bluuebunny/crossref_metadata_2025 huggingface dataset:
SWOG S0509: A phase II study of novel oral antiangiogenic agent AZD2171 (NSC-732208) in malignant pleural mesothelioma
Authors: Garland L. L. , Chansky K. , Wozniak A. , Tsao A. , Gadgeel S. , Vershraegen C. , Da Silva M. , Redman M. , Gandara D.
Published: August 2020

7511

Background: Preclinical studies suggest the autocrine growth loop involving VEGF and its receptors is a relevant therapeutic target for malignant pleural mesothelioma (MPM). We evaluated AZD2171, a potent tyrosine kinase inhibitor (TKI) of VEGFR1/2 in MPM. Methods: MPM patients (pts) after platinum-based chemotherapy, with PS 0–2, measurable disease and adequate organ function were treated with oral daily dosing of AZD2171 45 mg. Study endpoints were response rate, progression free survival (PFS), overall survival (OS), frequency/severity of toxicities, and correlation of clinical outcomes with tumor and serum biomarkers. Results: 54 pts were registered between November 2005 and April 2008; 45 pts are eligible for response and 46 for toxicity analysis. Median age was 66.8 yrs; M/F: 37/9. Tumor response by RECIST was seen in 4/45 (9%) of pts; of these responders, 2 pts with bulky disease had 56% and 91% tumor shrinkage, respectively. 15/45 (33%) had SD; 21/45 (47%) had PD; 1/45 (2%) had early death. Thirty-five pts have died. For 46 pts, median PFS is estimated at 3 months; median OS is estimated at 10 months. For 46 pts, frequent grade 1–3 toxicities included anorexia (30%), diarrhea (63%), fatigue (60%), hypertension (67%), and proteinuria (28%). There were 8 grade 4 events: Cognitive disturbance, colitis, confusion, ileal perforation, hypertension, hyponatremia, hypotension, and renal failure. Conclusions: AZD2171 has antitumor activity in MPM, with a DCR (CR/PR/SD) of 42% by RECIST, which has limitations in measuring response in pleural tumors. Notably, 2 pt tumors were exquisitely sensitive to this drug. Toxicities were consistent with those of the anti-angiogenic TKI class of drugs. Studies correlating outcome measures with tumor hypoxia- and angiogenesis-related gene expression and circulating endothelial cells are underway. Based on these data, we are proceeding in SWOG with a study of pemetrexed/cisplatin ± AZD2171 (S0905). This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA14028, CA46441, CA105409, CA13612, CA45808, CA20319, CA86780, CA35090, CA67663, CA46282, CA42777, CA76448, CA04919, CA35176, CA63848, CA27057, CA16385.

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Outcome of surgical resection for pathologic Nx and N0 non-small cell lung cancer (NSCLC)
Authors: Osarogiagbon R. U. , Allen J. W. , Farooq A. , Ninan M. , Ratliff T. W.
Published: August 2020

7513

Background: Metastasis to lymph nodes (LN) connotes poor prognosis in NSCLC. Sufficient LN must be examined to accurately determine LN negativity. Patients with no LN examined (pNx) may be incompletely staged and erroneously assigned to a low risk group. To evaluate this possibility, we compared the survival of patients with node negative disease and at least 1 LN examined (pN0) to those with pNx. Methods: Retrospective analysis of all resections for NSCLC from January 1, 2004 to December 31, 2007 identified through a search of pathology databases at hospitals in the Memphis Metropolitan Area. Benign and metastatic disease, pre-operative chemo/radio therapy, bronchoalveolar cell, small cell lung, carcinoid tumors and repeat lung resection were excluded. Date of death was obtained from a National Death Index search. Variables were compared by chi-squared test, survival estimates calculated by Kaplan Meier analysis, survival estimates compared by log-rank test. Results: 746 of 809 resections met inclusion criteria. 86 (11.5%) were pNx and 510 (68.4%) pN0. Demographic and histologic characteristics were similar ( Table 1 ). 55.8% of the pNx group had sublobar resection, compared to 5.7% of pN0 (p<0.0001). 179 pN0 patients (35.1%) had only hilar-intrapulmonary LN (stations 10–14), median 3 (range 1–18) examined. 46 patients (9.02%) had only mediastinal LN (stations 1–9), median 2 (1–13); 281 patients (55.1%) had both stations 10–14 and 1–9, median 7 (2–45). 85% of pN0 patients had <10 LNs examined. 3-year survival estimate for the T1NxM0 vs T1N0M0 patients was 69% vs 70% (p= 0.14); for T2NxM0 vs T2N0M0 it was 25% vs 65% (p <0.01). Conclusions: A high percentage of patients (11.5%) undergoing surgical resection for NSCLC had pNx. These patients were more likely to have sublobar resections. Most (85%) patients with pN0 had <10 nodes examined and a large proportion (35.1%) had no mediastinal LNs, raising the possibility of understaging. Patients with pT2NxM0 did significantly worse than those with pT2N0M0.

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Impact of positive pleural lavage cytology on survival in patients undergoing lung resection for non-small cell lung cancer: An international multicenter study
Authors: Lim E. , Clough R. , Goldstraw P.
Published: August 2020

7519

Background: Pleural lavage cytology (PLC) is the instillation of saline into the chest during surgery for non-small cell lung cancer (NSCLC). The aims of this study were to collate multi-institutional individual patient data to determine independence as a prognostic marker and characterise impact of positive results on stage adjusted survival. Methods: We identified 31 publications from 22 centers/research groups that performed pleural lavage cytology during surgery for NSCLC and invited submission of individual patient data. Actuarial survival was calculated using Kaplan Meier methods and comparisons were performed using the log-rank test. Cox proportional hazards regression was utilised to ascertain the covariates associated with survival. Results: By 1 January 2008, submissions were received internationally from 11 centers with individual data from 8763 patients. In total, 511 (5.8%) patients had a positive pleural lavage cytology result, and this was shown to be an independent predictor of adverse survival associated with a hazard ratio of 1.465 (1.290 - 1.665; P<0.001). On statistical modelling, the best adjustment for patients with a positive PLC result was a single increase in the T category assigned to the case, up to a maximum of T4. Correction for differences in survival were obtained in stage IB (P=0.315) and IIB (P=0.453), with a degree of correction in stage IIIA (P=0.07). Conclusions: Pleural lavage cytology should be considered in all patients with NSCLC suitable for resection. A positive result is an independent predictor of adverse survival and the impact on survival suggests that it may be appropriate to upstage patients by one T category.

No significant financial relationships to disclose.
Impact on disease-free survival of adjuvant erlotinib or gefitinib in patients with resected lung adenocarcinomas that harbor epidermal growth factor receptor (EGFR) mutations
Authors: Janjigian Y. Y. , Park B. J. , Kris M. G. , Miller V. A. , Riely G. J. , Zheng J. , Dycoco J. P. , Shen R. , Azzoli C. G.
Published: August 2020

7523

Background: Patients with stage IV adenocarcinoma whose tumors harbor EGFR mutations have high rates of response (∼ 75%) and prolonged progression free survival after EGFR tyrosine kinase inhibitor (TKI) treatment. Adjuvant cisplatin-based chemotherapy improves disease free survival (DFS) and overall survival (OS) in patients with resected stages IB-IIIA NSCLC. To see if adjuvant treatment with EGFR TKI (gefitinib or erlotinib) improves DFS in patients with EGFR mutation NSCLC, we conducted a retrospective review of patients with resected lung adenocarcinoma harboring EGFR mutations, some of whom received EGFR TKIs postoperatively. Methods: With Institutional Review Board approval, clinical information was obtained on all patients with stage I-III lung adenocarcinoma harboring EGFR exon 19 or 21 mutations that underwent resection at MSKCC between May 2002 and August 2008. Age, gender, type of surgery, histology, EGFR mutation status (exon 19 deletions and exon 21 L858R), stage, perioperative therapy and survival were recorded. Kaplan-Meier analysis and Cox regression analysis were performed. Results: We studied 150 patients (112 women, 38 men) with completely resected stage I-III lung adenocarcinoma whose resection specimens contained EGFR activating mutations in exon 19 or 21. Median age was 69. Forty two patients (28%) received cytotoxic chemotherapy. Forty eight (32%) received either erlotinib (n=26) or gefitinib (n=22) postoperatively. The median time on TKI was 16 months. The median DFS was 43 months in the group that received a TKI vs. 31 months for those that did not. After controlling for stage, individuals who received adjuvant gefitinib or erlotinib had a better DFS (HR=0.38, 95%CI: 0.16–0.90) than the non-TKI group (p=0.03). The median overall survival has not been reached. Conclusions: These data indicate that the adjuvant use of either gefitinib or erlotinib improves DFS in patients with completely resected stage I -III lung adenocarcinomas with mutations in EGFR exons 19 and 21. These data justify a randomized trial in similar patients.

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Analysis of IGF1R gene copy number by silver in situ hybridization (SISH) in non-small cell lung cancer (NSCLC)
Authors: Wynes M. W. , Singh S. , Dziadziuszko R. , Dziadziuszko K. , Jaskiewicz K. , Jassem J. , Aumen N. , Hirsch F. R.
Published: August 2020

7525

Background: IGF1R is a potential biomarker for predicting outcome of NSCLC patients (pts) treated with therapeutics targeting the IGF1R signaling pathway. SISH can be expeditiously analyzed on a bright field microscope given that the morphology of the tissue is observed concurrent to the scoring of discrete gene signals. Methods: An experimental SISH probe designed by Ventana Medical Systems (Tucson, AZ) was used to evaluate IGF1R gene copy number on a tissue microarray containing triplicate samples from 189 pts surgically treated for NSCLC (median follow-up 4 years and 5-year survival probability of 40%). Valid results, at least one core with sufficient tumor content for assessment, were obtained for 166 patients. There were 128 males; 93 squamous cell carcinomas (SCC), 47 adenocarcinomas, 5 large cell carcinomas and 21 other histologies. The pathological stages were I: 68, II: 37 and III/IV: 60. The mean number of IGF1R gene copies/nuclei/core was determined by a board certified pathologist counting 50 nuclei in each core. The mean number of IGF1R gene copies/nuclei/patient was determined by using, within the triplicates, the core with the highest gene copy number/nuclei. Results: The mean number of IGF1R gene copies/nuclei per patient was 2.26 (range: 1.12 - 7.56; standard deviation 0.81). The median copy number was 2.11. The pts were divided into two groups, those with 2.1 genes/nuclei or less and those with greater than 2.1 genes/nuclei. There was no statistical difference related to gender (p=0.422) or between pathological stages, (p=0.221). However, there was a highly significant difference between the two categories when considering histological pattern. Among patients with SCC, 66.3% had high copy number compared to 33.7 % in non-SCC histologies (p=0.008). Analysis of overall survival comparing pts with low vs. high IGF1R gene copy number revealed no statistical difference in the median survival: 1.5 yrs (95% CI 0–3.7 yrs) vs. 3.3 yrs (2.0–4.5 yrs) or the 3-year survival: 46% (35–57%) vs. 52% (41–63%). Conclusions: IGF1R gene copy number detected by SISH is higher in SCC than in other histologies of NSCLC, but does not associate with gender, pathological stage or survival. IGF1R SISH should be further explored as a predictive biomarker for IGF1R therapeutics.

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A phase II study of accelerated high-dose thoracic radiation therapy (AHTRT) with concurrent chemotherapy for limited small cell lung cancer: RTOG 0239
Authors: Komaki R. , Paulus R. , Ettinger D. S. , Videtic G. M. , Bradley J. D. , Glisson B. S. , Choy H.
Published: August 2020

7527

Background: Inter-group(IG) study 0096 showed that hyperfractionated and accelerated radiotherapy (HFXART) and concurrent etoposide/cisplatin(EP) improved 5-yr survival (26 %) for patients (pts) with limited small cell lung cancer (LSCLC) compared to daily treatment (TRT) with EP (16%), (p=0.04), HFXART/ EP still had high local failure (LF 40 %) and acute severe esophagitis (ASE) rate (27%). Radiation Therapy Oncology Group (RTOG) 0239 was developed to improve local control (LC) and overall survival (OS) without increasing ASE.Methods: Eligibility included limited stage SCLC, age ≥ 18; P.S. 0–1, with adequate hematologic, hepatic, and renal function. RT was given to large field to 28.8 Gy: 1.8 Gy/ fraction (Fx), 5 days (d) / wk for 16 Fx followed by BID with AP/PA fields in AM @ 1.8 Gy /Fx; boost with 2nd treatment in PM @ 1.8 Gy/Fx on d: 23–26; then off-cord boost, 1.8 Gy, BID, x last 5 days for a total dose of 61.2 Gy in 5 wks. EP was started on day 1 of TRT with P, 60 mg/m2 i.v; E, 120 mg/m2 i.v.; E, 240 mg/m2 p.o. d 2 and 3 or E 120 mg/m2 i.v. / d on d 2 or 3. Repeat cycle every 3 wks x 2 cycles with RT, followed by adjuvant EP alone x 2 cycles. CR pts were asked to participate in the prophylactic cranial irradiation (PCI) study RTOG 0212. RTOG 0239 was designed to detect an improvement in the 2-year survival rate from 47% to 60% with less than 30% of ASE.Results: RTOG 0239 accrued 72 pts (71 eligible) from June 20, 2003 to May 23, 2006. The median follow-up time is 19.0 months for all pts, and 30.4 months for pts still alive. The median age was 63, 52% female, 58% Zubrod PS 0. The 2 -year survival rate was 37 % [95% CI: 25.6, 47.7]. 13 pts (18 %) experienced severe esophagitis. 2 treatment related deaths (2.8%) were reported. Response rates 2 months post RX showed CR 41%, PR 39%, SD 10% and PD 6%. Locoregional control rate at two years was 80%. RT compliance was 95 %.Conclusions: RTOG 0239, AHTRT/EP for LSCLC resulted in 37% 2-year OS, 80% 2 year LC and 18% ASE. Compliance with treatment was high and treatment-related death rate was similar to other chemoradiation regimens. Although 2-year OS did not achieve 60%, excellent LC and low ASE were achieved by RTOG 0239 which became one of 3 arms in an ongoing randomized trial of LSCLC RTOG0538/CALGB30610.

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Results of the IFCT 0002 phase III study comparing a preoperative and a perioperative chemotherapy (CT) with two different CT regimens in resectable non-small cell lung cancer (NSCLC)
Authors: Westeel V. , Milleron B. , Quoix E. , Breton J. L. , Braun D. , Puyraveau M. , Bigay-Game L. , Pujol J. L. , Morin F. , Depierre A.
Published: August 2020

7530

Background: Association of surgery and CT is standard for early-stage NSCLC. Meta-analyses showed comparable efficacy of adjuvant and neoadjuvant CT. The primary objective was to compare survival between two different CT strategies: all before surgery (PRE) versus perioperative (PERI). Methods: Between 2001 and 2005, 528 patients with a stage IA-II resectable NSCLC were randomized to 4 parallel arms (A: 2 GP + 2 GP in responders, then surgery, B:2 GP - surgery + 2 GP in responders, C: 2 TC + 2 TC in responders then surgery, D: 2 TC - surgery + 2 TC in responders; GP: Gemcitabine 1250 mg/m2/d1, 8 and cisplatin 75 mg/m2/d1 q3 wk; TC: Paclitaxel 200 mg/m2/d1 and carboplatin AUC 6, q3 wk). Results: 501 patients were operated on, 96.2% in the preoperative CT arms (PRE: A+C) and 95.8% in the perioperative CT arms (PERI: B+D). Ninety- day postoperative mortality was 4.9% and 4.2%, respectively. Pathological complete response was not significantly influenced by the number of preoperative cycles (PRE:8.6%, PERI:6.4%). In an intent-to-treat analysis, 3-yr survival was 67.8% and 68.6%, respectively (p=0.96). In responders, despite a dramatic difference in CT compliance (90.4% and 75.2% having received the 4 cycles, respectively, p=0.001), 3-yr survival was 75.1% and 79.5%, respectively (p=0.82). Survival did not differ with the CT regimen (GP versus TC, p=0.84). Three-yr survival increased from 68.1% in the PRE arms to 77.2% in the PERI arms in squamous cell carcinomas (SCC), and decreased from 67.7% to 61.6% in non SCC, respectively (Cox model interaction, p=0.35). Three-yr survival was 74.6% in the GP arms and 70.7% in the TC arms, in SCC, and was 64.2% and 65.4%, in non SCC, respectively (interaction, p=0.51). There was no interaction between CT strategy and stage. In stage II patients, 3-yr survival was 59.1% but 76.5% in responders, comparable to that of all stage I patients (72.9%). Conclusions: Despite an increased compliance of the all preoperative chemotherapy strategy, no difference was observed between the PRE and PERI arms. There might be an advantage for perioperative CT and for gemcitabine-based in SCC and for preoperative CT and for taxane-based in non SCC.

No significant financial relationships to disclose.
Cetuximab in combination with concurrent chemoradiotherapy (CRT) in locally advanced non-small cell lung carcinoma (NSCLC): A feasibility study
Authors: van den Heuvel M. M. , Belderbos J. , Dalesio O. , van der Pol M. , Uitterhoeve L. , van de Vaart P. , Verheij M. , van Zandwijk N.
Published: August 2020

7540

Background: Despite modest benefits from CRT regimens in patients with locally advanced NSCLC, more efficacious treatment options are needed. Cetuximab, a monoclonal antibody that selectively binds to the epidermal growth factor receptor, has demonstrated activity in patients with metastatic NSCLC. This trial was initiated to assess the feasibility of combining cetuximab with concurrent CRT. Methods: Patients with non-operable locally advanced NSCLC received cetuximab (400 mg/m2 on day 1, 250 mg/m2 q1w from weeks 2–6) in combination with cisplatin (6 mg/m2 q1d from weeks 2–6), and RT (66 Gy in 24 fractions from weeks 2–6). Results: Between April and July 2008, 12 consecutive, eligible patients entered the study. The mean age was 61 years (range: 43–77) and 50% were male. Baseline NSCLC staging was: IIb (1 patient), IIIa (5 patients), and IIIb (6 patients). Treatment was generally well tolerated. Acne-like rash and radiation esophagitis were the most common side effects (grade ≤3 according to CTCAE v 3.0) (see table). No unexpected toxicities were observed. Early-response monitoring using PET-CT scans was performed 4 weeks after the last fraction of RT in 10/12 patients. A metabolic response was seen in 50% (complete: 3 patients; partial: 2 patients) of patients. One patient showed progressive disease. Conclusions: Cetuximab added to CRT in patients with NSCLC was generally well tolerated and produced promising early clinical responses. A randomized phase II study comparing CRT with CRT and cetuximab is ongoing.

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Radiotherapy (RT) dose escalation study with concurrent cisplatin and S-1 in patients with inoperable stage III non-small cell lung cancer (NSCLC)
Authors: Harada H. , Nishio M. , Murakami H. , Ohyanagi F. , Kozuka T. , Ishikura S. , Horiike A. , Morota M. , Nishimura T. , Yamamoto N.
Published: August 2020

7542

Background: Standard treatment for inoperable stage III NSCLC is concurrent chemoradiotherapy using 3-D conformal RT to a total dose of 60 Gy, but the outcome is still dismal with median survival time (MST) of 16 months and 5-year survival of 15%. We conducted a phase II trial using cisplatin, S-1 and concurrent RT of 60 Gy (J Clin Oncol 2008;26:a7556). MST (33months) was encouraging, however, local failure rate with this trial remained still high. The purpose of this study was to establish the recommended dose (RD) of RT with concurrent cisplatin and S-1. Methods: The eligibility criteria were: histologically or cytologically proven NSCLC, 20–75 years old, performance status 0–1, without any prior chemotherapy or RT. Patients were treated with cisplatin (60 mg/m2 on day 1) and S-1 (orally at 40 mg/m2/dose b.i.d., on days 1–14) repeated every 4 weeks for 4 cycles and RT was started on day 1. Radiation dose was escalated from 66 Gy in 33 fractions (Arm 1) to 70 Gy in 35 fractions (Arm 2), then 74 Gy in 37 fractions (Arm 3). The dose was to be escalated if DLTs were observed in 2 or less patients. The target volume of RT included primary tumor and metastatic node only and elective nodal irradiation was not performed. Dose constraints to the organs at risk were: the lung, V20 < 30%; the esophagus, mean dose < 34 Gy and V55 < 30%; the spinal cord, max dose < 50 Gy. Results: Six patients in each arm were enrolled. Two patients in Arm 1 experienced DLTs: one patient developed grade 3 febrile neutropenia, grade 3 mucositis in oral cavity and grade 3 diarrhea and one patient developed grade 3 febrile neutropenia. One patient in Arm 3 has not been completed evaluation yet. Otherwise no DLT was observed. Conclusions: The radiation dose of 74 Gy in 37 fractions with concurrent cisplatin and S-1 seemed to be tolerable and was judged to be the RD. This study is still open to accrue another six patients to confirm the safety of the RD.

No significant financial relationships to disclose.
Survival of patients (pts) treated with high-dose radiotherapy (RT) and concurrent chemotherapy for unresectable non-small cell lung cancer (NSCLC)
Authors: Schild S. , Graham D. , Hillman S. , Vora S. , Yolanda G. , Molina J. , Shahidi H. , Kugler J. , Adjei A.
Published: August 2020

7544

Background: NCCTG N0028 was a trial that determined the MTD of RT that could be given with carboplatin & paclitaxel was 74 Gy/34 fractions. This secondary analysis was performed to determine the survival of pts treated on this trial. Methods: Eligible pts had medically or surgically unresectable NSCLC, PS=0–1, weight loss <10% in the prior 3 months(mo), no prior therapy, adequate laboratory & pulmonary functions. Included were 25 pts with clinical stages I (4pts), II (1 pt), IIIa (12 pts), & IIIb (8 pts). Treatment included: weekly I.V. paclitaxel (50mg/m2) & carboplatin (AUC=2) during RT. The RT included 2 Gy daily to an initial dose of 70 Gy. The total dose was increased in 4 Gy increments until the MTD was determined. RT was delivered with 3-D treatment planning but no elective nodal RT. Three pts received 70 Gy, 18 pts received 74 Gy, & 4 pts received 78Gy. Results: Pts were followed until death or from 10–67 mo (median: 28mo) in those alive at last evaluation. The median survival (MS) of the entire cohort was 42mo. The 5 stages I-II pts had a MS of 53 mo & the 20 stage III pts had MS of 42mo. Conclusions: Standard dose RT is unable to sterilize disease in the majority of pts with unresectable NSCLC. While the addition of chemotherapy has significantly improved survival of these pts, the MS is generally 15–24 mo. These preliminary results suggest higher than standard doses of RT may improve disease control & prolong survival. A phase III trial comparing standard-dose RT(60Gy) to high-dose RT (74Gy) is open and should more definitively address the issue of RT dose with concurrent chemotherapy for unresectable NSCLC. Future technological improvements in imaging & targeting will provide methods to safely administer even greater RT doses which will likely further improve disease control.

No significant financial relationships to disclose.
Phase I study of concurrent high-dose three-dimensional conformal radiotherapy (3D-CRT) without elective nodal irradiation with chemotherapy using cisplatin and vinorelbine for unresectable stage III non-small cell lung cancer (NSCLC)
Authors: Sekine I. , Sumi M. , Ito Y. , Nokihara H. , Yamamoto N. , Kunitoh H. , Ohe Y. , Tamura T.
Published: August 2020

7546

Background: The optimal dose of radiotherapy remains unclear in concurrent chemoradiotherapy for unresectable stage III NSCLC. Methods: Eligible patients (unresectable stage III NSCLC, age ≥ 20 years, PS 0–1, V20 ≤ 30%) received cisplatin (80mg/m2 day 1) and vinorelbine (20mg/m2 days 1 and 8) repeated every 4 weeks for 3–4 cycles. The dose of 3D-CRT was 66 Gy in 33 fractions, 72 Gy in 36 fractions, and 78 Gy in 39 fractions at levels 1–3, respectively. The dose-limiting toxicity (DLT), defined as grade ≥3 esophagitis, pneumonitis, myelitis, dermatitis and heart injury, and early stop of protocol treatment, was evaluated in 6–12 patients at each level. Results: Of the 17, 16 and 24 patients assessed for eligibility, 13 (76%), 12 (75%), and 6 (25%) were enrolled into levels 1–3, respectively, of the study. A total of 26 patients were excluded because of V20 > 30% (n=10), overdose to the esophagus (n=8) and brachial plexus (n=2), comorbidity (n=3), or patient refusal (n=3). There were 26 men and 5 women with a median (range) age of 60 (41–75) years. Of these, 23 (74%) had adenocarcinoma and 20 (65%) had stage IIIA disease. The full planned dose of radiotherapy could be administered in all the patients, and more than 80% of the patients received 3–4 cycles of chemotherapy. Grade 3–4 neutropenia and febrile neutropenia were noted in 24 (77%) and 5 (16%) of the 31 patients, respectively. Grade 4 infection, grade 3 esophagitis and grade 3 pulmonary toxicity were noted in one, two and one patients, respectively. DLT was noted in 17% of the patients at each level. Two (6%) complete and 27 (87%) partial responses were obtained. In a preliminary survival analysis, the median progression-free and overall survivals were determined to be 15.0 months and 37.6 months, respectively. Conclusions: At the level of 78Gy, only 25% of the patients assessed for eligibility were actually eligible. Toxicity was relatively mild up to 78 Gy in this highly selective patient group. Thus, we determined that the recommended dose of 3D-CRT administered concurrently with cisplatin and vinorelbine chemotherapy was 72Gy.

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The serial effects of multimodality therapy for stage III non-small cell carcinoma on lung function
Authors: Mazzone P. J. , Videtic G. , Murthy S. , Mason D. , Rice T. , Pennell N. , Rich T. , Machuzak M. , Mekhail T.
Published: August 2020

7551

Purpose: To describe the effects of multimodality treatment on lung function in patients with stage III non-small cell carcinoma of the lung (NSCLC) Methods: Pulmonary function tests (PFTs) were reviewed for 32 patients with stage III NSCLC who were enrolled in a multimodality protocol that included neoadjuvant (NAd) combined chemoradiotherapy (taxol 50 mg/m2, carboplatin AUC 2 weekly X 3, radiation (XRT) 1.8 Gy BID to 30 Gy + erlotinib 150 mg/d for 28 days, followed by resection (R) and adjuvant (Ad) chemoradiotherapy (same as induction) followed by erlotinib 150mg/d maintenance (M) for 2 years. Changes in PFTs were analyzed at multiple time points (baseline to after NAd, after NAd to after R, after R to after Ad) and for the overall effect of treatment (baseline to the end of treatment). Results: The table below shows changes in percent predicted pulmonary function test values at each step in the treatment course. + signifies an increase and - a decrease. P indicates pneumonectomy and L lobectomy. Numbers in parentheses are the number of patients with complete testing at that time point. Conclusions: Neoadjuvant combined chemoradiotherapy has a small effect on lung function testing. The combined effect of multimodality therapy for stage III lung cancer that includes surgical resection leads to larger declines in lung function than have been reported historically for resection alone.

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Analysis of four sorts of clinical factors associated with radiation-induced lung injury in patients with NSCLC after 3D-CRT
Authors: Zhang Y. , Liang C. , Li J. , Tian S. , Yu J.
Published: August 2020

7552

Background: There are different clinical factors associated with radiation-induced lung injury in patients with non-small cell lung cancer (NSCLC) after three-dimensional conformal radiation therapy (3D-CRT) that have been studied, whereas their value are not same. According to their source, the factors can be sorted to four types. Methods: 119 NSCLC patients treated with 3D-CRT during 2003–2005 were retrospectively reviewed. They were divided into two arms according to whether grade >2 radiation- induced lung injury named by RTOG 3.0 were observed. The clinical parameters related to radiation-induced lung injury were divided into four sorts: general state of health and systematic sickness (gender, age, KPS, COPD, heart disease, diabetes), tumor-related factors (location, stage, volume), radiotherapy-related factors (dose, fraction per day, target margin, dosimetric parameters), other treatment factors (chemotherapy timing and agents). Univariate and multivariate analyses of the relation between clinical parameters and radiation pneumonitis were performed. Results: Occurrence of grade >2 radiation-induced lung injury was observed in 17/119 patients. In univariate analyses, GTV (p=0.009), ipsilateral mean lung dose (MLD)(p=0.017), ipsilateral lung V20 (p=0.036)and total lung MLD (p=0.034) were associated with radiation-induced lung injury. In multivariate analysis, ipsilateral lung MLD was the only independent factor associated with radiation-induced lung injury (p=0.019). A significant correlation was also observed between the three volumetric parameters (p≤0.001). Conclusions: Ipsilateral lung MLD was the only independent factor associated with grade >2 radiation-induced lung injury in our study, so that it should be included as a dose constraint factor for 3D-CRT of NSCLC.

No significant financial relationships to disclose.
Operative outcomes using bevacizumab, docetaxel, and cisplatin as induction therapy in patients with operable lung cancer
Authors: Finley D. J. , Shen R. , Rizvi N. A. , Rusch V. W. , Kris M. G.
Published: August 2020

7559

Background: Induction chemotherapy in patients with operable non-small cell lung cancer (NSCLC) is better tolerated than adjuvant chemotherapy. Bevacizumab improves survival in patients with advanced NSCLC; however its impact as an induction agent in patients undergoing lung resection is unknown. Here, we evaluated surgical outcomes in patients undergoing resection for NSCLC after induction therapy with bevacizumab (Bev), docetaxel (D) and cisplatin (C). Methods: Patients with stage IB-IIIA NSCLC, who could undergo resection with curative intent, were eligible for this phase II trial. None had squamous histology, large central tumors, or recent hemoptysis. All patients received up to 4 cycles of D 75 mg/m2 and C 75 mg/m2 and also received 3 cycles of Bev 15 mg/kg, followed by surgery. Two age and stage matched controls who received induction chemotherapy were selected per study patient. Fisher's exact tests compared pathologic stage, gender, and smoking history. Conditional logistic regression explored the association between clinical variables and outcomes in study versus control patients. Results: 30 patients received Bev-DC. Gender, smoking history, operative time, blood loss, and overall 30-day morbidity was similar between study and control patients. The 30 patients who received Bev-DC preoperatively had 12 complications vs 23 in the 60 controls. In the Bev-DC group there were 7 grade 3/4 complications (abscess (1), empyema (1), bronchopleural fistula (2), sigmoid volvulus (1), anastomotic dehiscence (1), GI bleed (1)) as compared to 2 in the control group (p=0.004). There were no deaths in the Bev-DC group and 2 among the controls. After controlling for age, gender and stage, patients in the study group had a trend towards increase incidence of overall complications (OR=3.89 (95%CI: 0.61–24.77) p=0.151). Conclusions: Although rates of 30-day morbidity were comparable, patients receiving Bev-DC induction had a higher incidence of grade 3/4 complications. There was no 30-day mortality among the patients receiving Bev-DC. Based on this interim analysis, patients receiving Bev-DC in the preoperative setting merit close monitoring.

[Table: see text]
A multicenter, phase III study of carboplatin/paclitaxel versus oral uracil-tegafur as the adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC): Planned interim analyses
Authors: Toyooka S. , Hotta K. , Nakamura H. , Nakata M. , Tada H. , Yamashita M. , Watanabe N. , Sakamoto J. , Aoe M. , Date H.
Published: August 2020

7560

Background: Recent studies have demonstrated that adjuvant chemotherapy provides a survival benefit in patients with resected NSCLC. In Japan, uracil-tegafur has been recognized as a standard adjuvant strategy for resected NSCLC, however, carboplatin based adjuvant chemotherapy has not been fully evaluated for the treatment of NSCLC patients in an adjuvant setting. The present phase III study assessed the efficacy and safety of carboplatin/paclitaxel and oral uracil-tegafur as the first study to compare intravenous and oral drugs in resected stage IB-IIIA NSCLC. Methods: The patients with pathological stage IB-IIIA NSCLC who underwent complete resection were randomized 1:1 to carboplatin (AUC 5) /paclitaxel (175 mg/m2) every 3 week for 4 cycles (A arm) or uracil-tegafur (250 mg/m2) daily for 2 years (B arm). The primary endpoint was overall survival (OS) and secondary endpoints were disease-free survival and toxicity. The accrual of 200 patients per arm is required to demonstrate an improvement of OS (15% increase) in the A arm compared to B arm. Randomization was stratified by histology and tumor stage. An interim analysis was planned to perform on the first 200 patients recruited and data of survival and toxicity were examined in the first 100 patients. Results: Between November 2004 and November 2008, 200 patients from 31 Japanese centers were randomized and the first 100 patients were included for interim analysis. Median age was 69 (range; 50–80) years. Ninety-eight patients had PS of 0–1 and 2 patients had PS of 2. Sixty-seven patients were male and 23 patients were female. Sixty patients had adenocarcinoma, 30 had squamous cell carcinoma, and 10 had other histologies. Disease stage was IB in 53, IIA in 14, IIB in 19, and IIIA in 14 patients. Toxicities observed during adjuvant chemotherapy were well tolerable. There was no toxic death. The median survival time of A and B arms combined was 4.1 year. Monitoring Committees approved to continue the present study. Conclusions: The present phase III trial with carboplatin/paclitaxel or uracil-tegafur is feasible with manageable toxicity. The study is on course to achieve its primary endpoint.

[Table: see text]
Randomized phase II trial of the biweekly schedule of adjuvant chemotherapy with carboplatin plus paclitaxel versus carboplatin plus gemcitabine in patients with non-small cell lung cancer (NSCLC)
Authors: Sugio K. , Nagashima A. , Nakanishi R. , Uchiyama A. , Inoue M. , Osaki T. , Yoshimatsu T. , Takenoyama M. , Hanagiri T. , Yasumoto K.
Published: August 2020

7562

Background: Carboplatin plus paclitaxel and carboplatin plus gemcitabine chemotherapy have shown a good response and an improved survival against advanced NSCLC. This phase II trial assessed the feasibility, safety and efficacy of a bi-weekly schedule for adjuvant chemotherapy. Methods: Patients with completely resected stage IB-IIIB NSCLC were randomized to either carboplatin (AUC3) plus paclitaxel (90mg/m2) (arm A) or carboplatin (AUC3) plus gemcitabine (1000 mg/m2) (arm B), q2w for 8 cycles within 8 weeks after surgery. The main inclusion criteria were no prior chemotherapy or radiotherapy, ECOG PS 0–1, an age of less than 80 years, and an adequate organ function. The primary endpoint was compliance, and secondary endpoints were the disease free survival (DFS) and toxicity. The patients were stratified by gender, histology (adenoca vs. non-adenoca) and disease stage. Results: Between 07/2005 and 06/2007, 76 patients were randomized and 75 were eligible (including 48 males, 27 females; median age 66 years) for intent-to-treat analysis (39 in arm A, 36 in arm B). The histologic types included adenocarcinoma (n=51), squamous cell carcinoma (n=18), large cell carcinoma (n=5), and adenosquamous cell carcinoma (n=1). The pathological stages were IB/IIA/IIB/IIIA/IIIB: 22/10/13/29/1. Twenty-one of 39 pts (54%) in arm A and 25 of 36 pts (69%) in arm B completed 8 cycles, and 59% in arm A and 81% in arm B completed ≥6 cycles. Grade 3/4 hematologic toxicities (%) in arms A/B were respectively; neutropenia 36/53, anemia 0/17, thrombocytopenia 3/0, nausea 3/3. No treatment related deaths were observed. Up to 12/2008, 11 of 39 pts in arm A and 13 of 36 pts in arm B had recurrent disease, but no significant difference was observed. Conclusions: This adjuvant bi- weekly scheduled chemotherapy in both arms resulted in a good compliance and feasible with acceptable levels of toxicity in completely resected NSCLC.

No significant financial relationships to disclose.
The impact of PET-based staging on survival of patients with stage I lung cancer
Authors: Begum M. , Robinson L. , Sommers E. , Bepler G.
Published: August 2020

7570

Background: Patients with completely resected stage I lung cancer have the best survival. Stage I, as defined by Mountain in 1997, includes tumors of any size located within one lobe of the lung without involvement of the parietal pleura, a distance of 2 cm or more from the carina, and no evidence for metastatic disease in any pulmonary, hilar, or mediastinal lymph node or distant site. The 5-year survival for such patients is 57–67% (Mountain, 1997). We hypothesized that the introduction of FDG-positron emission tomography (PET) scanning would lead to upstaging of stage I patients with a consequential increase in survival. Methods: To test this hypothesis, we compiled a database of all patients with stage I lung cancer that underwent a complete surgical resection at the Moffitt Cancer Center from 1996 to 2006. Results: During this 11-year period, 1230 patients fulfilled these criteria. Surgery was performed by two thoracic surgeons (LR and ES). Description of pts: 638 women, 592 men; 11 African-American, 1215 Caucasian; 18 Hispanic, 1202 Non-Hispanic; age range 28.1–94.0 y, mean 68.9 y, median 69.9 y; 26 pneumonectomies, 243 segmentectomies or wedge resections; 699 adeno-, 15 adenosquamous, 325 squamous, 25 large cell, 57 neuroendocrine carcinomas; maximum tumor diameter range 0.1–25 cm, mean 2.9 cm, median 2.3 cm; 477 dead (survival 0.0–138.8 months), 753 alive (survival 0.1–144.4 months). The median OS by year of resection was: 88.0 m (1996, N=49), 61.2 m (1997, N=52), 72.1 m (1998, N=73), 58.0 m (1999, N=87), 83.6 m (2000, N=100), 75.0 m (2001, N=114), 70.7 m (2002, N=133), >55.7 m (2003, N=140), >41.5 m (2004, N=158), >33.1 m (2005, N=164), and >17.9 m (2006, N=160). These differences were not statistically significant (log-rank p=0.72). PET scanning was initiated at the beginning of the year 2000. The median OS for the 261 patients treated between 1996 and 1999 was 70.7 m (95% CI: 53.9–84.0), and the median OS for the 969 patients treated between 2000 and 2006 was 75.1 m (95% CI: 66.4–83.7). This difference was not statistically significant (log-rank p=0.34). Conclusions: We conclude that the introduction of PET scanning has not impacted on the survival of patients with stage I lung cancer at our institution.

No significant financial relationships to disclose.
Comparison of primary tumor maximal standardized uptake value (SUVmax) on preoperative [18F]fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) and histological subtype in patients with non-small cell lung cancer (NSCLC)
Authors: Davidson J. A. , Wong V. , Fraser R. , Hirsh V.
Published: August 2020

7571

Background: The routine preoperative use of PET/CT in patients with potentially resectable NSCLC is rapidly expanding. The SUVmax is a semiquantitative measure of metabolic activity that can distinguish benign from malignant tissue but published data are conflicting regarding its ability to discriminate between major histological subtypes. Methods: Pathology and PET/CT reports of 39 NSCLC patients who underwent a preoperative scan and curative resection at the McGill University Health Centre were reviewed. Only patients with Adenocarcinoma (AC), Squamous Cell carcinoma (SC), or Large Cell carcinoma (LC), and definitive pathological staging, were included. The SUVmax values for each histological subtype, along with primary tumor sizes, were compared using F test and t-test analyses. Results: The 15 patients with SC and 5 with LC histology were found to have significantly greater preoperative SUVmax values than the 19 patients with AC (mean 12.7 and 17.2 vs. 9.4, respectively, P < 0.05), despite the fact that no significant differences in tumor size were observed between histological subtypes. Patients with LC histology displayed higher SUVmax values than patients with SC histology, but this was not found to be significant (P = 0.057).Conclusions: These data suggest that SC pulmonary tumors have significantly greater uptake on PET/CT than AC tumors. This finding may be helpful in the future when sufficient tissue cannot be obtained for pathological diagnosis or to identify the predominant pathology of mixed tumors. Larger studies are required to confirm our results.

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No significant financial relationships to disclose.
The study of FDG PET-CT on the value in predicting of patient outcome after treatment of stage III non-small cell lung cancer
Authors: Zhang H. , Yu J.
Published: August 2020

7572

Background: Up to the present study, the value of FDG PET-CT in patients of non-small cell lung cancer (NSCLC) before and after treatment has been approved. However, the significance of FDG PET-CT during the treatment has not been confirmed. The objective of this study was to evaluate 18FDG PET-CT for assessment of therapy response and prediction of patient outcome after concurrent chemo-radiotherapy (CCRT) of NSCLC. Methods: Forty six patients with histologically proven stage III NSCLC had two repeated FDG PET-CT scans either one week before therapy and at the dose of 40∼50Gy, the SUVmax and Changes of the two group after completion of NARCT were compared with (1) the therapy response and (2) treatment results and long-term survival. Results: Of the 46 eligible patients, the pretreatment SUVmax of the responding and nonresponding groups was7.59±3.14 and 14.72±4.67 respectively. The midtreatment SUVmax of the two groups was 2.89±1.39 and 9.82±3.31 respectively. Significantly difference (t= 4.74,P=0.001; t=7.23,P=0.001) in SUVmax were observed either before and during treatment. Furthermore, the percent change of SUVmax of pretreatment and midtreatment was ΔSUVmax=61.91±86.69 and ΔSUVmax=33.56±90.37, difference between the two groups was also significantly (t=2.83, P=0.007). In addition, the 1 year survival rate of the the respond and non-respond group were 73% and 69% respectively, the 2-year survival rate of the two groups were 40% and 37% respectively, significant difference was observed between the two groups (P=0.001; P=0.001). Conclusions: 18FDG PET-CT is highly effective in detecting therapy response in stage III NSCLC patients, the analysis of percent change of SUVmax provides incremental value in early prediction of therapy response and patient outcome.

No significant financial relationships to disclose.
Phase I trial of neoadjuvant dasatinib in patients with resectable malignant pleural mesothelioma
Authors: Mehran R. , Gil J. , Rice D. , Swisher S. , Lee J. J. , Lippman S. , Pisters K. , Blumenschein G. , Hong W. K. , Tsao A. S.
Published: August 2020

7580

Background: The optimal multi-modality treatment for resectable malignant pleural mesothelioma (MPM) remains unknown. We designed a biomarker-based neoadjuvant trial from our preclinical studies showing that dasatinib, a multi-targeted Src kinase inhibitor, has activity against MPM and target specificity to Src Tyr419. Methods: Untreated MPM patients underwent extended surgical staging (ESS) with multiple biopsies to account for tumor heterogeneity, lymph node status and to rule out sarcomatoid features. If deemed a surgical candidate for either pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP), patients received 4 weeks of oral dasatinib (70 mg BID) followed by P/D or EPP. If either a radiographic or molecular response (de-phosphorylation of Src Tyr419 in tumor) is achieved, an additional 2 years of dasatinib maintenance after adjuvant radiotherapy and systemic chemotherapy is given. The primary endpoint of this trial was biomarker modulation of Src Tyr419. Secondary endpoints included response, survival, safety/toxicity, and biomarker modulation in tumor/serum/platelets/pleural effusion. The total planned sample size is 24 to detect a 50% reduction in positive p-Src Tyr419 expression with 80% power, one-sided 10% type I error rate, and 10% inevaluable rate. Results: To date, ten patients have registered on the trial (4/08 - 12/08); six have successfully completed the ESS, neoadjuvant dasatinib, and P/D (n=3) or EPP (n=3). Two patients are still receiving neoadjuvant dasatinib; and 2 patients were deemed to not be surgical candidates due to a rapid decline in PS and one was found to have bilateral mesothelioma. The main side effects to dasatinib were grade 1–2: anemia, nausea, vomiting, anorexia, electrolyte abnormalities, fatigue, and anxiety. Grade 3 toxicities included hyperkalemia (1), infection - pneumonia (1), and hypoxia (1). There were no grade 4–5 toxicities. Post-surgical grade 3 toxicity included anemia, electrolyte abnormalities, arrhythmia, HTN, and pleural effusion; one grade 4 episode of hyperglycemia was seen. Conclusions: This study demonstrates that biomarker-based neoadjuvant MPM trials with novel agents are feasible. Updated clinical and translational correlative results will be presented.

No significant financial relationships to disclose.
Mesothelin as a marker of response in malignant pleural mesothelioma
Authors: Wheatley-Price P. , Yang B. , Patel D. , Ma C. , Xu W. , Leighl N. , Feld R. , Cho B. , De Perrot M. , Liu G.
Published: August 2020

7581

Background: Malignant pleural mesothelioma (MPM) is a rare malignancy related to asbestos exposure. Radiological assessment of disease status and treatment response using RECIST criteria is often difficult, therefore blood markers of disease burden may be useful adjunctively. Soluble mesothelin related peptide (sMRP) can distinguish between MPM and benign pleural disease. We performed an exploratory analysis to determine whether sMRP correlates with MPM disease course. Methods: From December 2006 to August 2008 blood samples were collected from MPM patients during clinic visits. Plasma sMRP levels were measured using the MESOMARK assay (Fujirebio diagnostics). Changes in sMRP levels were compared with corresponding radiological tests, scored as progression, stable or disease shrinkage. Results: From 41 patients, 165 samples were collected (median 4/patient; range 2–10). At study entry 34/37 (92%) patients with measurable disease had elevated sMRP (>9ng/ml, range 14–60). In 22 patients receiving chemotherapy or biologic therapy, relative (Fisher's exact test, p=3.2x10–6) and absolute (p=2.6x10–5) changes in sMRP correlated with radiological assessment (Table). All 4 post-surgery surveillance patients, with no evidence of recurrence, had normal sMRP levels (1.8–4.9). Of 8 patients who underwent surgical resection, 7 had elevated pre-operative sMRP that fell to normal post-operatively (Wilcoxon rank (WR) p=0.02). Absolute sMRP rose in all patients with radiological progression (systemic therapy, n=9, WR p=0.004; supportive care, n=10, WR p=0.02). Conclusions: sMRP levels not only correlate with surgical debulking but we report, for the first time, that they also correlate with treatment response and radiological progression in MPM patients undergoing systemic therapy or supportive care. sMRP may be a clinically useful biomarker in MPM clinical trials and in patient management. These findings should be validated prospectively.

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