bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of annual screening of lung cancer with low dose computed tomography in 5,000 high-risk individuals
Authors: Veronesi G. , Bellomi M. , Spaggiari L. , Pelosi G. , Sonzogni A. , Paganelli G. , Preda L. , Solli P. , Maisonneuve P. , Leo F. , Veronesi U.
Published: March 2020

7566

Background: Screening detected lung cancers are correlated with good prognosis however most of the reported cases were detected at baseline screening and little is known about the evolution of pulmonary nodules at annual screening. We report the results of the first and second year of a single centre screening trial focusing the attention on the evolution of pulmonary nodules. Methods: The Cosmos trial started in October 2004 and enrolled 5,202 asymptomatic persons at high risk for lung cancer in one year. Between October 2005 and October 2006, the participants of the study, have been recalled to undergo the annual low dose CT. New lesions were treated according to the baseline diagnostic work up protocol. Previously detected lesions grown at annual screening were investigated with repeated low dose CT and/or Pet scan. Surgical biopsy was scheduled in case of Pet positive or growing nodules. Stable lesions were sent to one year follow up. Results: 4,745 out of 5,202 underwent the annual screening (compliance 92%). Recall rate was 10.7% at baseline and 4% at annual screening. Rate of malignant disease was 1.03% at baseline and 0.7% at annual screening. Patients with stage I disease were 68% at baseline and 76% at annual screening. Of the 32 lung cancers diagnosed at annual screening 8 were new nodules, 1 nodules was stable and 23 nodules progressed from the previous year. Among these, 9 nodules were lower than 5 mm at baseline (out of 2,190 subjects = 0.4%) and 14 were larger than 5 mm (out of 560 subjects =2.5%). Conclusions: Screening low dose spiral CT is an effective tool for the early detection of lung cancer. At first annual screening malignancy rate decreased from 1% to 0.7% and stage distribution was more favourable. However the high rate of delayed diagnosis (2.5%) in cases of nodules larger than 5 mm at baseline CT may require a revision of our proposed diagnostic work up protocol to further anticipate detection of these cases.

No significant financial relationships to disclose.
A multi-gene assay to predict long-term mortality in early stage lung adenocarcinoma
Authors: Raz D. J. , Kim J. Y. , Ray M. R. , Jablons D. M.
Published: March 2020

7569

Background: The likelihood of long-term mortality for patients with early stage lung adenocarcinoma is poorly defined by clinical stage and histopathological findings. Our hypothesis was that a multigene quantitative polymerase chain reaction (PCR) assay can predict risk of mortality among patients with early stage lung adenocarcinoma. Methods: We identified 65 genes that were previously identified as prognostic for long-term mortality in early stage lung cancer in 3 published microarray studies and 2 PCR-based studies. RNA was extracted from 124 fresh-frozen tumor samples from consecutive patients with completely resected lung adenocarcinoma with at least 3 years of clinical follow-up. 80 samples were randomly assigned to a test group and the remainder assigned to a validation group. Real-time PCR of the 65 identified genes were run on the test set using Taq-man assays. A prediction model was created using a proportional hazards model of normalized gene expression levels using backwards model selection. A model score was calculated for each patient using model coefficients and individual gene expression levels. Patients were defined as high-risk if the model score was greater than the median score. Results: Adequate real-time PCR profiles were identified in all 80 patients. Eighteen genes were included in the final model. The proportion of patients identified as high-risk and low-risk was 52% and 48% percent, respectively. The Kaplan-Meier estimated five-year survival in the low-risk group was 82% and 5% in the high-risk group (P<0.001, log-rank test). Median survival was 22 months in the high-risk group and was not reached in the low-risk group. In multivariate survival analysis, the prognostic score predicted survival independent of tumor stage and size (P<0.001). Prognostic score predicted mortality better than clinical stage, based on model log-likelihood values (P<0.001). Conclusions: This multi- gene assay aids in predicting long-term mortality among patients with surgically resected early stage lung adenocarcinoma. We are currently validating this model in our test set of samples.

No significant financial relationships to disclose.
The NATCH trial: Observations on the neoadjuvant arm
Authors: Felip E. , Rosell R. , Massuti B. , Alonso G. , González-Larriba J. L. , Camps C. , Isla D. , Mas C. , Sanchez J. J. , Maestre J. A.
Published: March 2020

7578

Background: In early-stage NSCLC the neoadjuvant approach is a promising option since relatively low compliance rate with adjuvant therapy and incomplete recovery after surgery are commonly reported. The NATCH trial was therefore designed to address whether neoadjuvant or adjuvant paclitaxel (P)/carboplatin (C) improves disease-free survival compared to surgery alone in early-stage NSCLC. Patients randomized to the neoadjuvant arm have now undergone analyses of toxicity, radiographic response, resectability and surgical mortality. Methods: Consenting patients with clinical stage I (>2 cm), II, T3N1 NSCLC are randomized to surgery alone or 3 cycles of neoadjuvant PC (P: 200 mg/m2/ C:AUC=6 on day 1 every 3wk), or surgery followed by 3 cycles of adjuvant PC at the same schedule. Planned sample size of this prospective, randomized trial is 628 patients. Results: Since 2000, 616 patients have been accrued, 200 in the neoadjuvant arm, 208 in the adjuvant arm, and 208 in the surgery arm. Demographic data is now available for 162 patients in the neoadjuvant arm: 89% male; median age 64 years (range, 37–78); 45% PS 0; 53% squamous cell, 27% adenocarcinoma, 13% large cell; 7% stage IA, 64% IB, 2% IIA, 24% IIB, 2.5% T3N1. Neoadjuvant chemotherapy has been well tolerated with a median number of cycles per patient of 3. No unexpected toxicities have been seen with 12% of patients having grade 3–4 neutropenia and 43% grade 1–2 anemia. Major radiographic response has been observed in 59% of patients and progression during chemotherapy occurred in 6%. No patient characteristics were predictive for clinical response. Resection procedures at thoracotomy: lobectomy or bilobectomy in 70%, pneumonectomy in 26%, and explorative thoracotomy due to unresectable disease in 3% of patients. Post-operative mortality was 4%. Median tumor size was 4.5 cm at baseline CT-scan and 2.5 cm at surgery. At surgery, 9% patients had pathologic complete response, 75% N0–1 disease (with persistent T tumor), and 15% pathologic N2 disease. Conclusion: Neoadjuvant chemotherapy in early NSCLC has proven feasible and safe in this large multicenter sample. Chemotherapy compliance has been high and resectability rates as expected. Our findings are comparable with those of previous studies (BLOT and S9900). Mature survival results of the NATCH trial are expected in 2009.

No significant financial relationships to disclose.
Triplets vs. doublets in the management of advanced non-small cell lung cancer (NSCLC) using third generation chemotherapeutic agents: A meta-analysis
Authors: Azim H. A. , Ganti A. K. , Elattar I. , Azim H. , Loberiza F. R.
Published: March 2020

7580

Background: A platinum-based doublet is the current standard of care in the management of NSCLC. Addition of a third agent to the doublet has not shown to improve outcomes in a previous meta-analysis. Since one of the reasons for this may have been the inclusion of trials utilizing agents inferior to the currently used, we conducted a meta-analysis to evaluate the benefit of adding a third generation cytotoxic chemotherapeutic agent to a platinum doublet in terms of response rate, survival, and toxicity in patients with advanced NSCLC. Methods: Randomized controlled trials for advanced NSCLC, published as full papers in English, comparing doublets to triplets restricted to platinum salts and third-generation cytotoxic chemotherapeutic agents (vinorelbine, gemcitabine, docetaxel, paclitaxel) were analyzed. A Medline search was performed using the search terms “lung cancer” and “randomized trials”. Manual searches were also performed in the Journal of Clinical Oncology and Annals of Oncology. Pooled odds ratios (ORs) for the objective response and toxicity rates were calculated using the Mantel-Haenszel estimate. Pooled median ratios for median survival were calculated using the weighted sum of the log-ratio of median ratios of individual study. Results: Eight trials (2,107 patients) published between 2000 and 2006 were eligible. Patients receiving triplet therapy had a significantly increased response rate (OR 1.86; 95% CI, 1.53 –2.26; P<0.001) and median survival (41.9 weeks vs. 37.05 weeks; OR: 1.14, 95% CI: 1.00–1.31; P=0.047), at the expense of higher grade III/IV hematological and neurological toxicity (P<0.001) ( Table ). Conclusions: The addition of a third-generation cytotoxic agent to a platinum-based doublet was associated with improved response rate and survival, but with increased hematological and neurological toxicity. Thus, triplet therapy may be considered in selected good performance status patients with advanced NSCLC.

No significant financial relationships to disclose.

[Table: see text]
Skin rash as surrogate marker of efficacy in patients with non-small cell lung cancer treated with erlotinib
Authors: Cobo M. , Cardenal F. , Insa A. , Domine M. , Lianes P. , Guillot M. , Montesinos J. , Bover I. , Amador M. L. , Paz-Ares L.
Published: March 2020

7602

Background: Erlotinib is an orally EGFR TKI approved for the treatment of advanced non-small-cell lung cancer. Its most frequent and specific toxicity is a rash which generally occurs in a dose-dependent manner. A relationship between rash and clinical outcome have been suggested. Methods: The TargeT trial was an open-label, non-randomized, phase II study carried out in 101 Spanish institutions. Patients (p) with confirmed NSCLC (stage IIIB-IV) were treated with 150 mg/day po until disease progression or unacceptable toxicity. Primary objective was time to progression. Here we report a retrospective analysis describing outcomes in terms of response and survival in the group of patients who developed rash and those who did not. Results: Data were available for 1,255 p. Key baseline characteristics were similar in p with and without rash. Median age 65y (range 26–95) Most p were male (75%); active/former smoker (82%) 51% adenocarcinoma histolog. ECOG PS 0/1/2 were (%) 20/53/27. The % p receiving erlotinib as 1st/2nd/3rd- line treatment were 26/39/35. 698 patients were evaluable for response. Objective response rate (ORR) 12.6% with 51% control disease rate. Skin rash of any grade was observed in 73.4% p, among these p, responses were observed in 14.3%. In p with no rash ORR was 8.1% (p=0.03). Control disease rate was significantly higher among p experiencing rash (56.6%) than those without rash (35.48%; p<0.0001). Median time to progression for p with rash were 3.8 mo (95% CI: 3.4–4.3), compared with 2.3 mo (95% CI: 2.1–2.6) in those with no rash (p<0.001). Similar trend was found in overall survival 6.5 mo (95% CI: 6.1–7.3) in p with rash versus 2.3 mo (95% CI: 2.3–2.7; p<0.001). In addition p who developed rash grade =2 had significantly longer TTP (4.2 m; 95% CI 3.6–4.8; p<0.001) and OS (7.9 mo; 95% CI 6.5–8.8). Conclusions: This retrospective analysis suggest a correlation between skin rash development and severity and treatment outcome. Skin rash seems to be a surrogate marker of efficacy. Studies to prospectively investigate the association between increased dosing of erlotinib, skin rash and optimal response are currently ongoing. However, data from our analysis indicate that skin toxicity is neither sufficient nor necessary condition for an optimal outcome.

No significant financial relationships to disclose.
Concomitant chemoradiation plus induction (I) or consolidation (C) chemotherapy (CT) with docetaxel (D) and gemcitabine (G) for unresectable stage III non-small cell lung cancer (NSCLC) patients (p). Results of the randomized SLCG 0008 phase II trial
Authors: Garrido P. , Massutí T. , Morán T. , Cardenal F. , Juan O. , Dómine M. , Cobo M. , García R. , Maestu I. , Isla D.
Published: March 2020

7620

Background: Neither the optimal sequence of treatment nor the best combination CT is yet well-defined in p receiving concomitant therapy Methods: P with unresectable stage III NSCLC with IK ≥ 70 and weight loss < 5% were initially randomized to sequential treatment (arm A), concurrent CT/TRT followed by consolidation CT (arm B) or induction CT followed by CT/TRT (arm C). Based on RTOG 9410 results, arm A was closed and the study continues with two concomitant arms (B, C). All p receive 2 cycles of D 40 mg/m2 d1, 8 plus G 1,200 mg/m2 d1, 8 as I or C therapy. Concomitant treatment includes D 20 mg/m2 and carboplatin (Cb) AUC 2 weekly plus 60 Gy TRT. Results: From May 01 to Jun 06, 151 p were included (A: 19, B: 66, C: 66). Due to the early closing of arm A, only data of evaluable arms B and C p are shown: toxicity 127 p (B: 63, C: 64) and response 110 p (B: 53, C: 57). All groups are well-matched for baseline disease characteristics. Toxicity grade 3–4 by CTC and RTOG criteria was: esophagitis 19.5% (arm B) and 14.2% (arm C); pneumonitis 8.8 % (arm B) and 10% (arm C). Neutropenia during I or C therapy: 22% (B) and 6.2% (C). Thrombocytopenia 8% (B) and 3% (C). Neutropenia during concomitant therapy: 6.3% (B) and 6% (C). No thrombocytopenia or severe anemia was found during CT/TRT. The reduction CT rate was superior in consolidation (35%) than in induction (15%) and in arm C during concomitant therapy (22.4% C, 6.5% B). Delay of CT dose was similar in B and C arms during I or C (22% B, 20% C) but superior in arm C during concurrent treatment (19.6% B, 30.6% C). The final response rates were 57% (B) and 56.9% (C). A trend for longer time to progression (TTP) was found (B: 7.6 months (m) and C: 9.2 m; p= 0.12) but with similar overall survival (B: 14.3 m and C: 14.7 m; p=0.38). Conclusions: Non- platinum CT plus concomitant chemoradiation offer similar response rate and a favorable hematological toxicity profile in unresectable stage III NSCLC p. No differences in OS but a trend for longer TTP in the arm C (I followed by concurrent approach) has been found. Final data are pending in order to select the best sequence for further studies.

No significant financial relationships to disclose.
Stereotactic bradiotherapy (SRT) for operable stage I non-small cell lung cancer: Is SRT comparable to surgery?
Authors: Onishi H. , Shirato H. , Nagata Y. , Hiraoka M. , Kotaro G. , Karasawa K. , Niibe Y. , Hayakawa K. , Takai Y. , Kimura T.
Published: March 2020

7623

Background: Stereotactic radiotherapy (SRT) has been aggressively performed as a radical treatment for stage I non-small cell lung cancer (NSCLC) in Japan, however most cases were medically inoperable. In a large Japanese multi-institutional experience, we reviewed the treatment outcome of SRT for medically operable stage I NSCLC cases with the patients’ refusal to surgery. Methods: In 1995–2004, 86 medically operable patients with stage I NSCLC (median age, 74 years; 62 T1N0M0; 24 T2N0M0) were treated with SRT alone in 14 reliable institutions. Stereotactic three-dimensional treatment was performed using non-coplanar dynamic arcs or multiple static ports. A total dose of 20 to 72.5 Gy at the isocenter was administered in 1 to 10 fractions. Median calculated biological effective dose (BED) was 115 Gy (range, 100–153 Gy). The data was collected and analyzed in a retrospective manner. Results: During follow-up (median, 43 months), pulmonary complications of above grade 2 arose in 4 patients (5.8%). Local control rates at 3 and 5-year post SRT were 88.1% and 85.5%, respectively. Three and 5-year overall survival rates were 80.7% and 71.3%, respectively. Five-year overall survival rate for patients whose age was over 70 years (n=27) and under 70 years (n=58) were 74.3% and 69.6%, respectively. Five-year overall survival rate for stage IA (n=62) and IB (n=24) cases were 72.3% and 68.4%, respectively. Conclusions: SRT is safe and promising as a radical treatment for operable stage I NSCLC. The survival rate of SRT is potentially comparable to that of surgery.

No significant financial relationships to disclose.
Activated c-Met[pY1003]: A potential marker of intrinsic resistance and therapy target to restore sensitivity to gefitinib
Authors: Zucali P. A. , Gallegos Ruiz M. , Giovannetti E. , Destro A. , Floor K. , Ceresoli G. L. , Rodriguez J. A. , Roncalli M. , Santoro A. , Giaccone G.
Published: March 2020

7624

Background: Epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) show anti-tumor activity in only 10% of Caucasian non-small cell lung cancer (NSCLC) patients. Aim of this study was to evaluate several biological parameters potentially related to EGFR, including c-Met activation, as potential markers of intrinsic resistance to EGFR-TKIs in NSCLC. Methods: P-Akt, p-Erk, c-Src, E-Cadherin, c-Met[pY1003] and c-Met[pY1230/1234/1235] status was immunohistochemically determined on a tissue micro-array of tumor samples from 51 NSCLC patients treated with gefitinib. EGFR, k-ras, and c-Met mutation analysis was also carried out. A panel of NSCLC cell lines expressing c-Met[pY1003] were treated with gefitinib (0.01–100μ M) alone or in combination with hepatocyte growth factor (40 ng/ml) and the c-Met-agonistic antibody DN-30 (80 μg/ml) for 72 hours in 0.5% FCS medium. Drug interaction between gefitinib and DN-30 was assessed, at a non-constant concentration ratio, using the combination index (CI) method. Results: There was no association between p-Erk, c-Src, E-Cadherin, c-Met[pY1230/1234/1235], and k-ras status and response or survival. EGFR exon 19 deletion and p-Akt nuclear staining were significantly associated with response (P<0.0001; Fisher's exact test) and longer time to progression (TTP) (P=0.007; log-rank test), respectively. High c-Met[pY1003] membrane staining was significantly associated with progressive disease (P=0.019; Fisher's exact test) and shorter TTP (P=0.0416; log-rank test), but not with survival. Multivariate analysis confirmed a significant relationship between c-Met[pY1003] and increased risk of disease progression (HR=2.464, 95% CI 1.293–4.696, P=0.006). No c-Met mutations were found. In vitro, the combination with DN- 30 synergistically (CI<1) enhanced gefitinib-induced growth inhibition in all c-Met[pY1003]-expressing NSCLC cells studied (H460, SW1573, A549 and H292). Conclusions: Activation of c-MET may be a biological marker of intrinsic resistance to gefitinib in NSCLC patients, and combined inhibition of c-Met and EGFR may be a suitable therapeutic approach in patients with activated c-Met[pY1003] tumors.

No significant financial relationships to disclose.
Bevacizumab: Analysis of clinical benefit in females across trials in colorectal cancer and non-small cell lung cancer
Authors: Ramies D. A. , Sandler A. , Gray R. , Giantonio B. , Brahmer J. , Lyons B. , Schiller J.
Published: March 2020

7634

Background: Bevacizumab (Bv) has demonstrated significant improvement in overall survival (OS) in randomized trials in first- and second-line (FL and SL) metastatic CRC (mCRC), FL NSCLC, and progression-free survival (PFS) in metastatic breast cancer (mBC). However, in FL metastatic non-squamous NSCLC, OS benefit was less robust in females treated with Bv + chemotherapy (CTx). In order to examine whether there is a gender effect upon efficacy in other trials, an analysis of results from randomized ph II and open-label ph III trials with Bv in mCRC (and a randomized ph II trial in SL NSCLC) was conducted for females. Methods: RR, PFS and OS are summarized for females in the following trials (primary endpoint): 1] ph II FL mCRC (PFS); 2] ph III: FL mCRC (OS); 3] ph III SL mCRC (OS); 4] ph II SL NSCLC (PFS); 5] ph III FL NSCLC (OS). Results: Table 1 presents results of Studies 1 - 5. RR is presented as the difference in RR between Bv and respective control arms. Conclusions: Clinical benefit with Bv + CTx compared to CTx-alone was observed in OS for females in studies which included Bv in treatment of mCRC. OS observed in females in Study 5 (FL NSCLC) is inconsistent with findings in mCRC, mBC and SL NSCLC, and the improvement for PFS and RR for females in Study 5. As such, there is no compelling evidence to suggest lack of benefit with Bv in females.

[Table: see text] [Table: see text]
Vaccination of patients with advanced non-small cell lung cancer with an optimized cryptic hTERT peptide (Vx-001)
Authors: Kosmatopoulos K. , Bolonaki E. , Kotsakis A. , Papadimitraki E. , Agouraki D. , Kosnoslakis G. , Vagia A. , Christophylakis C. , Georgoulias V. , Mavroudis D.
Published: March 2020

7642

Background: To evaluate the immunological and clinical efficacy of the optimized peptide TERT572Y (Vx-001) presented by HLA-A*0201 in patients with advanced non-small cell lung cancer (NSCLC). Methods: Twenty-two patients with residual (n=8) or progressive (n=14) advanced NSCLC following chemotherapy and/or radiotherapy received two subcutaneous injections of the optimized TERT572Y peptide followed by four injections of the native TERT572 peptide given every 3 weeks. Peptide-specific immune responses were monitored by Elispot assay and/or TERT572Y pentamer staining. Clinical outcome was compared with that of 22 case-matched historical control patients. Results: Thirteen (59%) out of 22 patients completed the vaccination program. Toxicity consisted primarily of local skin reactions. TERT572-specific CD8+ cells were detected in 16 (76.2%) out of 21 patients after the 2nd vaccination and 10 (90.9%) out of 11 patients after the 6th vaccination. Stable disease occurred in 8 (36.4%) patients with a median duration of 11.2 months. Patients with an early immunological response (n=16) had a significantly longer time to disease progression and overall survival than non-responders (n=5) (log-rank tests p=0.046 and p=0.012, respectively). The estimated median overall survival was 30.0 (range, 2.8–40.0) and 4.1 (range, 2.4–10.9) months for immunological responders and non-responders, respectively. Moreover, median overall survival was 30.6 months (95% CI:10.9–48.9) and 6.1 months (95% CI:4.4–7.8) for the vaccinated and case-matched historical control patients, respectively (p=0.074). Conclusions: TERT572Y peptide vaccine is well tolerated and effective in eliciting a specific T-cell immunity which seems to be associated with prolonged patients’ survival.

No significant financial relationships to disclose.
Erlotinib in non-small cell lung cancer (NSCLC): Interim safety analysis of the TRUST study
Authors: Gatzemeier U. , Ardizzoni A. , Horwood K. , van Meerbeeck J. , Magyar P. , Gottfried M. , Arrieta O. , Krzakowski M. , Franke F. , van Zandwijk N.
Published: March 2020

7645

Background: In patients (pts) with relapsed NSCLC, erlotinib 150 mg/d significantly prolonged survival, delayed symptom progression, and improved quality of life versus placebo (Shepherd et al, N Engl J Med 2005;353:123–32). TRUST is an open label, non- randomized trial initiated to provide erlotinib access to pts with advanced NSCLC. Methods: Eligible pts had stage IIIb/IV NSCLC, and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/d p.o.) was given until disease progression or unacceptable toxicity. Pts were monitored monthly. Results: In November 2006, data were available for 5,015 pts (ITT population) from 51 countries. Median age was 63y (range 19–95). Pt characteristics (%) were: male/female 62/38; Caucasian/Oriental/other 76/19/5; non-smoker/ex- or current-smoker 28/71 (no data 1); ECOG PS 0/1/2/3 21/53/20/6; adenocarcinoma/squamous cell/other 53/25/21; stage IIIb/IV 22/78; erlotinib 1st/2nd/3rd-line/other 14/48/37/1. Safety data were available for 4,423 pts, 55% of whom had at least one adverse event (AE). Only 5% had one or more erlotinib- related serious AEs, the most common being gastrointestinal (GI) disorders (86 pts; 63 grade [gr] 3/4). 6% of pts discontinued treatment due to erlotinib-related AEs: GI disorders in 96 pts (54 gr 3/4), skin disorders in 92 (50 gr 3/4). Unexpected erlotinib-related AEs occurred in 10% of pts (4% gr 1, 3% gr 2, 3% gr 3/4). As expected, rash was observed in 70% of pts, with the majority (84%) being of gr 1/2. 80% pts received >4 weeks of erlotinib. Among 4,405 pts, only 14% had dose reductions, mainly due to rash (83%) and diarrhea (21%). Similar safety results were seen for 2nd-line pts only. Efficacy for all and 2nd-line pts will be presented. Conclusions: These results, achieved through routine clinical use of erlotinib in unselected pts with advanced NSCLC, confirm the favorable tolerability profile seen with erlotinib in selected patients in the clinical trial setting.

[Table: see text]
Prediction of distant relapse risk in stage I-II non-small cell lung cancer (NSCLC) by gene expression profiling
Authors: Jassem J. , Jarzab M. , Niklinski J. , Rzyman W. , Kowalska M. , Oczko-Wojciechowska M. , Kobierska-Gulida G. , Chyczewski L. , Szostakiewicz B. , Jarzab B.
Published: March 2020

7657

Background: Our aim was to determine the genes predictive for relapse-free and overall survival in stage I-II NSCLC. Methods: We analyzed the gene expression profiles in lung cancer specimens collected from 70 NSCLC patients (pts) who underwent curative pulmonary resection between 1999 and 2004 in two Polish centers (Gdansk, Bialystok). There were 54 men and 16 women aged 37–77 yrs (median 62.5 yrs), 45 with squamous cell ca, 22 with adenoca and 3 with large cell ca. Eight pts were staged pT1, 59 pT2 and 3 pT3; there were 49 and 21 pN0 and pN1 pts, respectively. 30 pts had a relapse and 32 pts died (median follow-up 36 months). Samples of tumor tissue were collected intraoperatively and snap-frozen, total RNA was isolated and gene expression profiling was carried out by Affymetrix HG-U133 2.0 Plus oligonucleotide microarray. Samples were pre-processed with RMA algorithm, gene selection was carried out by Support Vector Machines and Bayesian Compound Covariate Classifier, using own procedures and BRB-Array software developed by Simon and Peng Lam. Survival time prediction was carried out by method developed by Bair and Tibshirani (PLoS Biology 2004). Results: Based on the microarray gene expression profiling, the relapse could be predicted with 75.0% specificity and 53.3% sensitivity (positive predictive value [PPV] 61.5%, negative predictive value [NPV] 68.2%). The classifier, obtained by cross-validation of 70-sample dataset, consisted of 170 transcripts. Further gene selection was based on the prediction of the relapse-free survival: 1,919 genes, selected by fitting Cox proportional hazard model (p<0.05) and further used to predict survival by 4 principal components, distinguished between pts with high and low risk of relapse (p<0.05, log-rank test). The prediction of death was possible with 66.7% specificity and 57.1% sensitivity (PPV 53.3%, NPV 70%), but the distinction between high- and low-risk pts was significantly weaker than based on lymph node involvement (N0 vs. N1). Thus, for the final selection of genes this clinical variable was incorporated into the model as a covariate. Conclusions: Prediction of the risk of relapse in stage I-II NSCLC based on the gene expression profile is feasible, with NPV of 68.2%.

No significant financial relationships to disclose.
Predictive significance of bone sialoprotein and osteopontin for bone metastases in respectable non-small cell lung cancer: A retrospective study
Authors: Zhang L. , Hou X. , Rao H. , Hou J. , Luo R. , Huang H. , Huang P.
Published: March 2020

7666

Background: Bone sialoprotein (BSP) and osteopontin (OPN) have been demonstrated predictive of bone metastases in breast and prostate carcinoma, consistent with the proposed role of BSP as a stimulator of bone mineralization and OPN in differentiation and activation of osteoclasts. Bone metastasis (BM) is often developed in non-small-cell lung cancer (NSCLC), but no predictive biomarker was identified for high risk of metastatic bone dissemination. Methods: 180 completely resected NSCLC patients were included in this study. 38 patients subsequently developed BM. Paraffin embedded primary tumor tissue of patients were supplied to produce a tissue microarray, and immunohistochemistry method was used for evaluation the expression of BSP and OPN. Different expressions of these two biomarkers among BM group and non-BM group were estimated by χ2 test. Bone metastasis-free survival was analyzed by Kaplan-Meier method. The prognostic impact of clinicopathologic parameters and biomarker expression was evaluated by Cox propotional hazards model. Results: BSP expression was associated with BM (P=0.027), while OPN expression could not reach statistical significance (P=0.495). Univariate analysis demonstrated that expression of BSP (P=0.036), N stage (P=0.000) and clinical stage (P=0.001) were associated with time interval to BM. Multivariate analyses showed BSP expression (RR=1.779, P=0.012) and clinical stage (RR=1.620, P=0.005) were independent prognostic factors for BM. Conclusions: BSP protein expression in the primary resected NSCLC is strongly associated with BM and could be used to identify high-risk patients. Correlation of OPN protein expression and bone metastasis need further investigation.

No significant financial relationships to disclose.
Biomarker analysis from TRUST, a trial of erlotinib in non-small cell lung cancer (NSCLC)
Authors: Schneider C. , Schott-von Römer K. , Gütz S. , Raack B. , Dierkesmann R. , Laack E. , Guschall W. , Schmittel A. , Gatzemeier U.
Published: March 2020

7674

Background: The EGFR tyrosine kinase inhibitor erlotinib significantly prolonged survival and improved QoL in relapsed NSCLC patients (pts) (Shepherd et al. NEJM 2005;353:123). TRUST is an ongoing, single arm, international, multicenter trial providing erlotinib access to pts with advanced NSCLC (>6,500 enrolled). Methods: Stage IIIb/IV NSCLC; failed (1–2 regimens) or unsuitable for chemotherapy. Pts received erlotinib 150 mg/day p.o. until progression or unacceptable toxicity. Pts were assessed for response, progression free survival (PFS), overall survival (OS) and safety. Where possible, tumor tissue samples were collected from German centers and centrally assessed by; immunohistochemistry (IHC; EGFR, pMAPK), fluorescence in-situ hybridization (FISH; EGFR gene copy number), and DNA sequencing (EGFR, KRAS gene mutations). Results were assessed for correlations with treatment benefit. Results: Nov 2006, biomarker data were available for 287 of 393 German pts; median age 65 yrs (range 33–90). Baseline characteristics (%): male/female (59/41); Caucasian/Oriental/no data (99/1/<1); non-smoker/former or current smoker (25/75); adenocarcinoma/squamous cell/BAC/large cell/other/no data (57/33/3/2/1/4). 40% received erlotinib 2nd line. Of 230 pts with response data, 7.4% had a complete or partial response. Median PFS was 11.0 weeks (95% CI: 9.0–13.1). Preliminary analyses showed EGFR IHC+ (=10% staining; 223/278) pts (vs EGFR IHC-) had longer OS (HR=0.75; p=0.1) and PFS (HR=0.71; p=0.03). OS (HR=0.53; p=0.02) and PFS (HR=0.38; p=0.0001) were significantly prolonged in EGFR FISH+ (28/133) vs FISH- pts. Pts with KRAS mutations (17/107) had shorter OS (HR=1.5; p=0.18) and PFS (HR=1.6; p=0.08) vs wildtype. pMAPK+ status (29/108) was associated with shorter OS (HR=2.6; p<0.0001) and PFS (HR=1.6; p=0.0007). Conclusion: As TRUST is a single arm study, conclusions on the prognostic or predictive significance of these biomarkers cannot be drawn. Erlotinib treated NSCLC pts with EGFR IHC+, EGFR FISH+ or pMAPK- tumors may have better outcomes than those with EGFR IHC-, EGFR FISH-, and pMAPK+ tumors, but to prospectively assess the predictive value of these biomarkers, a randomized phase III study is ongoing (BO18192, SATURN).

[Table: see text]
Induction 3D-chemoradiation (CRT) yields a high rate of pathologic complete response in stage IIB(Pancoast)/III NSCLC operable patients (pts) without increasing perioperative mortality after (bi-)lobectomy: A review of 107 cases treated in a community- based center
Authors: Pourel N. , Hilgers W. , Santelmo N. , Naffaa N. , Reboul F.
Published: March 2020

7704

Background: Optimal preoperative treatment for stage IIB/III NSCLC remains a subject of controversy. According to the results of INT0139 trial (Albain KS et al in Proc ASCO 2005, abstr #7014), induction CRT appears to be superior to chemotherapy alone (CT) in terms of pathologic complete response (or microscopic residual foci, pCR), but increases postoperative (postop) mortality after pneumonectomy. Methods: Pts were selected through a multidisciplinary committee according to functional and resecability criteria. Induction treatment comprised 45 Gy/25 fractions/5 weeks. RT delivered to the primary tumor and pathologic hilar and/or mediastinal nodes (CTV) with an extra-margin of 1 to 1.5 cm (PTV). A 3D 5-field technique was used for all patients with 8–25 MV photons. Concurrent CT regimen was Cisplatinum 20 mg/m2 and Etoposide 50 mg/m2 (PE), d1–5, d29–33. Surgery was performed 4 to 6 weeks after CRT completion in deemed resectable pts. Inoperable pts were referred for a 20 Gy boost ± 1 extra-cycle of PE. Results: From 1996 to 2005, 107 NSCLC pts received CRT (stage IIB-Pancoast 18, IIIA 58 and IIIB 31). One hundred pts received the whole 45 Gy+PEx2; 72 pts had a thoracotomy (pneumonectomy 21, lobectomy 45, bi-lobectomy 5, exploratory only 1). During the 3-month postop time, 5 pts (6.9%) died, 4 after pneumonectomy (R 3, L 1, 19%), 1 after lobectomy (2.2%); 34 pts had 1–3 significant complication(s) (mainly, arrhythmia 10, pneumonia 8 (lethal 1), prolonged air leak 7, fistula 4, empyema 4 (lethal 2), pulmonary embolism 3 (lethal 2)).A pCR was observed in 39.5% of 71 resected pts; mediastinal nodes were sterilized in 60.9% of 46 cN2 pts. Analysis of survival and predictive factors is ongoing. Conclusions: Surgery is feasible after induction chemo-RT, particularly (bi-)lobectomy, in stage IIB/III NSCLC pts but pneumonectomy carries an inacceptable risk of postop death (particularly, right pneumonectomy). CRT yields an encouraging pCR rate of 39.5%.

No significant financial relationships to disclose.
Pemetrexed (P) in relapsed small cell lung cancer (SCLC): Preliminary results of a phase II trial
Authors: Raju R. N. , Neubauer M. A. , Smith D. A. , Richards D. A. , Asmar L. , Cunneen J. L. , Chen R. , Tai D. F. , Obasaju C. K. , Socinski M. A.
Published: March 2020

7716

Background: Pts with relapsed SCLC have a poor prognosis and few effective treatment options. P is a novel multitargeted antifolate that is active and well-tolerated as a single agent in lung cancer. We undertook a trial to assess the efficacy and safety of single- agent P in both chemosensitive (S) and chemorefractory (R) relapsed SCLC pts. Methods: Eligible pts had limited or extensive- stage SCLC, PS 0 to 2, and only 1 prior chemo regimen. S pts were defined as having had a prior response with disease progression >2 mos from end of 1st-line chemo. R pts were those who progressed while on 1st-line therapy, or had any response but progression <2 mos from end of 1st-line chemo. The initial P dose tested was 500 mg/m2 q 21 d. Planned sample sizes were 36 S pts in a 2-stage sequential fashion with potential early stopping for lack of efficacy or unacceptable toxicity, and 25 R pts in a single-stage design with no stopping rule. The stopping rule was invoked when <3 of 14 qualified S pts responded. The protocol was then amended to evaluate P at 900 mg/m2 in additional cohorts of 40 S and 40 R pts. Pts were to receive folic acid and Vitamin B12 prior to treatment with P. The primary outcome measure was response rate. Results: From 7/04 to 3/06, 121 pts were enrolled, with 116 pts treated. S and R pts were analyzed separately at both dose levels. S pts (n=56): M/F, 29/27; median age 65 (range 43–82); PS 0/1/2, 25/23/8. R pts (n=65): M/F, 31/34; median age 64 (range, 35–85); PS 0/1/2, 16/37/12. *3 S pts treated with P 900 mg/m2 remain with disease control after a minimum of 11 mos of follow-up. Conclusions: Preliminary clinical benefit rates (CR+PR+SD) of 20% and 17.4% achieved respectively in S and R pts treated with P 500 mg/m2 suggest modest activity of single-agent P in relapsed SCLC. P can be given at a dose of 900 mg/m2 without a significant increase in Grades 3–4 toxicities, although this does not appear to increase efficacy.

[Table: see text] [Table: see text]
The progress of small cell lung cancer management using irinotecan plus cisplatin chemotherapy
Authors: Lee J. S. , Han J. , Yu S. , Yoon S. , Lim E. , Pyo H. , Kim H. , Lee D. , Kim H. , Cho K. , Lee G.
Published: March 2020

7721

Background: Etoposide/cisplatin (EP) is the most widely used regimen resulting in a median survival of 8–10 mos and 17–20 mos respectively for patients (pts) with extensive-disease (ED) and limited-disease (LD). Encouraged by a phase III trial result that showed better survival outcome after Irinotecan/cisplatin (IP) combination as compared with EP, we previously reported promising activity of IP regimen for LD-SCLC and also for ED-SCLC. To further evaluate the role of IP in SCLC pts, we conducted two additional phase II studies. Methods: Between May 2003 and June 2006, a total of 196 SCLC pts (ED: 120, LD: 76) were enrolled in two separate trials. All pts were chemo-naive and ECOG PS of 0–2. Pts with ED-SCLC received irinotecan 60 mg/m2 intravenously (IV) and cisplatin 30 mg/m2 IV on days 1 and 8 every 21 days for 8 cycles followed by 6 cycles of irinotecan maintenance or observation. Treatment for LD-SCLC consisted of two 28-day cycles of cisplatin 30 mg/m2 IV on days 1 and 8 plus irinotecan 60 mg/m2 IV on days 1, 8, and 15, followed by two 21-day cycles of cisplatin 60 mg/m2 IV on day 1, plus etoposide 100 mg/m2 IV on days 1 to 3 with concurrent twice-daily thoracic radiation of total 45 Gy. Hoping to modify the treatment-related toxicity, 36 pts were given epoietin and 20 were given amifostine while 15 received neither during the concurrent chemo-radiation therapy. Results: For ED- SCLC, overall response rate was 92.6% with CR rate of 11.1%. The median survival was 13.8 mos (95% CI, 12.2 to15.3) with 1-and 2-year survival rates of 58.6% and 18.9%. The median progression-free survival (PFS) was 7.3 mos with 1-and 2-year PFS rates of 18.1% and 5.4%. Irinotecan maintenance did not affect the outcome, however. For LD-SCLC, the response rate was 97.1% with CR rate of 44.9%. The median survival was 24.9 mos (95% CI, 18.5 to 31.3) with 1-and 2-year survival rates of 75.2% and 51.4%. The median PFS was 11.0 mos (95% CI, 7.8–14.2) with 1-year PFS rates of 46.8%. The most common toxicity associated with IP treatment was grade 3 or 4 neutropenia (64.6% for ED, 45.3% for LD). Grade 3 diarrhea was developed in 12.4% for ED and 4% for LD pts. Conclusion: Significant antitumor activity of IP chemotherapy as shown suggests further progress in SCLC therapy.

No significant financial relationships to disclose.
CHOP-R + bortezomib as initial therapy for diffuse large B-cell lymphoma (DLBCL)
Authors: Leonard J. P. , Furman R. R. , Cheung Y. K. , Vose J. M. , Glynn P. W. , Ruan J. , Martin P. , Niesvizky R. , LaCasce A. , Chadburn A. , Coleman M.
Published: March 2020

8031

Background: Bortezomib is a proteasome inhibitor with anti-tumor activity in B cell malignancies. These effects, which may relate to NF-kappaB associated pathways, could sensitize tumor cells to standard chemotherapy-based regimens and enhance efficacy. We report findings of a phase I/II trial of dose-escalated bortezomib + standard CHOP-rituximab in DLBCL patients (accrual of the MCL cohort of this study remains ongoing). Methods: Patients with previously untreated DLBCL (n=40) received CHOP-21 + rituximab (375 mg/m2 each cycle) plus bortezomib at 0.7 mg/m2 (Arm 0, n=4), 1.0 mg/m2 (Arm 1, n=8) or 1.3 mg/m2 (Arm 2, n=28 including phase I and all phase II) on days 1 and 4 of each cycle Results: Median age (n=40) was 58 years (range 21–86), thirty-five subjects (88%) had stage III/IV disease at study entry, and 29 (73%) had elevated serum lactate dehydrogenase (LDH). Patients generally had unfavorable baseline international prognostic index (IPI) scores of 2 in 16 subjects (40%) and 3–5 in 19 subjects (48%). Median follow-up is 21 months (range 9 - 35 months). Treatment was generally well tolerated. Peripheral neuropathy occurred in 22 subjects (55%), with 45% grade 1, 5% grade 2 and 5% grade 3. Grade 4 hematologic toxicity included thrombocytopenia (15%) and leukopenia (15%). Four subjects (3 over age 75 and all with high risk IPI) died prior to first response assessment. Intent to treat (ITT) overall response rate (n=40) is 90% with 68% CR/CRu. For the evaluable subset (n=36), ORR was 100% with CR/CRu 75%. Kaplan-Meier estimate (n=40) of 2-year progression-free survival is 72%. Of all 19 enrolled (ITT) patients in the high-intermediate or high-risk IPI groups, 14 (74%) were alive without progression at last assessment. Correlation of outcome with cell of origin type (activated B cell vs germinal center) is ongoing. Conclusions: Bortezomib can be administered with acceptable toxicity in conjunction with CHOP-R chemotherapy. Efficacy findings with this combination regimen in newly-diagnosed DLBCL are encouraging and warrant further study.

No significant financial relationships to disclose.
Low doses of humanized anti-CD20 antibody, IMMU-106 (hA20), in refractory or recurrent NHL: Phase I/II results
Authors: Morschhauser F. , Leonard J. P. , Fayad L. , Coiffier B. , Petillon M. , Coleman M. , Horne H. , Teoh N. , Wegener W. A. , Goldenberg D. M.
Published: March 2020

8032

Background: An open-label, multicenter study has shown that the humanized anti-CD20 antibody, IMMU-106 (hA20), which has framework regions of epratuzumab, has a good safety and efficacy profile in NHL pts when administered once-weekly × 4 at different doses. The trial is now focused on confirming the efficacy of lower doses (80–120 mg/m2/wk × 4). Methods: A total of 68 pts (35 male, 33 female; age 34–84) received hA20 at 750 (N=3), 375 (N=27), 200 (N=11), 120 (N=21), or 80 mg/m2 (N=6). They had follicular (FL, N=47) or other (N=21) B-cell NHL, were predominantly stage III/IV (N=47) at study entry, and had received 1–8 prior treatments (median, 2), including 1 (N=40) or more (N=21) rituximab regimens (without progression within 6 months). Results: Sixty- six pts completed all 4 infusions; 1 pt progressed during treatment and withdrew, while another pt with hives and chills after prior rituximab discontinued treatment after a similar episode at 1st infusion. hA20 was generally well tolerated, with shorter infusion times (typically 2 h initially and 1 h subsequently) at lower doses. Drug-related adverse events were transient, Grade 1–2, most occurring only at 1st infusion, and there was no evidence of HAHA in 54 pts now evaluated. Mean antibody serum levels increased with dose and infusions; serum clearance at 375 mg/m2 appears similar to rituximab. Currently, 48 pts with at least 12 wks follow-up were evaluated by Cheson criteria: 32 FL pts had 15 (47%) OR's with 7 (22%) CR/CRu's, even after 2–4 prior rituximab-regimens, and 17 non-FL pts had 6 (38%) OR's, with 1 CRu in a marginal zone NHL pt. At a median follow-up of 11 mo., 9/21 pts with ORs are continuing responses, including 4 long-lived responses (15–20 mo). The evaluated pts include 17 pts at 120 mg/m2 who had 5 (29%) ORs with 3 (17%) CR/CRu's. Responses at 80 mg/m2 remain to be evaluated, but B-cell depletion occurs after the 1st infusion even at this low dose. Conclusions: hA20 appears well-tolerated, with no evidence of significant adverse events other than minor infusion reactions, even at short infusion times. B-cell depletion and responses have occurred at all doses evaluated, with no clear-cut evidence of a dose-response. As such, the study is continuing to confirm the efficacy of lower doses.

No significant financial relationships to disclose.
Efficacy and toxicity of dose-adjusted EPOCH-rituximab in adults with newly diagnosed Burkitt lymphoma
Authors: Dunleavy K. , Healey Bird B. R. , Pittaluga S. , Grant N. , Shovlin M. , Little R. , Yarchoan R. , Steinberg S. , Jaffe E. S. , Janik J. , Wilson W. H.
Published: March 2020

8035

Background: Burkitt Lymphoma (BL) is a rare and highly aggressive lymphoma, characterized by a high tumor proliferation rate. While the standard therapy of BL is highly effective, it involves intensive, multi-agent chemotherapy that is associated with considerable treatment-related toxicity and mortality, especially in older patients. We hypothesized that the regimen DA-EPOCH may be effective in BL, based on the observation that it overcomes the adverse effect of high proliferation in diffuse large B-cell lymphoma. Methods: We investigated DA-EPOCH-rituximab (R) in untreated BL in an attempt to maintain the high cure rates of standard therapy with minimal treatment related toxicity. Eligible patients had a diagnosis of untreated BL and could be HIV negative or positive with HIV negative patients (n=13) receiving 6 cycles of DA-EPOCH-R as previously described (Blood 99: 2685, 2002) and HIV positive (n=6) patients receiving 3–6 cycles of DA- EPOCH-R for 1 cycle beyond CR for a minimum of 3 cycles. All patients received intrathecal methotrexate prophylaxis and outpatient therapy where possible. Results: The characteristics of 19 enrolled patients are: median age (range) 29 (18–66) and ECOG PS 1(1–3); stage III/IV 10 (53%); LDH > N 11 (61%); male sex 15 (79%); extranodal sites 13 (68%) and ileocecal disease 13 (68%). No patients so far had CNS involvement at diagnosis. Response is CR/CRu in 100% of patients with one patient receiving consolidative radiotherapy to a site of residual disease. OS and PFS are both 100% and EFS 93.3% at a median potential follow-up time of 29 months. Toxicities were fever/neutropenia in 16%, grade 4 neutropenia in 47% and grade 3/4 thrombocytopenia in 22% of cycles. There was one case of tumor lysis syndrome and no treatment related deaths. Conclusions: DA-EPOCH-R is highly effective in BL. It appears to be associated with much lower toxicity compared to standard high-dose regimens and may significantly advance the therapeutic index of BL treatment. Accrual continues.

No significant financial relationships to disclose.