bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: Results on radiation dose in RTOG 0617.
Authors: Bradley Jeffrey D , Paulus Rebecca , Komaki Ritsuko , Masters Gregory A. , Forster Kenneth , Schild Steven E. , Bogart Jeffrey , Garces Yolanda I. , Narayan Samir , Kavadi Vivek , Nedzi Lucien Alexander , Michalski Jeff M. , Johnson Douglas , MacRae Robert Malcolm , Curran Walter John , Choy Hak ,   Radiation Therapy Oncology Group
Published: March 2020

7501

Background: The first objective of RTOG 0617 was to compare the overall survival(OS) of patients(pts) treated with standard-dose(SD)(60Gy) versus high-dose(HD)(74Gy) radiotherapy with concurrent chemotherapy(CT). Methods: This Phase III Intergroup trial randomized 464 pts with Stage III NSCLC to the SD(60Gy) vs. HD(74Gy) arms prior to closure of the HD arm. Concurrent CT included weekly paclitaxel(45 mg/m2) and carboplatin(AUC=2). Pts randomized to cetuximab received a 400 mg/m2 loading dose on Day 1 followed by weekly doses of 250 mg/m2. All pts were to receive consolidation CT. We are reporting the final results on radiation dose. Results: 464 pts were accrued prior to closure of the HD arm in 6/11, of which 419 were eligible for analysis. Median follow up was 17.2 months. There were 2 and 10 grade 5 treatment-related adverse events(AEs) on the SD and HD arms, respectively. Grade 3+AEs were 74.2% and 78.2% on SD and HD arms, respectively (p=0.34). The median survival times and 18-month OS rates for the SD and HD arms were 28.7 vs 19.5 months, and 66.9% vs 53.9% respectively (p=0.0007). The primary cause of death was lung cancer (72.2% vs 73.5%)(p=0.84). Local failure rates at 18 months were 25.1% vs 34.3% for SD and HD patients, respectively(p=0.03). Local-regional and distant failures at 18 months were 35.3% vs 44%(p=0.04) and 42.4% vs 47.8%(p=0.16) for SD and HD arms, respectively. Factors predictive of less favorable OS on multivariate analysis were higher radiation dose, higher esophagitis/dysphagia grade, greater gross tumor volume, and heart volume >5 Gy. Conclusions: In this setting of chemoradiation for locally-advanced Stage III NSCLC, 60 Gy is superior to 74 Gy in terms of OS and local-regional control. The effect of the anti-EGFR antibody (cetuximab) awaits further follow up. This project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC U24 CA 81647 from the National Cancer Institute (NCI) and Eli Lilly and Company. Clinical trial information: NCT00533949.
Impact of brachytherapy on local recurrence after sublobar resection: Results from ACOSOG Z4032 (Alliance), a phase III randomized trial for high-risk operable non-small cell lung cancer (NSCLC).
Authors: Fernando Hiran Chrishantha , Landreneau Rodney Jerome , Mandrekar Sumithra J. , Nichols Francis C , Hillman Shauna L , Heron Dwight Earl , Meyers Bryan F , DiPetrillo Thomas A. , Jones David Randolph , Starnes Sandra Lynne , Tan Angelina D. , Daly Benedict , Putnam Joe B. ,   Alliance for Clinical Trials
Published: March 2020

7502

Background: Prior studies suggest that adjuvant brachytherapy reduces local recurrence (LR) after sublobar resection (SR) for NSCLC. A multicenter randomized study was undertaken in patients (pts) with stage I NSCLC ≤3cm comparing SR to SR with brachytherapy (SRB). Methods: High-risk operable patients with NSCLC were randomized to SR or SRB. Brachytherapy involved placement of I125 seeds incorporated into Vicryl sutures or into Vicryl mesh placed over the staple line. Wedge or segmental resection was allowed. The primary endpoint was time to local recurrence (LR) defined as recurrence within the primary tumor lobe at the staple line (local progression), away from the staple line or within hilar nodes. The trial was designed to have 90% power to detect a hazard ratio (HR) of 0.315 in favor of the SRB arm using a one-sided α of 0.05 with a sample size of 100 eligible pts per arm. Follow-up CT scans were obtained serially for 36 months. Results: 224 pts were randomized; 213 (109 SR,104 SRB) were eligible. Median (range) age was 71 (49-87) yrs; 94 (44%) were male. No differences were found in baseline characteristics. Adverse events, previously reported, were not different between arms. Median (range) follow-up was 4.06 (0.04, 5.0) yrs. There was no difference between arms in time to LR (HR = 0.87; 5% CI: 0.41, 1.86, p=0.72) or to LR or death (LRD) (HR = 0.81, 95% CI: 0.50, 1.32, p=0.40). There was no difference between arms in pattern of LR (table). In subgroups of pts with potentially compromised surgical margin (margin < 1cm; margin:tumor ratio <1; positive staple line cytology) SRB did not reduce LR or LRD at 3-yrs. Overall 3-yr survival was similar for SR (71%) and SRB (72%) (p=0.81). Conclusions: LR remains a concern after sublobar resection. However, local progression at the staple line was low. This trial demonstrated that adjuvant brachytherapy does not impact oncologic outcomes. Clinical trial information: NCT00107172. [Table: see text]
Result of phase III trial of amrubicin/cisplatin versus etoposide/cisplatin as first-line treatment for extensive small cell lung cancer.
Authors: Sun Yan , Cheng Ying , Hao Xuezhi , Wang Jie , Hu Chengping , Han Baohui , Liu Xiaoqing , Zhang Li , Wan Huiping , Xia Zhongjun , Liu Yunpeng , Li Wei , Hou Mei , Zhang Helong , Xiu Qingyu , Zhu Yunzhong , Feng Jifeng , Qin Shukui
Published: March 2020

7507

Background: Etoposide combined with cisplatin (EP) has been the first-line chemotherapy regimen for small cell lung cancer (SCLC) for >20 years; however, a more effective regimen has been recommended by many clinical oncologists. Thus, we here present our preliminary results of a phase III clinical trial of the novel drug amrubicin in combination with cisplatin (AP) in comparison to EP in patients with previously untreated extensive SCLC (ED-SCLC). Methods: A total of 299 previously untreated ED-SCLC patients were randomized (ratio, 1:1) into two treatment groups: (1) the AP group (n = 149): 4–6 cycles of amrubicin (40 mg/m2/day on days 1–3) and cisplatin (60 mg/m2/day on day 1) and (2) the EP group (n = 150): 4–6 cycles of etoposide (100 mg/m2/day on days 1–3) and cisplatin (80 mg/m2/day on day 1 every 21 days). Patients were evaluated for therapy response and electrocardiography results every 2 cycles. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and general safety. Results: Baseline characteristics were similar among the two groups. For AP and EP groups, the median OS was 11.79 and 10.28 months, the median PFS was 7.13 and 6.37 months, and ORR was 69.8% and 57.3%, respectively. The most frequent adverse events (≥grade 3) in AP and EP groups were bone marrow failure (23.5% and 21.3%, respectively), neutropenia (54.4% and 44.0%, respectively), and leukopenia (34.9% and 19.3%, respectively). Conclusions: Our phase III trial demonstrated that for previously untreated ED-SCLC patients, AP therapy was not inferior to EP therapy in terms of OS and offered predictable and manageable toxicities. Clinical trial information: NCT00660504.
Three-arm randomized phase II study of cisplatin and etoposide (CE) versus CE with either vismodegib (V) or cixutumumab (Cx) for patients with extensive stage-small cell lung cancer (ES-SCLC) (ECOG 1508).
Authors: Belani Chandra Prakash , Dahlberg Suzanne Eleanor , Rudin Charles M. , Fleisher Martin , Chen Helen X. , Takebe Naoko , Ramalingam Suresh S , Schiller Joan H.
Published: March 2020

7508

Background: Targeted inhibition of the Hedgehog (HH) pathway by V & Insulin-like Growth Factor type-1 Receptor (IGF-1R) by Cx enhances efficacy of chemotherapy, and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in SCLC. Methods: Patients (Pts) with newly diagnosed ES-SCLC with measurable disease, ECOG PS 0-1 were randomized to receive (four 21-day cycles) CE alone [(C 75 mg/m2 D1 & E 100 mg/m2 D1-3) Arm A] or in combination with either V [(150 mg/day PO) Arm B] or Cx [(6mg/kg weekly IV) Arm C]. Pts with responsive or stable disease on Arms B & C were continued on V or Cx respectively until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), stratified on gender. Circulating tumor cells (CTCs) were isolated/enumerated by Veridex Cell Search Platform at baseline, after 1or 2 cycles of chemotherapy, at completion of 4 cycles & 3 months (m). thereafter for correlation with efficacy parameters. The study was designed to detect a PFS HR of 0.58 with 90% power & an overall one-sided type I error rate of 0.10 for each of the comparisons of the V and Cx arms to CE alone. Results: 155 eligible pts were treated; 136 have died & 149 have experienced a PFS event. Pt. demographics & disease characteristics are well-balanced between the three arms except higher rate of PS 0 on Arm B (p=0.03). The median PFS on Arms A, B & C are 4.7, 4.4 & 4.6 m, the median OS 9.1, 9.8 & 10.1 m, & the RR are 43%, 52% & 49% respectively. None of the comparisons of these outcomes are statistically significant. PFS HR for V+CE vs. CE: 1.32, p=0.21, and for Cx+CE vs. CE: 1.12, p=0.58. The median OS among those with low CTC count (≤100 per 7.5ml) at baseline is 10.7 m vs. 7.2 m for those with high CTC count [HR1.70, p=0.01]. Toxicities in all three arms are as expected with the combination of CE alone. Conclusions: There is no significant improvement in PFS or OS with the addition of either V or Cx to CE vs.CE alone in pts with ED-SCLC. Low baseline CTC count is associated with improved OS, suggesting its role as a prognostic biomarker in SCLC. Clinical trial information: NCT00887159.
Multitrial evaluation of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in previously untreated extensive-stage small cell lung cancer (ES-SCLC): An Alliance-led analysis.
Authors: Foster Nathan R. , Renfro Lindsay A. , Schild Steven E. , Redman Mary Weber , Wang Xiaofei F. , Dahlberg Suzanne Eleanor , Ding Keyue , Bradbury Penelope Ann , Ramalingam Suresh S. , Gandara David R. , Vokes Everett E. , Adjei Alex A. , Mandrekar Sumithra J.
Published: March 2020

7510

Background: We previously demonstrated that PFS may be a candidate surrogate endpoint for OS in ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). Here, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 9 additional randomized phase II and III trials conducted by the NCI-funded cancer cooperative groups since 1986. Methods: Individual patient data from all 12 trials (3178 patients: 9 phase III and 3 phase II) were pooled. OS was the primary endpoint in all phase III trials; 3 phase III and 1 phase II trial were positive per protocol. Patient-level surrogacy (Kendall’s tau) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including: weighted (by trial size) least squares regression of Cox model effects (R² WLS) and weighted (by trial size) correlation of the copula effects (R² Copula). One trial had 4 treatment arms thus 14 total two-arm comparisons were made. Results: With a median follow-up of 41.8 months in the 106 patients still alive, the median OS and PFS across trials were 9.7 months (95% CI: 9.5, 9.9) and 5.7 months (95% CI: 5.5, 5.8), respectively. There were 3120 PFS events in total (2564 disease progressions and 556 deaths without progression). The median time from progression to death was 4.1 months (95% CI: 3.9, 4.3). PFS showed modest association with OS at the patient-level (tau= 0.56) and at the trial-level (R² WLS = 0.58; R² Copula (standard error) = 0.55 (0.29)). The 95% CIs for the predicted HR for OS given observed HR on PFS under a weighted leave-one-out prediction always included the observed HR for OS; however such intervals were wide, suggesting uncertainty on the practical use of PFS as a surrogate for OS in this setting. Conclusions: PFS failed to demonstrate surrogacy for OS in ES-SCLC based on this large pooled analysis. Given that the difference in the median PFS and OS is less than 6 months, we recommend using OS as the primary endpoint in phase III trials of previously untreated ES-SCLC.
Surgery for early non-small cell lung cancer with preoperative erlotinib (SELECT): A correlative biomarker study.
Authors: Sacher Adrian G. , Lara-Guerra Humberto , Waddell Thomas K. , Kim Lucia , Chen Zhuo , Salvarrey Alexandra , Darling Gail , Yasufuku Kazuhiro , Keshavjee Shaf , de Perrot Marc , Shepherd Frances A. , Liu Geoffrey , Tsao Ming Sound , Leighl Natasha B.
Published: March 2020

7516

Background: Erlotinib has demonstrated major activity in EGFR mutation positive NSCLC, but may also benefit those with wild-type tumours. We conducted a single-arm trial of pre-operative erlotinib in early stage NSCLC to assess radiologic and functional response as well as correlation with known and investigational biomarkers. Methods: Patients with clinical stage IA-IIB NSCLC received erlotinib 150 mg daily for 4 weeks followed by surgical resection. Tumor response was assessed using pre- and post-treatment CT and PET imaging. Pharmacodynamic changes were assessed through comparison of pre- and post-treatment tumour samples (including Sequenom MassARRAY analysis) and measurement of circulating markers/ligands for EGFR activation (TGF-α, amphiregulin, epiregulin, EGFR SNP, EGFR ECD). Secondary endpoints included pathological response, toxicity and progression-free survival. Results: Twenty-five patients were enrolled; 22 received erlotinib treatment with a median follow up of 4.4 years (range 2.2 to 6.4 years). Histology was predominantly adenocarcinoma (14) with smaller numbers of squamous carcinoma (7) and large cell carcinoma (1). PET response (25% SUV reduction) was observed in 2 patients (9%), both with confirmed squamous carcinoma histology. All patients met criteria for stable disease by RECIST and several experienced minor radiographic regression with histologic findings of fibrosis/necrosis, including 2 with squamous histology. The presence of an EGFR exon 19 deletion was detected in one adenocarcinoma case; the patient experienced a minor radiographic response to treatment. Genotyping, functional protein assays and ligand analysis are ongoing. Conclusions: Erlotinib appears to demonstrate some activity in patients with squamous histology. While EGFR mutations have been infrequently demonstrated in squamous NSCLC, the potential exists for other biomarkers predictive of benefit. Clinical trial information: NCT00462995.
Blinded assessment of radiological changes after stereotactic ablative radiotherapy (SABR) for early-stage lung cancer: Local recurrences versus fibrosis.
Authors: Senan Suresh , Huang Kitty , Senthi Sashendra , Spoelstra Femke , Warner Andrew , Slotman Ben J. , Palma David
Published: March 2020

7520

Background: Stereotactic ablative radiotherapy (SABR) is a guideline-recommended treatment for unfit patients with early-stage lung cancer. The 5-year local recurrence rates are approximately 10% but fibrotic changes are common during follow-up, leading to difficulty with timely detection and salvage therapies. Previously reported high-risk features (HRFs) on computed tomography (CT) are 1) enlarging opacity at the primary site; 2) sequential enlarging opacity; 3) enlarging opacity after 12 months; 4) bulging margin; 5) loss of linear margin and 6) loss of air bronchograms. We performed a blinded assessment of CT imaging of patients with and without local recurrences. Methods: Patients treated with SABR for early stage lung cancer between 2003 and 2012, who developed pathology-proven local recurrence (n=12), were matched 1:2 to patients without recurrences (n=24), based on baseline factors. The median age at diagnosis was 68 years and median post-SABR imaging follow-up was 24 months (range 6 to 67 months). Patients were well-matched in the recurrence and non-recurrence groups. A total of 153 CT scans were available. Serial CT images were assessed by 3 radiation oncologists blinded to outcomes, viewing anonymized images projected onto a large screen. Results: All established HRFs were significantly associated with local recurrence (p<0.01), and one additional HRF was identified: cranio-caudal growth (p<0.001). The best individual predictor of local recurrence was opacity enlargement after 12 months(100% sensitivity, 83% specificity, p<0.001). The odds of recurrence increased 4-fold for each additional HRF detected in an individual patient. The presence of ≥3 HRFs in an individual patient was highly sensitive and specific for recurrence (both >90%). The HRFs enlarging opacity and cranio-caudal growth were each detected ≥3 months prior to the actual diagnosis of local recurrence in 42% of patients. Conclusions: Local recurrences following SABR can be accurately predicted by the presence of HRF’s on post-treatment CT scans. This approach may reduce unnecessary diagnostic procedures, and ensure earlier use of salvage therapies.
Factors impacting oncologic outcomes after sublobar pulmonary resection: Results from ACOSOG Z4032 (Alliance), a randomized trial for high-risk operable non-small cell lung cancer (NSCLC).
Authors: Kent Michael S , Landreneau Rodney Jerome , Mandrekar Sumithra J. , Nichols Francis C , DiPetrillo Thomas A. , Meyers Bryan F , Heron Dwight Earl , Putnam Joe B. , Jones David R , Starnes Sandra Lynne , Daly Benedict , Tan Angelina D. , Fernando Hiran Chrishantha ,   Alliance for Clinical Trials
Published: March 2020

7524

Background: A multicenter study (Z4032) compared sublobar resection (SR) to sublobar resection with brachytherapy (SRB) for stage I NSCLC. Local recurrence (LR) and overall survival (OS) rates at 3-years (3-yr) were similar between arms (see abstract 113613). This analysis combines arms, and evaluates the effect of factors previously reported to impact oncological outcomes after SR. Methods: 213 patients (pts) were evaluable for analysis. LR was defined as recurrence at the staple line (local progression), same lobe away from the staple line, or within hilar nodes. Factors assessed for impact on 3-yr outcomes were: resection type (wedge/segmentectomy), margin size (<1cm /≥1cm), margin:tumor ratio (<1/ ≥1), tumor size (≤2cm/>2cm) and staple line cytology (+/-). Results: LR occurred in 27/213 (12.6%) pts and included local progression in 12/213 (5.6%). OS rate at 3-yr was 152/213 (71.4%). Trends favored the use of segmentectomy, margin:tumor ratio≥1, tumor size ≤2cm and negative staple line cytology; no factor reached statistical significance at 3-yr. The only factor significantly (p=0.02) associated with decreased 3-yr LR was margin size ≥1cm (8.3%) compared to margin<1cm (19.3%). Conclusions: SR is a good option for high-risk pts with NSCLC. The 3-yr OS rate of 71.4% and local progression rate of 5.6% are useful benchmarks to compare to other therapies. A resection margin of at least 1 cm is desirable. Clinical trial information: NCT00107172. [Table: see text]
A phase I study of cediranib (NSC #732208) in combination with cisplatin and pemetrexed in chemonaive patients with malignant pleural mesothelioma (SWOG S0905).
Authors: Tsao Anne S. , Moon James , Wistuba Ignacio Ivan , Vogelzang Nicholas J. , Kalemkerian Gregory Peter , Redman Mary Weber , Gandara David R. ,   Southwest Oncology Group
Published: March 2020

7527

Background: The VEGF/VEGFR and PDGF/PDGFR pathways are potential therapeutic targets in mesothelioma. Cediranib, a VEGFR/PDGFR inhibitor, showed anti-tumor activity in a salvage monotherapy study S0509. Methods: S0905 combined cediranib (2 dose cohorts 30 mg and 20 mg daily) with cisplatin and pemetrexed for 6 cycles followed by maintenance cediranib in unresectable chemo-naïve MPM patients. Results: A total of 20 patients (7 to cohort 1 - 30 mg, 13 to cohort 2 - 20 mg) were enrolled. In first cohort, 2 patients reported grade 3 DLTs of diarrhea and fatigue. Cohort 2 DLTs included 2 patients with grade 3 hyponatremia/dehydration and mucositis. For all cycles, 12 patients reported Grade 3 AEs, the most common being diarrhea (4), dehydration (3), fatigue (3) and neutropenia (3). Two grade 4 thrombocytopenia were reported with 1 treatment-related death (cohort 2) due to pneumonia/sepsis. Based on the toxicity profile, a decision was made to proceed with cediranib 20 mg daily for the remaining phase I/II trial. Two radiographic response measurements were utilized (RECIST 1.1, modified RECIST). 18/20 patients were evaluable for response by RECIST 1.1 (7 - 30 mg cohort, 11 - 20 mg cohort). The RECIST 1.1 RR was 22% (95% CI: 6% - 48%) and median PFS was 14 months (95% CI: 8 – 17). Two patients had inadequate assessments and are classified as non-responders. There were 19 patients measurable by modified RECIST with RR 53% (95% CI: 29%-76%) and median PFS 10 months (7-13). For all patients, the median OS was 16 months (95% CI: 11-19). One patient in the 30 mg cohort remains on trial after 25 cycles of therapy; 2 patients at the 20 mg cohort remain on trial on cycles 19 and 15 of therapy. Conclusions: Cisplatin-pemetrexed-cediranib shows significant clinical activity and acceptable toxicity with cediranib 20 mg/day. The randomized phase II portion of the trial is ongoing. Clinical trial information: NCT01064648. [Table: see text]
Carboplatin versus cisplatin-based adjuvant chemotherapy in elderly patients with stages IB, II, and IIIA non-small cell lung cancer in the community setting.
Authors: Gu Fei , Wisnivesky Juan P. , Mhango Grace , Strauss Gary M.
Published: March 2020

7533

Background: It remains controversial whether completely resected elderly NSCLC patients should receive adjuvant chemotherapy (ACT) and with what treatment regimen. We previously reported from a SEER-Medicare analysis of cases diagnosed up to 2005, that carbo-ACT is given much more frequently than cis-ACT and both are associated with improved overall survival (OS). Since randomized ACT trials were published around 2005, an update is necessary to reflect more recent practice patterns. Methods: We identified 16,420 patients >65 years in the SEER-Medicare database with resected stage IB-IIIA NSCLC, diagnosed between 1992 and 2007. Among these patients, 1,803 (11%) received platinum-ACT. Propensity score methods and Cox regression analyses were used to assess survival outcomes, as well as to compare carbo- versus cis-based therapy, while controlling for potential confounders. Results: Among those receiving platinum-based ACT, of whom 83% received carbo, there was a significant OS survival advantage compared to those receiving no ACT (TABLE). Carbo-ACT is associated with similar OS as compared to cis-ACT. The carbo/paclitaxel doublet was the most commonly used regimen, given to 52%. Chemotherapy-related toxicities requiring hospitalization were comparable between carbo- and cis-ACT groups, except for significantly less dehydration and anemia among those receiving carbo-ACT. Conclusions: In community practice reflected in this SEER-Medicare study, a minority of completely resected stage IB-IIIA NSCLC received platinum-based ACT that is associated with improved OS. Carbo-ACT was given in a 5:1 ratio compared to cis-ACT, had comparable OS advantage, and a somewhat more favorable toxicity profile. [Table: see text]
Test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumors.
Authors: Pattenden Holly , Beddow Emma , Dusmet Michael , Nicholson Andrew G , Swetha Iyer , Marchbank Adrian , Greenwood Amy , West Douglas , Ariyaratnam Priyadharshanan , Loubani Mahmoud , Granato Felice , Kirk Alan , Lim Eric Kian Saik ,   UK Thoracic Surgery Collaborative
Published: March 2020

7544

Background: PET-CT is a standard investigation to stage the mediastinum in non-small cell lung cancer when radical management is planned. The clinical utility of PET-CT in carcinoid tumours is uncertain as its test performance at identifying mediastinal lymph node disease in these tumours is as yet undefined with such tumours being rare and FDG avidity often variable or low. We sought to determine the test performance of PET-CT for mediastinal lymph node staging of pulmonary carcinoid tumours. Methods: We collated retrospective data from 5 institutions for a consecutive series of patients who underwent thoracic surgery for carcinoid tumours and had preoperative PET-CT staging prior to surgery (with lymph nodal dissection). PET-CT results were compared against the reference standard of pathologic results obtained from lymph node dissection, and test performance reported using sensitivity and specificity. Results: From November 1999 to May 2012, a total of 153 patients with a preoperative PET-CT scan from 5 institutions underwent surgery for a carcinoid tumour. The mean age of the patients was 60 (SD 16) and 67 were male (44%). The pathologic sub-type was typical carcinoid in 138 patients (90%) and atypical carcinoid in 15 patients (10%). The mean SUV uptake in the primary tumour was 4.9 (SD 5). Results from lymph node dissection were obtained in 125 patients and the sensitivity and specificity of PET-CT to identify mediastinal lymph node disease was 40% (95% CI 5-85%) and 93% (93-99%) respectively. Conclusions: In this largest cohort study to date, our results suggest that PET-CT has a poor sensitivity but good specificity for mediastinal lymph node metastases for pulmonary carcinoid tumours. Therefore lymph node metastases cannot accurately be ruled out in carcinoid tumours with a negative PET-CT. If treatment decisions are based on the N2 status, invasive mediastinal staging should be undertaken in carcinoid tumours.
Concurrent chemoradiation (CChRT) with bi-weekly docetaxel and cisplatin and thoracic radiotherapy for stage III non-small cell lung cancer (NSCLC): A phase II study from the Galician Lung Cancer Group.
Authors: Casal Rubio Joaquin , Brozos EM , Lázaro Quintela Martin , Vazquez-Estevez Sergio , Firvida Jl , Taboada MB , Caeiro M , Castro JE , Vieito Villar Maria , Senin Estor Clara , Villanueva MJ , Varela Ferreiro Silvia , Areses MC , Pena C , Calvo P , Hernandez E. , Martinez N. , Anido Urbano , Huidobro Gerardo
Published: March 2020

7549

Background: CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly docetaxel (D) and cisplatin (C) and thoracic radiotherapy. Methods: 50 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 > 1.1, V20 < 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 14,5 months. Results: The p characteristics were: mean age 59,1 years (34-75); male/female 44/6; squamous/adeno/large cell carcinoma: 52%/34%/14%; stage IIIAN2 14 p (28%) and stage IIIB 36 p (72%). All p were evaluable for response and toxicity. RR: 4 CR, 36 PR (RR 80%; 95% CI:69-91), 4 SD (8%) and 6 PD (12%). The median PFS was 13 months (95% CI:8-18) and median OS was 19 months (95% CI:14-24). The PFS and OS at 1/2 years were 52%/30% and 79%/40% respectively. A total of 50 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 2/16; anemia 12/0; nausea/vomiting 28/2; diarrhea 22/4; there were two episodes of febrile neutropenia. Main toxicities per p in CChRT (D-C doses: 192, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28/6; anemia 60/0; esophagitis 52/4 and pneumonitis 34/0; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p. Conclusions: CChRT with bi-weekly docetaxel and cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.
Fibroblast growth factor receptor 1 (FGFR1) gene copy number gain in adenocarcinoma and squamous cell carcinoma of the lung.
Authors: Tang Ximing , Xue Yuwen , Su Xinying , Harun Nusrat , Cai Yiran , Behrens Carmen , Papadimitrakopoulou Vassiliki , Blowers David , Moran Cesar , Kalhor Neda , Rice David C. , Beran Garry , Lee J. Jack , Kilgour Elaine , Wistuba Ignacio Ivan
Published: March 2020

7552

Background: FGFR-1 is a novel target for therapy in non-small cell lung carcinoma (NSCLC). FGFR1 gene has been shown to be amplified in ~20% of squamous cell carcinomas (SCC) of the lung. The frequency of FGFR1 copy number gain (CNG) and gene amplification (GA) in lung adenocarcinoma (AC) is unknown, and the clinicopathological and molecular characteristics of the NSCLC tumors with FGFR1gene increase have not been fully described. Methods: We examined FGFR1 gene copy number (GCN) by fluorescent in-situ hybridization (FISH) and FGFR1 protein expression by immunohistochemistry in 475 surgically resected NSCLCs (162 SCCs, and 313 ACs) stages I-III in tissue microarrays. Three FGFR1 FISH categories were identified: a) no CNG; b) CNG, defined as ≥4 gene copies in ≥40% of cells; c) GA, defined as ratio of copies of FGFR1:CEP8 ≥2 or presence of tight gene clusters in ≥10% of cells. FGFR1 protein expression in the cytoplasm and membrane of tumor cells was quantified using H score. Results: FGFR1 GA was detected only in SCCs (14 cases, 9%). CNG was detected in both SCC (39 cases, 24%) and AC (80 cases, 26%). In AC, significantly higher frequency of CNG was detected in patients with smoking history (P=0.008) and in tumors with low differentiated histology (P=0.0005). No correlation was detected between FGFR1 CNG and mutation of KRAS and EGFR in AC. In SCC, tumors with FGFR1 CNG/GA had higher cytoplasmic FGFR1 protein expression than those with no copy changes (49±39 vs. 26±21, P<0.001), and the protein expression correlated with GCN (R=0.55; P<0.001). In multivariate analysis, patients with stage I/II SCCs having FGFR1 gene copy ≥6 or GA showed a significantly better overall survival (HR=0.26; 95% CI: 0.08-0.84, P=0.02) than patients with <6 gene copy, after adjusting for smoking, gender and tumor size. An increase on FGFR1copy number was detected in 8/45 (18%) brain metastasis compared with primary tumors. Conclusions: In NSCLC, FGFR1 GA occurs only is a small subset of SCCs (9%), whereas CNG is a relatively frequent phenomenon in both SCC (24%) and ACs (25%). FGFR1 copies ≥6 or GA is associated with better outcome in patients with surgically resected stages I/II SCCs of the lung.
The role of lymphatic vascular invasion in the prognosis and determination of therapy in surgically resected non-small cell carcinoma of the lung.
Authors: DeCamp Malcolm M. , Andrei Adin-Cristian , Ramakrishna Satvik , Medford-Davis Laura Nyshel , Shelkey Julia , McClean Megan , Recht Abram , Varlotto John M.
Published: March 2020

7554

Background: Lymphatic-vascular invasion (LVI) is not currently considered in staging of non-small cell lung cancer (NSCLC). We assessed the impact of LVI on overall survival (OS), local/distant recurrence (LR/DR) and patterns of recurrence. Methods: 869 consecutive patients who underwent a definitive surgical resection ± adjuvant chemotherapy for NSCLC from 2000–2008 were qualified for analysis if they did not receive any adjuvant/neo-adjuvant radiotherapy, had at least three months of follow-up, and did not have a history of other cancers within 5 years. Tumors with LVI (N = 160) were compared to tumors without LVI (N = 705). LR/DR rates at 2,3, and 5 years were calculated by the methods of Kaplan-Meier. Association between LVI and OS and LR/DR were compared in the total population and in a propensity matched population (PS) by factors affecting OS and LR/DR (n=160 matched pairs). Results: OS, LR, and DR were significantly worse in patients with LVI in the total population and in the subset of patients matched by propensity score (Table). In the PS-matched pairs, LVI was associated with a greater number of N1 nodes involved, a longer length of stay, higher histologic grade, and higher T-stage. Patterns of local failure (P<.001) but not distant failure (P=.11) differed between patients with and without LVI. Tumors with LVI were 3-fold more likely to recur in ipsilateral mediastinal nodes. In a subset analysis of tumors < 4cm (n=121 PS matched pairs), LVI was also associated with higher LR, DR, a lower OS and a 4-fold risk of mediastinal nodal recurrence. Conclusions: Detection of LVI in resected NSCLC predicts aggressive biologic behavior and provides important prognostic information. LVI may help identify high-risk cohorts within discreet TNM stages who could benefit from adjuvant therapies. [Table: see text]
The role of molecular profiling to differentiate multiple lung primary adenocarcinomas from intrapulmonary metastases from a lung primary.
Authors: Mino-Kenudson Mari , Miyamoto Atsushi , Dias-Santagata Dora , Morales-Oyarvide Vicente , Bernardo Lindsay Ann , Pawlak Amanda , Han Jae Young , Davies Diane L. , Lanuti Michael , Mark Eugene J. , Iafrate Anthony John
Published: March 2020

7555

Background: In the case of patients with multiple lung adenocarcinomas (ADCs) (whether synchronous or metachronous), the distinction of intrapulmonary metastases from independent primaries is clinically important as it impacts staging and thus therapeutic strategy. Currently the distinction is made based principally on histology of the tumor. Molecular profiling is becoming a routine diagnostic procedure for lung cancer to help treatment decision-making. Thus, we sought the role of mutation assays to differentiate multiple primaries from metastases. Methods: 45 synchronous and 37 metachronous cases of multiple tumors were obtained at 103 surgeries in 68 patients. Each of the resultant 156 tumors was tested with the SNaPshot multiplex PCR genotyping assay and each case, based on molecular profiling, was classified as synchronous multiple primaries (SP), metachronous primaries (MP), synchronous intrapulmonary metastases (SM), or metachronous metastases (MM). Each case was also classified into 4 groups by a comprehensive histologic analysis. Clinical outcomes were compared between multiple primaries (SP and MP) and metastases (SM and MM) in the molecular and histologic analyses using Log-rank test. Results: Based on histology alone, SP were present in 37 cases, MP in 32, SM in 8 and MM in 5. The molecular results were interpreted as SP in 25, MP in 21, SM in 10 and MM in 11. 15 of the 82 cases were non-informative, since no mutations were identified in any lesions. Of the 67 cases harboring mutations, 21 (31%) showed discordant results consisting of 16 with SP or MP by histology and SM or MM by molecular profiling. 5 cases showed the opposite results. Molecular profiling showed a trend toward the 5-year survival of the patients with metastases being shorter than those with multiple primaries (57 months vs. 87 months, P=0.068), which was not observed by histology (P=0.84). Conclusions: Although its performance is limited by non-informative results in 18% of cases of multiple ADCs, SNaPshot profiling for clinical use appears to be useful in determining whether multiple ADCs are primaries or metastases. Thus, it may allow for more accurate staging and optimal therapeutic management.
Human papillomavirus (HPV)-associated early stage non-small cell lung cancer (NSCLC).
Authors: Pillai Rathi Narayana , Ragin Camille , Sica Gabriel , Behera Madhusmita , Chen Zhengjia , Kim Sungjin , Mayfield William , Hermann Robert C. , Saba Nabil F. , Gal Anthony A , Khuri Fadlo Raja , Ramalingam Suresh S. , Owonikoko Taofeek Kunle
Published: March 2020

7560

Background: HPV is an established risk factor for cervical and oropharyngeal cancer. It has been suggested as a potential risk factor for lung cancer based on studies conducted mostly in Asian patients with advanced NSCLC. We characterize potential role of HPV in a North American patient population with early stage NSCLC. Methods: We analyzed surgically resected samples of NSCLC patients diagnosed between 2002-2007. HPV status was determined by polymerase chain reaction (PCR) using the INNO-LiPA genotyping Extra Amplification and Genotyping Extra kits, followed by reverse hybridization line probe assay to identify specific HPV serotypes. Differences between HPV+ and HPV- patients were assessed by Chi-square, Fisher’s exact, and Wilcoxon rank-sum tests. Survival was estimated by the Kaplan-Meier method and differences between HPV+ and HPV- patients were assessed by Log-rank test. Multivariable logistic regression modeling was employed to select predictors of HPV+ NSCLC. The significance levels were set at 0.05 for all tests. Results: Paraffin-embedded tumor samples from 208 patients were analyzed; M/F (49%/51%); stage I: 80%; II: 11%; III: 9%; IV: <1%; Caucasians 95.6% and African-Americans (AA) 4.4%. There were 32 (14.9%) HPV+ cases including 10 cases with HPV 16/18. Ethnicity was significantly associated with HPV status (p-value=0.033). AA patients are more likely to be HPV+ (OR: 7.373; p=0.01) and more likely to harbor high risk serotypes 16/18 (OR: 10.8; p=0.05). Regression modeling identified AA ethnicity, adenocarcinoma (ADC) histology and current smoking (parameter estimates of 2.04, -2.34 and -2.82 respectively) as predictors of HPV+ NSCLC. Smoking status and histology showed significant interaction in predicting HPV+ tumors: OR: 0.06; p=0.0023 for smokers with squamous cancer; 2.52; p=0.24 for smokers with ADC and 10.339; p=0.0293 for smokers with adenosquamous cancer. Median disease free survival (NR; p=0.42) and median overall survival (71 months; vs. 55 months) were not significantly different between HPV+ and HPV- patients. Conclusions: HPV positivity is observed in 15% of early stage NSCLC with strong association with AA ethnicity, adenosquamous histology and non-smoking status.
Identification of actionable mutations in surgically resected tumor specimens from Japanese patients with non-small cell lung cancer by ultra-deep targeted sequencing.
Authors: Koh Yasuhiro , Kenmotsu Hirotsugu , Serizawa Masakuni , Isaka Mitsuhiro , Mori Keita , Imai Hisao , Akamatsu Hiroaki , Ono Akira , Naito Tateaki , Taira Tetsuhiko , Murakami Haruyasu , Takahashi Toshiaki , Endo Masahiro , Nakajima Takashi , Ohde Yasuhisa , Yamamoto Nobuyuki
Published: March 2020

7572

Background: Detection of tumor genetic alterations is critically needed for lung cancer clinic as well as for the development of molecular targeted therapeutics. Here we report the results of a broad spectrum of genetic alterations identified in Japanese non-small cell lung cancer (NSCLC) patients by ultra-deep targeted sequencing. Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens. TruSeq amplicon cancer panel was used for the detection of somatic mutations in 48 cancer related genes followed by ultra-deep sequencing (Illumina) at an average coverage of approximately 2800x. ALK, ROS1 and RET traslocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications were also detected by multiplex RT-PCR and quantitative PCR, respectively. Results: The demographics of 204 consecutive patients enrolled in this prospective study at Shizuoka Cancer Center between July 2011 and November 2012: median age 69 years (range: 38-92); male 66%; never smoker 25.5%; histology: adenocarcinoma 68.6%, squamous cell carcinoma (SQ) 27.0%, others 4.4%; tumor stage: I 53.9%, II 28.4%, III 12.7%, IV 4.9%. TP53 mutation was most frequently detected (44.4%) in all patients, particularly in SQ (67.9%). Mutations in genes such as MLH1 (4.9%), STK11 (6.3%), CTNNB1 (5.6%), SMAD4 (1.4%), VHL1 (1.4%), PTPN11 (0.7%) and GNAS (0.7%) were detected besides major mutations in genes such as EGFR (43.0%), KRAS (17.6%) and PIK3CA (14.1%) in adenocarcinoma. PIK3CA (21.4%), MLH1 (5.4%), APC (3.6%), STK11 (3.6%), FGFR2 (1.8%) and VHL (1.8%) mutations were identified in SQ and notably, 48.2% of SQ patients harbored simultaneous gene mutations, suggesting the genetic complexity of this histology. FGFR1 amplification was found in 8.9 % of SQ, suggesting lower frequency in Asian population than in Caucasian population. Conclusions: We managed to detect a wide range of genetic alterations and identified additional actionable mutations besides popular driver mutations. This approach may facilitate elucidation of detailed molecular characteristics of NSCLC, thereby implementing personalized cancer medicine.
Has the paradigm changed away from lobectomy for stage I non-small cell lung cancer (NSCLC)? Anatomic segmentectomy: Surgery’s answer to image-guided ablation/radiation therapy for the small peripheral lung lesion.
Authors: Schuchert Matthew J. , Wizorek Joseph J. , Normolle Daniel Paul , Wilson David O , Siegfried Jill , Awais Omar , Abbas Ghulam , Luketich James D. , Landreneau Rodney Jerome
Published: March 2020

7577

Background: Lobectomy has been the “gold standard” for stage I NSCLC management. Image guided ablation/radiation therapy approaches are now being touted as alternatives to surgery despite concerns regarding diagnosis, pathologic staging, local control, and delayed toxicities. We evaluated the diagnostic utility and oncologic efficacy of lung sparing, anatomic segmentectomy for indeterminate pulmonary nodules and clinical stage I NSCLC. Methods: Retrospective review of 1,005 anatomic segmentectomies from 2002-2012 for indeterminate pulmonary nodules and clinical stage I NSCLC. Outcome variables included perioperative data, morbidity and mortality. Survival was assessed with the Kaplan-Maier method. Results: Mean age was 66.7 years. Median lesion size was 1.9 cm. VATS was employed in 62.8% of cases. Median operative time and blood loss was 112 minutes and 80 ml, respectively. Median hospital stay was 5 days. Major complications occurred in 12.7%. Thirty-day mortality was 1.0%. Of these, NSCLC was identified in 71.6%, metastases in 8.7%, and other benign conditions in 19.7%. Among patients with clinical stage I NSCLC, clinical: pathological upstaging was seen in 34.5%. Local recurrence rate was 5.2% and five-year freedom from any recurrence was 69%, equivalent to lobectomy in our experience. Conclusions: Anatomic segmentectomy is a valuable primary surgical approach today. In this era of competing image-guided ablation modalities, anatomic segmentectomy provides safety, diagnostic accuracy and adherence to oncologic surgical principles including completeness of resection with adequate surgical margins, systematic nodal staging improving pathologic accuracy, and tissue for pharmacogenomic assessment to guide individualized adjuvant therapy.
Multi-institutional study of reirradiation with proton beam radiotherapy for non-small cell lung cancer.
Authors: Berman Abigail T. , Martin Christine Agnes , Lin Haibo , Both Stefan , Langer Corey J. , Varillo Kristi , Rengan Ramesh , Hahn Stephen M. , Fagundes Marcio , Hartsell William F. , Simone Charles B. , Plastaras John Peter
Published: March 2020

7578

Background: The management of recurrent non-small cell lung cancer (NSCLC) in the setting of prior radiation (RT) is complex. Proton radiotherapy (PRT) is ideally suited to minimize toxicity by sparing dose to previously-irradiated organs. Herein we report the safety and feasibility of PRT for NSCLC reirradiation. Methods: Patients (pts) with recurrent NSCLC in or near their prior RT field were identified in three proton centers. An interval of 3 months was required between original RT course and PRT start. Pts were classified as low volume (LV, clinical target volume [CTV] ≤250 cc) or high volume (HV, CTV >250 cc). PRT was deemed infeasible if pts were unable to tolerate 15% of fractions or complete all treatments in <10 days of estimated end date and without a break ≥5 days. Results: Between 10/2010-11/2012, 24 pts were reirradiated, with 12 on a prospective trial of PRT for reirradiation. Median age was 69 (51-89). Histologies included squamous cell carcinoma (50%), adenocarcinoma (39%), and other (13%). Stage at initial diagnosis was I (8.3%), II (20.8%), III (50%), IV (12.5%), and unknown (8.3%). All pts were ECOG PS 0-2. Median prior dose was 62.4 Gy (30.6-80); 1 pt had 2 prior RT courses. The majority of pts (63%) were LV (median CTV 75.3, 11.9-236) and 38% were HV (359, 297.8-695.7). Concurrent systemic therapy (platinum-based or erlotinib) was given in 63%. Median PRT dose was 66.6 Gy (36-74). Average mean lung dose was 7.6 and 10.8 Gy and lung volume receiving 5 and 20 Gy was 16 and 24% and 26 and 33% in LV and HV pts, respectively. Follow up was >60 days in 17 pts. Overall, 46% of pts were hospitalized. PRT was infeasible in 3/9 HV and 1/15 LV pts. In HV pts, there were 2 grade 5 toxicities (hemoptysis and neutropenic fever). There was 1 in-field and 4 other thoracic recurrences, and 5 and 4 deaths in LV and HV pts, respectively. Conclusions: Preliminary results show promising early outcomes and acceptable toxicity in LV pts; due to the toxicity seen in HV pts, additional exclusion criteria were added for NSCLC pts in the ongoing trial. NSCLC reirradiation should continue to be studied in prospective trials to identify pts that may derive clinical benefit. Mature follow up is needed prior to standardizing NSCLC reirradiation with PRT.
Multiplexed genetic analysis of malignant pleural mesothelioma and the relationship to clinical outcome.
Authors: Shukuya Takehito , Serizawa Masakuni , Abe Masato , Akamatsu Hiroaki , Tokito Takaaki , Imai Hisao , Ono Akira , Taira Tetsuhiko , Kenmotsu Hirotsugu , Naito Tateaki , Murakami Haruyasu , Takahashi Toshiaki , Endo Masahiro , Nakajima Takashi , Koh Yasuhiro , Yamamoto Nobuyuki
Published: March 2020

7582

Background: Genotype-based stratification is essential to improve cancer treatment. We have developed a multiplexed tumor genotyping panel for detecting gene alterations relevant to molecular targeted therapies. We applied this genotyping panel to malignant pleural mesothelioma (MPM) and evaluate the relationship between clinical outcome and gene alterations. Methods: Surgical specimens and tumor biopsies from 40 patients with MPM were collected from 2003 to 2012. Pathological diagnoses were confirmed by immunohistochemistry in addition to HE stain. 37 patients were genotyped with multiplexed tumor genotyping panel developed to assess 9 gene mutations (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2) and 5 genes amplifications (EGFR, MET, PIK3CA, FGFR1 and FGFR2) using pyrosequencing plus capillary electrophoresis, and qRT-PCR, respectively. Other 3 patients were analyzed by ultra-deep targeted sequencing with next generation sequencer. 5 fusion genes (EML4-ALK, CD74-ROS1, SLC34A2-ROS1, KIF5B-RET and CCDC6-RET) were tested in 2 patients with fresh frozen specimens. Results: Gene alterations were detected in 6 patients (Table shown below). These patients harboring gene alterations showed poorer survival than the patients in whom gene alterations were not detected (median survival time (MST): 583 vs 164 days, log-lank: p=0.009). Moreover, the patients with PIK3CA amplification/mutation showed poorer survival than the patients without PIK3CA amplification/mutation (MST: 583 vs 103 days, log-lank: p=0.031). Conclusions: Gene alterations which could be a target for molecular targeted therapy were detected in MPM. Especially, PIK3CA pathway is a potential target. [Table: see text]