration was 175, 250, and 315 days. Pt with CR received 4 cycles of M and discontinued due to the CR. Pt remained in CR at day 504. Conclusions: Milataxel 35 mg/m2 as a 4 hr IV infusion every 3 weeks provided durable responses in heavily pretreated pts including pts who had previously received taxanes.

No significant financial relationships to disclose.
Phase III study comparing cisplatin/vinorelbine plus cetuximab versus cisplatin/vinorelbine as first-line treatment for patients with epidermal growth factor (EGFR)-expressing advanced non-small cell lung cancer (NSCLC) (FLEX)
Authors: Von Pawel J. , Park K. , Pereira J. R. , Szczesna A. , Yu C. , Ganul V. L. , Krzakowski M. , Roh J. K. , Pilz K. , Pirker R.
Published: March 2020

7109

Background: Cisplatin plus vinorelbine is a commonly used regimen for first-line therapy of advanced NSCLC, achieving response rates of 20–30% and median survival times of 6 to 11 months (mths). An earlier phase II trial investigated cetuximab in combination with cisplatin and vinorelbine in this setting and found improved response rates in the cetuximab arm, warranting this larger phase III trial. Methods: Patients (pts) with EGFR-expressing advanced NSCLC (stage IIIB with documented malignant pleural effusion and stage IV) were randomized 1:1 either to Group A (cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly, cisplatin 80 mg/m2 on day 1, vinorelbine 30 mg/m2 on day 1 and 8) or to Group B (cisplatin and vinorelbine as before) for a maximum of 6 three-weekly cycles. Cetuximab was administered until progression or unacceptable toxicity. Primary endpoint is overall survival time; secondary endpoints are progression-free-survival, tumor response, disease control, safety, and quality of life. Enrollment of 1,100 pts was planned to show an increase of median survival time of 25% with 90% power. The Data Safety Monitoring Board (DSMB) performed an independent preplanned safety analysis from the first 370 pts. Patients were followed for a minimum of 6 weeks (2 cycles). Results: Since November 2004, 1,037 pts have been randomized, 689 are under treatment, and 348 pts have discontinued the study. Demographics of the first 370 pts reflected known advanced NSCLC characteristics: 91% stage IV, median age 60 yrs (31–79), 38% female, 80% ECOG PS 0/1, 52% adenocarcinoma, 30% squamous cell carcinoma; 29% never-smokers, 17% Asian. The ten most frequent adverse events were: nausea, neutropenia, vomiting, anorexia, fatigue, constipation, anemia, febrile neutropenia, rash, and diarrhoea. Conclusions: The trial continued after review of all relevant baseline and safety information from the first 370 pts. Recruitment is ongoing.

[Table: see text]
Cisplatin plus gemcitabine with or without vinorelbine as neo-adjuvant therapy for radically treatable stage III non-small cell lung cancer. Results of a randomised study of the Grupo Oncológico del Norte de España
Authors: Esteban E. , Villanueva N. , Muñiz I. , De Sande J. , Fra J. , Fernández Y. , Vieitez J. , Luque M. , Jimenez P. , Buesa J. , Lacave A.
Published: March 2020

7121

The combinations of cisplatin (C) with gemcitabine (G) and/or vinorelbine (V) have shown to be effective and safe regimens in the first line treatment of NSCLC. This study has been designed to detect a 25% increase in objective response measured by CT scan with the triplet combination (CGV) with respect to cisplatin/gemcitabine combination (CG) administered as neo-adjuvant therapy in patients with radically-treatable stage III NSCLC. With 80% of power and one-sided 5% significant level, the simple size required to confirm this hypothesis is 75 evaluable patients in each arm of treatment. Patients (pts) ≤ 75 years old, Karnofsky index ≥ 70% and adequate haematological, renal and hepatic function are stratified by stage (IIIA versus IIIB) and randomly assigned to: C 50 mg/m2 i.v. and G 1250 mg/m2 i.v. d1 and d8 alone (CG) or in combination with V 25 mg/m 2 i.v. d1 and d8 (CGV) both regimens every 3 weeks for 3 consecutive cycles followed by definitive local treatment (LT). From December 1999 to December 2005, a hundred and forty-nine pts have been randomised (CG/CGV); median age 58/58; median Karnofsky index 80/80; stage IIIA 24/26; stage IIIB 51/48; squamous 37/39; adenocarcinoma 31/32; anaplastic 7/3. Major haematological toxicities grade 3–4 were (CG/CGV; %); Anaemia (5/5) neutropenia (31/34); thrombocytopenia (4/5). Two pts in CG (2.7%) and 4 in CGV arm (5.5%) developed neutropenic fever. Major non-haematological toxicities grade 2–3 were: N/Vomiting (31/32) and fatigue (12/20). Global recurrences have been registered in 57% and 54% of pts treated with CG and CGV arm respectively. Exclusive local/ distant failure (%) has been 16/23 in CG and 23/18 in CGV arm. Preliminary results show similar high efficacy associated with moderate toxicity in both groups of treatment. The study is continuing.

[Table: see text]

No significant financial relationships to disclose.
Interim results of two prospective trials measuring plasma total DNA and methylated genes before and after surgery, or chemotherapy, in patients with non-small cell lung cancer (NSCLC)
Authors: Azzoli C. G. , Park S. , Ginex P. , Vincent A. , Jones J. , Venkatraman E. , Danenberg K. , Danenberg P. , Rusch V. R. , Kris M. G.
Published: March 2020

7123

Background: Measuring DNA in plasma using quantitative RT-PCR is a promising method for surveillance of NSCLC. This strategy has the potential to assess response more accurately or quickly than radiologic tests, or to confirm the success of surgical resection and select patients for adjuvant therapy. Methylated genes may be more specific than total DNA for the presence of cancer. Methods: We are conducting two prospective trials measuring total DNA, and 10 commonly hypermethylated genes in the plasma of NSCLC patients before and after therapy. For patients undergoing surgery, plasma samples are collected before, and at three timepoints after surgery (3–8 d, 2–5 w, 2–4 m). For patients on chemotherapy, collections are before, and coincident with up to 3 radiologic response assessments. DNA is extracted from a fixed volume of plasma, and measured using quantitative PCR of the β-Actin gene. After treating DNA with sodium metabisulfite, methylation-specific RT-PCR is performed to amplify the promoter region of APC, p16, MGMT, GSTP1, DAPK, CDH1, RASSF1A, WIF-1, SOCS-3, METH-2, assuming the promoter is fully methylated. Gene levels are normalized to β-Actin in modified DNA. Results: To date, plasma analysis has been completed on 50 patients with advanced NSCLC undergoing chemotherapy (320 planned), and 60 patients with early-stage NSCLC undergoing surgery (400 planned). Pretreatment levels of total DNA are higher in metastatic NSCLC (median 9.2, range 2.2–1020 ng/ml) compared to early-stage (median 3.6, range 0–1280 ng/ml), p < 0.001 by Wilcoxon rank sum test. At least one methylated gene is detectable in pretreatment plasma in 36% of patients with metastatic NSCLC, and 20% of patients with early-stage NSCLC. Conclusions: Methylated genes are rarely found in the pre-treatment plasma of NSCLC patients in this experiment, despite testing a panel of 10 genes. Plasma total DNA levels correlate with NSCLC stage. Correlation of baseline levels of total DNA, and temporal trends during treatment, to overall survival and radiologic response are planned. Supported by R01-CA092315.

[Table: see text]
Randomized phase II cross-over sequential chemotherapy trial of irinotecan/cisplatin (IP) vs. gemcitabine/vinorelbine (GV) in chemo-naïve patients with stage IIIb/IV non-small cell lung cancer (NSCLC)
Authors: Lee J. S. , Lee D. H. , Lee J. J. , Han J. Y. , Park S. H. , Song J. E. , Kim H. Y. , Kim H. T.
Published: March 2020

7134

Background: To compare the efficacy and toxicity of IP vs. non-platinum-based GV in the treatment of advanced NSCLC, we conducted a randomized phase II trial with planned cross-over to the other regimen upon disease progression (PD) after the first-line therapy. Methods: Eligibility required stage IIIb/IV NSCLC, no prior chemotherapy, measurable disease, ECOG PS 0–2, adequate organ functions, and informed consent. After stratification by gender, stage (IIIB or IV) and performance status (PS: 0–1 or 2), eligible pts were randomized to receive either IP (I 65 mg/m2 & P30 mg/m2 on D1 & 8 q 3 weeks) first then GV (G 900 mg/m2 &V25 mg/m2 on D1 & 8 q 3 weeks) upon PD (Arm A) or GV first then IP upon PD (Arm B). Results: Between 12/2003 and 06/2005, 146 pts were enrolled in either Arm A (n = 75) or Arm B (n = 71). There was no difference in gender (male: 77.3% vs. 81.7%), age (median: 58 vs. 60 yrs), PS (PS 2: 10.7% vs. 8.5%), histology (adenocarcinoma: 72.0% vs. 76.6%) and stage (IV: 88.0% vs. 87.3%). IP tended to generate more responses than GN (42.0% vs. 29.0% as first-line, 30.2% vs. 14.3% as second-line), but there was no difference in total response rate by the treatment arm (Arm A: 45.6%, B: 43.5%). During the first-line therapy, IP caused more G3+ anemia (20.0% vs. 7.1%, p = 0.048), G2/3 nausea/vomiting (41.4% vs. 12.9%, p < 0.001), G2 alopecia (35.7% vs. 10.0%, p = 0.001) than GN while pneumonitis was noted only with GN (11.4%). Toxicity profile was similar after the second-line therapy. Both arms resulted in excellent survival outcome with no significant difference between the Arm A and B (median: 16.5 mo vs. 15.1 mo, p = 0.595). Conclusions: Platinum-based IP regimen seemed to be more effective in terms of response rate. Given the overall survival data and the mild toxicity profile of GV regimen, however, either treatment sequence seems to be acceptable for the treatment of advanced metastatic NSCLC. (Supported in part by NCC grants 0210140 and 0510140).

No significant financial relationships to disclose.
Two different schedules of docetaxel plus cisplatin as first-line therapy in advanced non-small cell lung cancer: A preliminary result from a randomized phase II study
Authors: Park S. , Bang S. , Cho E. , Shin D. , Lee J.
Published: March 2020

7135

Background: There has been increasing interest in the use of a weekly administration of docetaxel as a way of reducing its hematologic toxicity. The purpose of this randomized study is to evaluate the toxicity and efficacy of docetaxel and cisplatin combination on two schedules in patients with previously untreated, advanced non-small cell lung cancer (NSCLC). Methods: Consenting patients with stage IIIB/IV or recurrent NSCLC were randomized to receive first-line chemotherapy with cisplatin 75 mg/m2 on day 1, plus either weekly (35 mg/m2 on day 1, 8, 15 of a 4-week cycle) or 3-weekly (75 mg/m2 on day 1 of a 3-week cycle) docetaxel, both for up to 6 cycles. Objectives of this randomized phase II trial were response, toxicity and quality of life (QOL; measured with EORTC QLQ-C30). With a two-stage phase II design, the required number of patients was 39 per each arm. Results: Of 85 patients accrued, 71 patients were evaluable for response and 83 for safety. Baseline characteristics were well-balanced between the two arms: male (56 patients); median age (64 years); adenocarcinoma/squamous cell carcinoma (53/32); stage IIIB/IV/recurrent (12/63/10); ECOG performance status 0/1/2 (20/44/21). Median number of chemotherapy cycles was 3 (1–6) for both arms. Median dose intensities were docetaxel 88%, cisplatin 98% in weekly arm, and docetaxel 97%, cisplatin 98% in 3-weekly arm. The objective responses of weekly and 3-weekly arm were 38% (95% CI, 23–53) and 42% (95% CI, 27–57), respectively. There was significantly more grade 3/4 neutropenia (66% v 12%; P < .001) and febrile neutropenia (40% v 7%; P < .001) on 3-weekly arm but less grade 3/4 diarrhea (2% v 14%; P = .05) and severe skin/nail toxicity (5% v 29%; P = .003). No difference in the rates of treatment delay or dose reduction for both arms; however, 19% of day 15 docetaxel were omitted in weekly arm due to toxicity. Conclusions: Both weekly and 3-weekly docetaxel plus cisplatin appear to be active as first-line chemotherapy for advanced NSCLC, with different safety profiles. Updated results and QOL data, including a prolonged follow-up, will be presented.

No significant financial relationships to disclose.
An economic analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) JBR.10, a randomized trial of adjuvant vinorelbine plus cisplatin versus observation in early stage non-small cell lung cancer (NSCLC)
Authors: Ng R. , Mittmann N. , Florescu M. , Shepherd F. A. , Salvarrey A. , Seymour L. , Winton T. , Evans B. , Leighl N.
Published: March 2020

7155

Background: NCIC CTG JBR.10 is among the landmark trials to establish 3rd generation platinum-based adjuvant chemotherapy as standard of care after complete resection of stages IB-II NSCLC, improving 5-year survival by 15% and median survival by 21 months (p 0.04). The cost-effectiveness of adjuvant chemotherapy from the perspective of Canada’s public health care system was undertaken in a retrospective analysis based on the JBR.10 study population. Methods: Direct medical resource utilization data, from prospective trial data of patients enrolled onto the BR.10 trial at the 5 largest accruing Canadian centres, were identified and collected retrospectively. Direct medical costs included treatment, hospitalization and procedures. Data were captured from the time of randomization until death or study closure (April, 2004). Non-medical direct and indirect costs were not included. Available costs are presented both with and without discounting at 5% per year. Costs (2005 $CAN) were obtained from provincial sources. Average costs per treatment arm (adjuvant chemotherapy vs. observation) were calculated. Basic demographic statistics were calculated. Results: Utilization data were collected from 172 patients (36% of the trial population), 83 randomized to observation and 89 to chemotherapy. Preliminary results are available for the non-drug related costs of direct medical care including hospitalization and procedures. The mean cost of treatment for patients in the observation arm is $15,323 (25–75% IQR $1,933-$17,831), and $18,701 (25–75% IQR $2,873-$18,781) for patients in the adjuvant chemotherapy arm (2005 $CAN). Conclusion: Non-drug related costs are only slightly higher in patients treated with adjuvant chemotherapy in the NCIC BR.10 trial, despite substantially longer survival for this group of patients. These preliminary results will be updated and cost effectiveness data will be available in May 2006.

No significant financial relationships to disclose.
Previously documented mutations in the epidermal growth factor receptor (EGFR) gene in a non-small cell lung cancer (NSCLC) population treated with gefitinib are not associated with response
Authors: Bebb D. G. , Pugh T. , Sutcliffe M. , Barclay L. , Fee J. , O’Connor R. , Vielkind J. , Murray N. , Laskin J. J. , Marra M.
Published: March 2020

7163

Background: Mutations in the tyrosine kinase domain of EGFR that may correlate with clinical features and response of NSCLC to EGFR tyrosine kinase inhibitors have been described. But, varying methodologies have contributed to an uncertain relationship between EGFR mutational status and response. This study sought to characterize EGFR mutations in microdissected tumour tissue from pts with advanced NSCLC treated with gefitinib and correlate their clinical data. Methods: Biopsy material from pts treated with gefitinib for advanced NSCLC at the British Columbia Cancer Agency was analyzed. Malignant cells (cytology specimens) or tissue (paraffin embedded biopsies) was reviewed and tumour cells isolated by laser- capture microdissection or manual scrape. Genomic DNA was extracted and exons coding for the EGFR tyrosine kinase domain (18 - 24) were amplified by PCR and sequenced. When insufficient, the priority was 18, 19, 21, followed by 20, 23, 22, and 24. EGFR mutational analyses were correlated with response to gefitinib and clinical features. Results: 61 pts were identified, 14 (23%) radiological responders (CR, PR): 10 Asian, 10 female, 8 non-smokers, 8 adenocarcinoma, 2 BAC. Of 51 tumour samples available, 39 had adequate tissue for sequencing analysis. EGFR copy number by FISH is pending. Laser-capture microdissection allowed for high quality DNA to be extracted almost exclusively from tumour. Exons 18, 19, 20, 21, 22, 23 and 24 have been sequenced in 37, 34, 30, 33, 12, 10, and 13 patients, respectively. 4 mutations were identified: 2 in 2 non-smoking Asian pts (exon 19; deletion or substitution of L747-T751) and 2 in Caucasians (exon 20 point mutation resulting in a L798F substitution). None of these pts had a response to gefitinib. Conclusions: As with other series, most responders were female, non-smokers of Asian origin. Our results support the relationship between Asian ethnicity and EGFR mutations but question the role of EGFR mutational status in predicting response. Prospective studies will need to focus the detection of additional genetic features using accurate and reproducible techniques before recommendations for selecting populations to be treated can be made.

No significant financial relationships to disclose.
Preliminary analysis of biomarkers in plasma by SELDI to predict the response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC patients
Authors: Zhang L. , Ning L. , Zhang X. , Pan Z. Q. , Wang X. , Xu F. , Guan Z. Z.
Published: March 2020

7189

Background: The identification of NSCLC patients who are most likely to respond to EGFR tyrosine kinase inhibitors (TKIs) have been investigated intensively. Although screenings for EGFR mutation and gene copy number are promising, these tests are not yet widely available. New predictor markers are urgently needed. The objective of this study was to identify proteomic markers in plasma to predict benefits for patients treated with EGFR TKIs. Methods: Proteomic spectra derived from plasma samples from EGFR TKIs-responsive patients and non-responsive patients were generated by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). These proteomic spectra (WCX2 chips, Ciphergen Biosystems, Inc.) were then analyzed by comparing protein profiles in different response groups (PR Vs PD, training set). Another group of patients treaded with EGFR TKIs will be serving as testing set to validate the result of training set. Results: Totally, fifty-four advanced NSCLC patients were included in this study. All patients were treated with single agent of gefitinib or erlotinib. Twenty-nine patients were included in training set of this study. All were suitable for response evaluation. Ten patients (34.5%) were PR, 8 (27.6%) were SD, and 11 (37.9%) were progressive disease (PD). Total six significant protein peaks were significant (m/z 4288, 4595, 9191, 9349, 9397, and 9563) between PR group and PD group (table). Another twenty-five patients were included for testing set. Analyzing of testing set is still going on. Table shows PR and PD patients’ plasma comparison on WCX2 chips. Conclusions: This preliminary “training” set of spectra that uses SELDI-TOF MS technology found that six protein peaks seemed to be very important biomarkers to predict the response to gefitinib. Prospective tests to confirm these proteins and peptides will be present at this meeting. These results are promising for identifying new biomarkers of EGFR TKIs with SELDI.

[Table: see text]

No significant financial relationships to disclose.
Initial safety results of an expanded access program (EAP) of erlotinib in non-small cell lung cancer (NSCLC)
Authors: Reck M. , Perng R. , Groen H. , Riska H. , Pirker R. , Sederholm C. , Caspar C. , Boyer M. , Berzinec P. , Allan S.
Published: March 2020

7190

Background: Erlotinib is an orally active and selective inhibitor of HER1/EGFR tyrosine kinase. In the BR.21 phase III trial, erlotinib significantly prolonged survival, delayed symptom progression, and improved quality of life in NSCLC patients (pts) (Shepherd et al, NEJM, 2005;353:123). The EAP is an open label, non-randomized, multicentre phase IV trial. Methods: Eligibility criteria included stage III/IV NSCLC pts who failed or were unsuitable for chemotherapy. Pts were given oral erlotinib, 150 mg/d, for as long as treatment provided clinical benefit without unacceptable toxicity. Pts were monitored monthly. Results: In Dec 05, data were available for 1,140 pts from 25 countries, median age 64 y (range 25–91). Key base-line characteristics (% pts) were: males 58%; Caucasian/Oriental 82/15; non-smoker/former or current-smoker 26/73. The % pts with ECOG PS 0/1/2/3 were 20/52/20/8. Most pts (55%) had adenocarcinoma. The % pts receiving erlotinib as 1st/2nd/3rd-line treatment were 12/47/40. As expected, rash was a common adverse event (AE: any grade [gr]: 65%; gr 3/4: 9%). Full safety data were available for 581 pts. Unexpected erlotinib-related AEs were only seen in <2% pts. Erlotinib-related AEs leading to treatment discontinuation were GI disorders in 21 pts (12 pts had gr 3/4 AEs) and skin disorders in 14 pts (6 pts had gr 3/4 rash). Only 10% of pts had dose reductions, mainly due to rash (66%; gr 3 in 8 pts) and diarrhea (17%; gr 3 in 2 pts). The median daily dose of erlotinib was 150mg. Serious erlotinib-related AEs were GI disorders (19 AEs; 11 gr 3/4), mainly diarrhea (8 AEs, 5 were gr 3). Pt accrual and analyses of response, survival data and assessment of various predictive biomarkers are ongoing. Response and survival data will be presented. Conclusions: These interim safety results of erlotinib in the real-life clinical setting in a large number of unselected pts with advanced NSCLC confirm the good tolerability observed in clinical trials. To date, the trial demonstrates that erlotinib is well tolerated, thus, allowing full dose administration to most pts.

[Table: see text]
Prognostic value of blood levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in advanced non-small cell lung cancer (NSCLC) patients
Authors: Alberola V. , Camps C. , Sirera R. , Llobat L. , Blasco A. , Safont M. J. , Garde J. , Taron M. , Sanchez J. J. , Rosell R.
Published: March 2020

7196

Background: VEGF and bFGF are among the most important angiogenic factors. We have explored these angiogenesis mediators in plasma and its prognostic significance in advanced NSCLC. Methods: Were enrolled 451 patients with advanced NSCLC, stages IIIB and IV and treated with cisplatin and docetaxel. Blood was collected before chemotherapy. Plasma VEGF and bFGF levels were assessed by commercial ELISA (sensitivity 5 pg/ml). In parallel plasma from 32 age and gender-matched controls was used. Results: Median age was 61 years (35–82) and 84% were males. 99% had performance status 0–1. 84% were in stage IV and 16% in stage IIIB. The histological subtypes were: 32% squamous cell carcinoma, 50% adenocarcinoma, 14% anaplastic large cell, and 4% undifferentiated. 41% of the patients received second line chemotherapy. 1% achieved complete response (CR), 36% partial response (PR), 35% had stable disease (SD) and 28% progressive disease (PD). Patient’s median plasma levels of VEGF (20 pg/ml, [6–203]) differ significantly (p = 0.04) from controls (14 pg/ml, [7–53]), but in contrast bFGF levels were not different, 14 pg/ml [5–960] vs 10 pg/ml [6–278] respectively. There were not differences in patients according to histology, site of metastasis and ECOG; however we could observe a tendency with stage for both factors: bFGF 9 pg/ml [5–24] in stage IIIB vs 15 pg/ml [6–960], p = 0.071 and VEGF 17 pg/ml [6–145] in IIIB vs 21 pg/ml [6–203] in IV, p = 0.086. It could not be observed any differences in response to therapy for both angiogenic factors; CR+PR patients presented median VEGF of 18 pg/ml [6–71] and bFGF 11 pg/ml [6–960] vs 20 pg/ml of VEGF [6–203] and 15 pg/ml of bFGF [5–395] in the SD+PD group. In the multivariate analysis we could not find that VEGF and bFGF plasma levels were predictors for time to progression (TTP) and overall survival (OS). Conclusions: VEGF but not bFGF levels in patients are significantly higher in patients than in controls. In our cohort of patients with advanced NSCLC we have not found any relationship between serum VEGF and bFGF levels with stage, histology, response, site of metastasis, TTP and OS.

No significant financial relationships to disclose.
The influence of fluticasone inhalation on premalignant lesions in the bronchial epithelium of a high risk population: A double blind placebo-controlled randomised phase II study
Authors: Van Den Berg R. M. , Van Tinteren H. , Van Zandwijk N. , Sutedja T. G. , Baas P. , Visser C. , Grünberg K. , Mooi W. J. , Postmus P. E. , Smit E. F.
Published: March 2020

7200

Background: Bronchial epithelium exposed to cigarette smoke undergoes a series of histological changes that may ultimately lead to invasive cancer. In rats exposed to cigarette smoke inhaled corticosteroids reduce the number of lung tumors. We studied the effect of fluticasone on premalignant lesions in volunteers with a smoking history of ≥10 pack-years and patients cured of head and neck cancer or lung cancer. Methods: Participants were screened for premalignant lesions by bronchoscopy. At least 3 standard locations and suspicious lesions (if present) were biopsied. Use of systemic corticosteroids in the past 12 months or serious comorbidity precluded participation. Biopsies were classifed using WHO criteria. In case of a metaplasia index > 15%, participants were randomised to receive a powder inhalation device containing either fluticasone 500 μg or a placebo. Compliance and side effects were monitored monthly. After 6 months, biopsies were taken from the same locations as previously sampled. Efficacy of treatment was assessed by reversal of metaplasia/dysplasia; secondary end-points were reversal of increased p53 immunoreactivity and hTERT expression. CT-scans were obtained at baseline and after intervention. Results: From February 2002 until October 2004, 201 subjects were screened. Two were excluded because of lung cancer detected during screening. Of the 108 volunteers included, 74 were male, mean age was 53 years (35–71), mean number of pack-years 48 (18–99), mean metaplasia index 48%, 32% had some degree of dysplasia at baseline. There were no significant differences between these characteristics in the intervention and placebo groups. Outcome: there was no significant difference with respect to reversal of metaplasia/dysplasia. Additional molecular studies will be performed to assess possible changes at a molecular level. Results will be presented at the ASCO annual meeting 2006. Conclusions: Fluticasone does not alter the natural course of premalignant lesions in the central airways when standard histological criteria are applied.

No significant financial relationships to disclose.
Non-small cell lung cancer in the new millennium: The effect of FDG-PET on stage distribution
Authors: Goodgame B. , Morgensztern D. , Grove L. , Govindan R.
Published: March 2020

7205

Background: The stage-wise distribution of NSCLC at the time of initial presentation following the widespread use of positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose (FDG-PET) has not been characterized. Frequently quoted estimates of stage distribution are based predominantly on data prior to 2000. FDG-PET was approved in 1998 and has been widely utilized since 2000. We describe here the stage-wise distribution of NSCLC at the time of initial presentation over the past 15 years. Methods: Patients were identified and clinical data were obtained through our institutional tumor registry system. All patients diagnosed with NSCLC between January 1, 1990 and December 31, 2004 were included. All statistical comparisons were performed by X2 tests. Results: Of 6311 patients identified, 3926 were diagnosed prior to January 1, 2000 and 2385 thereafter. Pathological (surgical) staging was completed in 37% of patients. Given the widespread availability of FDG-PET since 2000, we grouped the analysis by date of diagnosis, before or after January 1, 2000. Before 2000, stage proportions were: I-29%; II-9%; III-31%; IV-30%; and unknown-1%. After January 1, 2000, stage proportions were: I-26%; II-9%; III-26%; IV-37%; and unknown-2%. The percentage of stage IV disease peaked at 40% in 2004. The difference in rates of stage IV disease before and after January 1, 2000 was highly significant (p < 0.0001). Conclusions: We have documented a significant change in the distribution of stages of non-small cell lung cancer in the last five years. The increase in stage IV disease and decreases in stages I & III disease coincide with the widespread adoption of FDG-PET, suggesting an earlier diagnosis of metastatic disease.

[Table: see text]
Pharmacokinetic of inhaled low molecular weight heparin
Authors: Scheuch G. , Haeussermann S. , Brand P. , Herpich C. , Meyer T.
Published: March 2020

7209

Background: Treatment with Heparin and low molecular weight (LMW) Heparin is frequently used in oncology settings. Usually, these drugs are delivered by subcutaneous (s.c.) administration. Since 1963, the clinical relevance of inhalation of unfractionated as well as LMW-Heparin has been investigated in various studies with over 500 subjects. In this study, a single inhalation of the LMW-Heparin Certoparin (Mono-Embolex, Novartis) was investigated in 10 healthy subjects. The goal was to assess the pharmacokinetic behavior. Inhalations were performed using a novel inhalation system, which allows an accurate dosing in the lungs by controlling patient’s breathing pattern (AKITA). Lung deposition is about 85% of the emitted dose. Methods: 10 non-smoking healthy subjects participated in this study. Inhalation of 9000 IU of LMW-Heparin was compared to 3000 IU s.c. administration to achieve factor-Xa-activity in the plasma of 0.2 to 0.3 U/ml. Intravenous blood samples were taken 0.25, 0.5, 1, 2, 4, 6, 24, 48 hrs after administration. Factor-Xa-activity in plasma was assessed using the Berichrom assay (Dade Behring, Marburg, Germany). Results: Inhalation of LMW-Heparin was well tolerated and did not result in any side effects or changes in lung function. The maximum anti-Xa-activity in the plasma was 0.3 U/ml for the s.c. administration of Certoparin and 0.32 U/ml after inhalation of 9000 IU. However, pharmacokinetics was considerably different. Inhaled LMW-Heparin resulted in a prolonged anti-Xa-activity. After 6 (24) hours, the anti-Xa-activity after s.c. administration was down at 0.16 U/ml (0.10) and after inhalation at 0.30 (0.18) U/ml. Even after 48 hrs, the anti-Xa-activity after inhalation was significantly higher than the baseline value. Comparing area under the curve (AUC), bioavailability for the inhalation was 9.4 U · h/ml ± 14% compared to 5.7 U · h/ml ± 27% after s.c. administration. Conclusions: These results suggest that with controlled inhalation, this administration route is an attractive alternative to s.c. administration, with the result of longer bioavailability and less variability. A once daily administration is possible. Inhalation therapy with these kind of systems might also be useful with different anticancer agents, which cannot be administered orally.

[Table: see text]
Clinical characterization of node-negative non-small cell lung cancer: Results of a prospective investigation
Authors: Yoshino I. , Ichinose Y. , Nagashima A. , Takeo S. , Motohiro A. , Yano T. , Ishida T. , Yamazaki K. , Sugio K. , Yasumoto K. , Maehara Y.
Published: March 2020

7218

Background: 20 to 30% of clinical stage IA non-small cell lung cancer cases were revealed to be node-positive by pathologic examination of resected specimens. In this prospective study, the clinical features of a truly node-negative population were prospectively investigated to search for candidates of a lesser resection or of a stereotactic radiotherapy. Methods: The clinical data and radiographic features of high-resolution computed tomography (HR-CT) were registered before operation in 169 clinical stage IA lung cancer patients, who were scheduled to undergo a standard lobectomy and systemic mediastinal node dissection. The nodal metastasis was pathologically defined, while the clinical factors associated with the presence of the nodal metastasis were evaluated. Results: In 130 evaluable cases, 16 of 114 adenocarcinoma and 3 of 16 other NSCLC were node-positive. Among all parameters, positivity of the serum carcinoembryonic antigen (CEA) was the only factor significantly associated with nodal metastasis (p = 0.0074). When we focused on adenocarcinomas, the serum CEA, retraction sign and intratumoral air-space on HR-CT were suggested to be predictive factors for lymph node metastasis with hazard ratios of 12.44 (p = 0.0003), 6.53 (p = 0.0533) and 0.17 (0.0073), respectively. In combination with the radiologic features of HR-CT imaging, none of 18 CEA-negative/retraction-negative cases and 3 of 65 CEA-negative/air-space positive cases showed nodal metastasis, in which the incidence of nodal metastasis was significantly lower than the counterparts with respective p-values of 0.0015 and 0.037. The tumor size and the proportion of ground glass attenuation were not associated with the incidence of nodal metastasis. Conclusions: The serum CEA and HR-CT features thus allowed us to identify node-negative lung adenocarcinomas. In clinical stage IA adenocarcinoma cases, a standard operation should be considered when positive serum CEA and/or retraction sign on HRCT is noticed.

No significant financial relationships to disclose.
Evaluation of radiologic diagnosis in peripheral clinical IA lung cancers—A prospective study for radiological diagnosis of peripheral early lung cancer (JCOG 0201)
Authors: Suzuki K. , Koike T. , Shibata T. , Kusumoto M. , Asamura H. , Nagai K. , Tada H. , Mitsudomi T. , Tsuboi M. , Kato H.
Published: March 2020

7220

Background: The spread of computed tomography (CT) screening for lung cancer (LC) leads to the increased detection of small sized LC. Performance and accuracy of radiological diagnosis had not been evaluated and indication of limited surgery for CT detected LC remains unknown. Methods: Between Dec/2002 and May/2004, a prospective study was performed. Patients (pts) having peripheral lung adenocarcinoma (AD) of T1N0M0 were eligible. Radiologic findings of LC were evaluated as to ground-glass opacity (GGO) with thin-section CT (TSCT). A radiological non-invasive cancer (NIC) was defined as a tumor having consolidation less than half of the maximum tumor dimension. A pathological NIC, which is future candidate for limited surgery, was defined as a tumor with no lymph node mets, lymphatic, nor vascular invasion. A validity of radiological diagnosis by above criteria was investigated. Primary endpoint is specificity as the proportion of pts with radiologically diagnosed invasive LC in pts with pathologically diagnosed invasive LC. Planned sample size was 450 with precision-base. We expected that lower limit of 95% CI of specificity is over 97%. Results: Totally 811 pts were enrolled onto the study at 31 institutions, including 357 men. Age ranged 27 to 75 (median 61). Primary endpoint was evaluated on central-reviewed 545 AD resected by lobectomy. Specificity and sensitivity for the diagnosis of pathological NIC were 96.4% (161/167 95% CI 92.3% to 98.7%) and 30.4% (115/378 95% CI 25.8% to 35.3%), respectively. As to relationship between radiologic NIC and pathological nodal involvement, specificity and sensitivity for the diagnosis were 98.3% (59/60 95% CI 91.1% to 100%) and 24.7% (120/485 95% CI 21.0% to 28.8%), respectively. Conclusions: Our pre-determined criterion for the specificity was not confirmed, and candidates for limited surgical resection can not be selected based on our criteria. However, radiological diagnosis of node-negative LC with TSCT was well coincide, and the criterion might be used for selecting node negative peripheral LC. A phase II study of limited surgical resection for peripheral LC 2.0 cm or less in size is now planned based on the results of exploratory analysis of this study.

No significant financial relationships to disclose.