bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival and prognostic factors in patients with malignant pleural mesothelioma (MPM) treated with neoadjuvant cisplatin- based chemotherapy and extrapleural pneumonectomy (EPP) (SITMP Study)
Authors: Mutri V. , Pinto C. , Marino A. , Di Bisceglie M. , Dell’Amore D. , Sacco R. , Boaron M. , Colucci G. , Martoni A. A.
Published: March 2020

18061

Background: The aim of this study is to evaluate the impact on survival of preoperative chemotherapy in potentially resectable MPM and correlations with prognostic factors. Methods: The eligibility criteria were: histologically MPM, stage T1–3N0–2M0, age =75 years, KPS = 80, adequate organ function. A first group of pts (group A) received cisplatin 75 mg/m2 d1 and gemcitabine 1,200 mg/m2 d1,8, every 3 weeks for 4 courses, followed by EPP and by 6 courses of adjuvant chemotherapy with mitoxantrone 10 mg/m2 d1, methotrexate 35 mg/m2 d1 and mitomycin 7 mg/m2 d1, every 3 weeks with mitomycin in alternate cycles. A second group of pts (group B) received cisplatin 75 mg/m2 d1 plus pemetrexed 500 mg/m2 d1 for 4 cycles. In each group, only those pts with metastatic lymph nodes and/or positive resection margins received radiotherapy after EPP. The prognostic factors evaluated were: sex, histotype, stage at diagnosis, clinical objective response. Results: Between February 2000 and December 2006, 32 pts were enrolled (8 group A, 24 group B). Pt characteristics were: 27M (84.4%), 5F (15.6%), median age 64 years (51–72), median KPS 100 (80–100), histological subtype: 27 (84.4%) epithelial, 2 (6.3%) sarcomatous, 3 (9.4%) mixed; IMIG stage: 6 (18.8%) I, 16 (50%) II, 10 (31.2%) III. The clinical response to neoadjuvant chemotherapy was: 10 (31.3%) CR + PR, 16 (50%) SD and 6 (18.7%) PD. Eighteen (56.3%) pts underwent EPP. In the 14 pts who did not undergo EPP: 5 (15.6%) were treated with pleurectomy and 9 (28.1%) were not treated with surgery. Two postoperative deaths (1 contralateral pneumonia and 1 ARDS) occurred after EPP. No pts were treated with radiotherapy after EPP. The estimated median overall survival, 1-year and 2-year survival rates in the pts treated with EPP and not treated with EPP were 20 and 12 months (p=0.468), 60 and 41%, 42 and 20%, respectively. In the multivariate analysis (Cox regression analysis), none of evaluated prognostic factors was significantly associated with an improved OS. Conclusions: These data show that preoperative chemotherapy followed by EPP is a feasible approach, while initial analysis suggests favourable survival. No significant prognostic factors were identified.

No significant financial relationships to disclose.
Clinical and prognostic significance of serum carcinoembryonic antigen level in patients with IIIB and IV stage lung cancer: A prospective study
Authors: Martinez-Velazco A. , Flores-Estrada D. , Silva-Godinez J. C. , Javier F. , Enrique G. , Martinez L. , De la Garza J. , Arrieta O.
Published: March 2020

18063

Previous studies have shown pre and post-operative serum CEA levels are a prognostic factor in patients with lung cancer (LC). We prospectively investigated the clinical and pathological characteristics, as well as, prognostic significance of patients with IIIB and IV stage LC and the CEA serum elevation. From March of 2005 to January of 2007, 307 patients with IIIB and IV stage were included; several chemotherapy protocols including gemcitabine, vinorelbine or paclitaxel combined with cisplatin, carboplatin, or erlotinib were used. Serum CEA levels were obtained before and after 2 cycles of treatment. Stage was determined by CT and bone scans; 120 patients had brain CT scan at diagnosis due to neurological symptoms. 28.6% of the patients were stage IIIB and 61.4% stage IV and 18% of patients had CNS metastasis at diagnosis. Histology was adenocarcinoma in 69.1% and epidermoid in 30.9%. Mean CEA was 11.3 ng/ml ± 24.5 with median of 6.7 (range 0.2 to 4,578). Patients with CEA levels > 10, 20, 50 and 100 were 43.6, 32.5, 24 and 17.9%; respectively. Associated factors with CEA >20 were age >62 (p=0.02), stage (p=0.05), CNS metastasis (p=0.0001) and histology (p=0.01). However, in the logistic regression analysis the only associated factors were histology (p=0.0001) and CNS metastasis (p=0.0001). Patients with CEA elevation >20 had a hazard ratio of 26.3 (CI 11.2 to 61.6) for the development of brain metastases. Overall survival associated factors were poor status performance (p=0.006), tobacco use (p=0.05), CEA elevation (p=0.0022), CNS metastases (p=0.01), male gender (p=0.08). There were no differences between stage IIIB, IV and CNS metastasis. The associated factors with survival by Cox proportional hazards regression multivariate analysis were poor performance status (p=0.05) and CEA elevation (p=0.008). The independent factors associated with CEA elevation were histology adenocarcinoma and brain metastasis. Patients with CEA >20 without neurological symptoms could benefit from early CT brain scan with stage IIIB and IV. In this group of patients, the 2 most important independent factors for survival were poor performance status and CEA elevation.

No significant financial relationships to disclose.
Feasibility of adjuvant carboplatin/docetaxel (C/D) in patients (pts) resected stage I-IIIB non-small cell lung cancer (NSCLC): Preliminary report of a phase II trial
Authors: Stinchcombe T. E. , Socinski M. A. , Harper H. D. , Hensing T. A. , Moore D. , Crane J. M. , Atkins J. N. , Willard E. M. , Tynan M. T. , Gulino S. E.
Published: March 2020

18069

Background: Adjuvant cisplatin-based chemotherapy has been shown to improve survival in patients with resected NSCLC; however, compliance with chemotherapy has been problematic. Carboplatin (C) is better tolerated than cisplatin, and therefore may improve adjuvant chemotherapy compliance. C/D is a commonly used treatment for advanced NSCLC with an acceptable toxicity profile. Methods: Pts with resected NSCLC with a good functional status, preserved renal, hepatic, and bone marrow function were enrolled. Therapy was initiated 2–8 weeks from surgery, and consisted of 4 cycles C (AUC=6), and docetaxel (D) 75 mg/m2 every 3 weeks. The primary end-point was the feasibility of delivering C/D. An “adequate exposure” was defined as receiving 4 cycles of C/D within 12 weeks of initiating therapy. A sample size of 72 pts provided 88% power to detect a true adequate exposure of rate of at least 80%. Results: 72 pts have been enrolled on the protocol, and 64 patients have completed therapy, 7 patients are currently receiving therapy, and data is incomplete on 1 patient. Pt demographics are: median age=65 years (range 47–84); gender: female 34%, male 66%, race: white 86%, African American 10%, other minorities 4%; performance status: 0 (38%), 1 (58%), 2 (1%), unknown (3%). The stage distribution was: I (41%), stage II (32%) stage IIIA (25%), stage IIIB (1%). To date, 45/64 pts (70%) have completed 4 cycles within 12 weeks, and total of 50 (78%) of pts completed 4 cycles within 14 weeks. 11 pts have had D dose reduced, and 2 pts have had C dose reduced. 35 pts (55%) completed the 4 cycles at full dose within 12 weeks, and 38 patients (59%) within 14 weeks. Reasons for discontinuing treatment: withdrew from treatment (n=3), withdrew consent prior to initiating therapy (n=2), disease progression (n=2, brain metastases), adverse events (n=5), complication of other medical conditions (n=1), unknown reasons (n=1). Therapy was well tolerated and no treatment-related deaths were observed. Conclusions: Preliminary results indicate that adjuvant therapy with CD results in a similar rate of chemotherapy compliance to that of cisplatin-based chemotherapy.

No significant financial relationships to disclose.
Effect of race on the safety and efficacy of pemetrexed (P) therapy in locally advanced and metastatic non-small cell lung cancer (NSCLC)
Authors: Tai D. F. , Kulkarni P. , Wang Y. , Gill J. , Obasaju C.
Published: March 2020

18082

Background: P is a multitargeted antifolate active in NSCLC. While a number of clinical trials have evaluated P safety and efficacy in general patient populations, little is known of the possible impact of race on the utility of P therapy in NSCLC. The objective of this post-hoc analysis was to evaluate the effect of race on the safety and efficacy of P (single-agent or in combination) in patients with locally advanced and metastatic NSCLC. Methods: Data from 6 trials with at least 5% non-Caucasian patients were pooled for analyses. One Phase III trial evaluated P in a second-line setting. All other trials used P in Phase II first-line settings. Patients were given at least one dose of P (single-agent or in combination) at 600 mg/m2 (59 patients) or 500 mg/m2 (469 patients) every 21 days. Demographic, safety, and efficacy data were stratified broadly by race, to either Caucasian or non-Caucasian groups. Kaplan-Meier method was used to estimate median survival. The Cox model was used to calculate the hazard ratio (HR) for survival, adjusting for significant prognostic factors, including disease stage, performance status, gender, and line of treatment. Results: Results are summarized in the data table below. The adjusted HR for survival (non-Caucasian versus Caucasian) was 0.89 (p=0.365). Conclusions: In this post-hoc analysis of results from clinical trials using P therapy in NSCLC, race did not have a statistically significant impact on response rate, disease control rate, or survival. However, P therapy appeared to be better tolerated by non-Caucasian patients.

[Table: see text]

No significant financial relationships to disclose.
Touch prep (TP) cytology as a tool for determining pulmonary parenchymal resection margin status
Authors: Brown K. M. , Flaherty J. , Ciocca V. , Ehya H. , Scott W. , Goldberg M.
Published: March 2020

18095

Background: Accurate determination of parenchymal resection margins is critical in excision of primary and metastatic lung cancers. Complete microscopic examination of the entire margin is difficult and may not give timely results. Staple-line excision may compromise the accuracy of histologic margin exam (HME). TP offers a novel method to obtain pulmonary parenchymal margin status intraoperatively. Methods: Patients undergoing wedge resection for a known malignant lung lesion were studied prospectively. At the time of resection, the specimen stapled margin underwent TP on 3 glass slides for cytological analysis. The presence or absence of malignant cells on TP was correlated to final HME. Local recurrence and overall survival by TP and HME status were compared using logrank test. Results: Thirty specimens from 29 patients were studied between December 2002 and April 2006. Fifteen specimens (50%) were right- sided; 9/29 patients (31%) were male. Median age was 66 years (range 28 - 81). Histologies included non-small cell lung cancer (NSCLC) in 22 (73%), and metastases from colorectal cancer (4/30, 13%), sarcoma (2/20, 7%), and breast (1/30, 3%). All TP negative specimens had negative HME. TP was positive in 10 of 30 (33%) specimens, 6 of which had negative HME. These included 4 NSCLC and metastases from sarcoma (1) and colon (1). Mean margin distance was 4 ± 1.7 mm for TP/HME negative specimens, 0.5 ± 0 mm for TP/HME positive specimens, and 5 ± 1.7 mm for TP positive/HME negative patients. There was no difference in time to local recurrence between patients with positive margins by TP vs HME (18.6 and 18.63 months), or in TP and HME negative patients (30.1 and 30.6 months). Conclusion: TP analysis of lung parenchymal margins is safe and feasible. A negative TP is highly predictive of negative HME. Factors contributing to false-positive TP remain unresolved. Multi-institutional prospective studies are indicated for further characterization of this promising tool.

No significant financial relationships to disclose.
Biweekly docetaxel (Doc) followed by gemcitabine (Gem) and cisplatin (Cis) in patients (pts) with advanced non-small cell lung cancer (NSCLC): A clinical proteomic study
Authors: De Castro J. , Belda- Iniesta C. , Casado Saenz E. , Feliu Batlle J. , Sereno Moyano M. , Gomez Raposo C. , Pinto Marin A. , Alvar J. , González-Barón M.
Published: March 2020

18096

Background: This phase II trial was carried out to test the feasibility and efficacy of sequential chemotherapy. The scheme was based on the concept of taxane sequencing in cisplatin-based doublet. Finally, we evaluated the predictive value of proteomic profile determined by SELDI-TOF for Doc responses. Methods: Eligible chemonaive stage IV and selected stage IIIB (pleural effusion) NSCLC pts received Doc 50 mg/m2 IV day 1, every 14 days for 4 cycles followed by Gem 1,000 mg/m2 on days 1, 8 and Cis 75 mg/m2 on day 1, every 21 days for 4 cycles. Primary endpoints were response rate and progression-free survival. Overall survival, toxicity and predictive value of the proteomic profile were secondary endpoints. Plasma for proteomic biomarker analysis (SELDI-TOF) was taken at screening and after Doc treatment. Results: From February-05 to December-05, 39 pts were enrolled with 37 being evaluable for efficacy. Pts characteristics: Median Age: 60 years(44–82); Sex: M/F:76%/24%; Stage:IIIB/IV:32%/68%; Performance status 0/1/2:24%/65%/11%; Pathological subtypes: squamous (38%), adenocarcinoma (30%) and large cell carcinoma(32%). 15 pts showed partial response and 1 pt a complete response (objective response rate of 43%) and 14 pts had stable disease (37%). The median survival time (intent-to-treat) was 13 months with an estimated 1-year survival rate of 53%. The median time to progression was 10 months in the evaluable population. Most common grade 3–4 toxicities: After Doc treatment: anemia G3 (2 pts) and asthenia G3 (1 pt); After Gem-Cis: anemia G3 (4 pts), nausea/vomiting G3 (4 pt), neutropenia G3 (4 pts) and asthenia G3 (2 pts). There were no treatment-related deaths. Conclusions: Doc followed by Gem-Cis in sequential setting is an active, feasible and well tolerated regimen. Proteomic profile for Doc responders and no responders will be presented at the time of the meeting.

No significant financial relationships to disclose.
Phase II study of simultaneous radiochemotherapy (RCT) with cisplatin/etoposide followed by consolidation chemotherapy (CT) with platin/gemcitabine for unresectable non-small cell lung cancer (NSCLC)
Authors: Fink T. H. , Melzner W. , Strnad V. , Sauer R. , Albrecht C. , Birkenhake S. , Ficker J. H.
Published: March 2020

18103

Background: This phase II study has been conducted to determine the feasibility, toxicity, response rate, local control, distant metastases, and survival of simultaneous RCT (3D conformal radiotherapy with cisplatin/etoposide) followed by consolidation CT with platin/gemcitabine in unresectable NSCLC. Methods: From April 2001 to April 2005, 30 patients with unresectable NSCLC were entered into this trial. All patients had a histological confirmed unresectable non-small cell lung cancer. One patient had stage II, but was functionally unresectable; all other patients had locally advanced NSCLC (IIIA and IIIB). Noncoplanar 3D conformal radiotherapy was given to a total dose of 66.6 Gy (1.4 - 1.8 Gy per day) together with 2 cycles of CT (cisplatin 20 mg/m2 d1–5, d29–33 plus etoposide 90 mg/m2 d1–3, d29- 31). After completion of RCT patients received 4 courses of gemcitabine 900 mg/m2 d1 and d8 with cisplatin 70 mg/m2 d2 (or carboplatin AUC 5 d1) every 21 days. Results: 27 patients went through RCT, 22 patients received consolidation CT. The predominant hematological toxicity was grade 3/4 leukopenia, reported in 33% of patients during the RCT and 36% during the consolidation CT. One patient showed grade 3 radiation pneumonitis during concurrent RCT. No patient died of treatment related toxicity. The response rate was 83% with 2 CR and 23 PR. With a follow up of 24 months median survival was 17.5 months, 2 year survival rate was 40%. We will present median survival and 3 year survival rate with a follow up of 36 months. Conclusions: The simultaneous RCT with cisplatin/etoposide followed by consolidation CT with platin/gemcitabine is feasible and well tolerated. This study should prompt further investigation in a phase III randomized trial.

No significant financial relationships to disclose.
Brain metastases in locally advanced NSCLC treated with radical radiotherapy (RT) in a single institution
Authors: Hansen O. , Hansen K. H. , Stolberg-Rohr A. , Sorensen P.
Published: March 2020

18107

Background: Brain metastases (BM) is a major problem in NSCLC. To evaluate the influence on survival in locally advanced NSCLC treated with radical RT, a retrospective analyses was performed of the patients treated at our institution. Methods: From June 1995 to Dec. 2003 200 patients with non-resectable NSCLC stage IIB-IIIAB received radical 3-D conformal radiotherapy with a planned dose =60Gy/30 F. Data on brain metastases were retrospectively obtained from the patient files. All patients were followed to death except in few cases in which data was obtained from other hospitals. End points were occurrence of BM and BM free survival (BM-RFS). A Cox multivariate analysis was performed including possible prognostic factors. Results: Stage at RT: IIB 8 (4%), IIIA 66(33%), IIIB+recurrent disease 126 (63%). Male/female ratio was 126 /74. The median survival was 15.5 months. The 2 yrs. survival was 34%. 42 (21%) cases of BM were observed. The median time to BM was 8.5 ms. with 86% occurring within 2 yrs. In 28 (67%) of the cases BM was the first site of failure, and in 10 (24%) BM remained the only site of failure. More women than men experienced BM 25 (34%) vs. 17 (14%), p= 0.0013. The survival after diagnosis of BM was 2.8 ms. The patients having BM as and these had better prognosis then patients experiencing BM at a later stage 5.3 vs 1.9 ms. (p<0.0001). The prognosis after BM as first failure were no worse than patients having other sites as first distant failure (3.6 ms, p=0.3). In a Cox multivariate analysis only female gender was associated with poorer BM-RFS while use of neoadjuvant chemotherapy, adeno.-histologi, age, stage at RT, and performance status at RT were insignificant factors. Conclusions: A significant number of cases with locally advanced NSCLC experienced BM especially in females. The survival after diagnosis of BM as first failure were no worse than patients experiencing other distant sites as first failure. The results indicates a that PCI should be considered to this group of patients

No significant financial relationships to disclose.
Prospective phase II trial of a combination of gemcitabine, cisplatin and UFT as first-line treatment in patients with advanced, unresectable, non-small cell lung carcinoma
Authors: Jin S. S. , Min Y. , Kim H. , Ahn J. , Jegal Y. , Seo K. , Park C. , Shin J. , Cha H. , Kwon W. , Park J.
Published: March 2020

18109

Background: Most patients with advanced non-small cell lung cancer (NSCLC) receive either single agents or doublet chemotherapy. For non-elderly patients in good performance status, platinum-based double combinations represent the standard treatment. And oral UFT had the survival advantage in adjuvant setting. Therefore we performed a phase II study using the combination of gemcitabine, cisplatin and UFT as a first line therapy in patients with advanced NSCLC. Methods: Eligible patients had histologically or cytologically confirmed stage IIIB or IV NSCLC with good performance status and were chemotherapy-naive. This study was two-stage design and planned number of patients was forty-seven. Gemcitabine (1,250 mg/m2, 10 mg/kg/min on days 1 and 8) and cisplatin (75 mg/m2 on day 1) were injected intravenously and UFT (400 mg/day) was administered orally on day 1–14. Treatment repeated every 3 weeks. Primary end point was overall response rate and secondary end points were overall survival, time to progression and toxicity. Results: Thirty seven patients with advanced NSCLC were enrolled. The median age of the patients was 60 years (range: 44 to 72). The performance status (WHO) was 0 in 4, 1 in 30 and 2 in 3 patients. Twenty three patients completed six cycles. Complete response was achieved in 1 (3%) patient, partial response in 22 (59%) patients, stable disease in 9 (24%) patients. Overall response rate was 62% on intent to treat basis. Among patients who response evaluation was possible (33 patients), response rate was 70%. The median survival time was 14.5 months (95% CI 6.9, 22.3) and the 1 year survival was 35% and then median time to progression was 3.4 months(95% CI 3, 3.9). Toxicities were moderate and mostly hematological adverse events. Grade 3/4 neutropenia occurred in 37%, 5 patients with febrile neutropenia. Grade 3/4 anemia and thrombocypenia was occurred in 37% and 5%. Nonhematologic toxicities were mild. Conclusion: The combination therapy consisted of gemcitabine, cisplatin and UFT is active and well tolerable first line regimen for NSCLC patients.

No significant financial relationships to disclose.
Treatment patterns of very elderly patients with non-small cell lung cancer
Authors: Oxnard G. R. , Fidias P. , Sequist L. V.
Published: March 2020

18110

Background: Among patients with non-small cell lung cancer (NSCLC), patients aged 80 or older, termed the ‘very elderly‘, have inferior survival. Treatment patterns within this patient population are poorly described. Methods: A retrospective chart review was performed of 111 outpatients with NSCLC presenting at age 80 or older to an academic referral center over 5.3 years. Based upon available literature regarding elderly patients with NSCLC, a guideline recommended therapy (GRT) was determined for each tumor stage. Each patient’s treatment regimen was evaluated for consistency with the GRT. Particular attention was paid to how patient characteristics and attitudes influenced therapy decisions. Results: Patients characteristics included: median age 82.6 (range 80–92); 50% male; 55% adenocarcinoma, 19% squamous cell; 30% stage I-II, 28% stage III, 39% stage IV; and 59% performance status (PS) 0–1, 25% PS = 2 (PS not available for 15%). 89% of patients received some form of anti-neoplastic therapy and 11% were treated with best supportive care alone. Of 34 patients with localized disease, 53% underwent tumor resection and 38% received definitive radiation. Of 74 patients with stage III or IV disease, 34% received cytotoxic chemotherapy. Radiotherapy (47%) and oral targeted therapy (35%) were the most common treatment modalities overall. 32% of patients received the stage-specific GRT. Multivariable analysis demonstrated that independent predictors for failing to receive GRT included PS = 2 (odds ratio [OR] 17.1, 95% confidence interval [CI] 2.2–135) and age =85 (OR 4.8, 95% CI 1.0–23.4) Of the patients who failed to receive GRT, 19% electively refused GRT that was offered (13% specifically refused chemotherapy), and 76% were not offered GRT (44% due to PS or comorbidities, 32% due to age or unstated reasons). Conclusions: The vast majority of NSCLC patients age 80 or above receive some form of anti-neoplastic therapy, but only one-third of this population receives the stage-specific GRT. The strongest predictor of treatment with GRT is PS 0–1; those with poor PS are 17-fold less likely to receive GRT. A small but clinically significant portion of patients elect against the offered GRT; more data is needed about the attitudes of these patients toward therapy.

No significant financial relationships to disclose.
Pemetrexed and carboplatin in the treatment of malignant pleural mesothelioma (MPM)
Authors: Papi M. , Genestreti G. , Tassinari D. , Tamburini E. , Nicoletti S. , Nicolini M. , Fabbri P. , Fabbri P. , Santo A. , Pasquini E. , Ravaioli A.
Published: March 2020

18114

Background. MPM is a poor prognosis disease, whose clinical negative outcome is due both to it’s aggressiveness and to the lack of active drugs for clinical practice. To assess activity and safety of pemetrexed-carboplatin combination in the treatment of MPM, an open trial has been recently concluded in our departments. Methods. All the consecutive patients with proven diagnosis of MPM admitted to our departments between 2003 and 2005 were considered eligible and enrolled into the trial. All the patients were treated with pemetrexed 500mg/m2 and carboplatin AUC 5mg/ml/minute every 21 days until progression of disease or unacceptable toxicity. All the patients were treated with steroid prophylaxis, folinic acid and vitamin B12 supplementation. Results. 26 patients (18 chemotherapy-naive) were considered eligible and enrolled into the trial. 21 patients were male and 5 female; median age of the patients was 67 years (range 49–77). 22 patients were affected by locally advanced or extensive disease and the other 4 ones by localized disease. All the patients were valuable for response, toxicity and survival. Overall response rate was 19,3%, with 5 partial responses and no complete regression of the disease. A stable disease was observed in 7 patients (26.9%), with an overall disease control rate of 46.2%. 201 complete courses of chemotherapy was performed with a median number of 6 courses/patients. Toxicity was mild with grade 3/4 WHO neutropenia in 4 patients (15.3%), grade 3 anemia and thrombocytopenia in 2 patients (7.6%). No grade 3/4 non-hematological toxicity was observed along all the conduction of the trial. Median survival was 9,3 months, assessed with the Kaplan Meyer non-parametric test. Conclusions. Pemetrexed and carboplatin seem to represent an active and well tolerated schedule against MPM, confirming their priority role in the treatment of the disease; nevertheless, further trials are probably needed to improve the outcome of chemotherapy in this rare poor-prognosis disease. Supported by IOR

No significant financial relationships to disclose.
Phase II study of meloxicam with carboplatin plus docetaxel in first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)
Authors: Ishida T. , Kanazawa K. , Oizumi H. , Yokouchi H. , Yamazaki K. , Akie K. , Sukoh N. , Harada M. , Munakata M. , Isobe H.
Published: March 2020

18121

Background: Preclinical and clinical studies showed that selective cyclooxygenase-2 (COX-2) inhibitor (celecoxib or rofecoxib) might improve efficacy of treatment of advanced NSCLC. Meloxicam is a non-coxib, non-steroidal anti-inflammatory drug (NSAID), and selectively inhibits COX-2. Comparing with coxibs, meloxicam shows less cardiovascular toxicity; however, anti-tumor efficacy has not been proved in clinical settings. Methods: Eligibility criteria included stage IIIB/IV histologically or cytologically confirmed NSCLC, no prior chemotherapy, no current use of NSAIDs, PS = 0–1, and no urgent symptoms. Patients received oral meloxicam (150 mg) daily, and carboplatin (AUC 5) plus docetaxel (60 mg/m2) day 1 every 3 weeks. Treatment was continued until disease progression or toxicity. The primary endpoint was anti-tumor effect, with secondary endpoints including the safety and time to progression. Calculated sample size was 45 patients (Simon’s two-stage minimax design). Results: From April 2005 to July 2006, a total of 50 patients (33 males/17 females, median age, 65 years) were accrued and 48 patients were eligible. Partial response was 40% (95% CI 24–56%), stable disease was 29% (95% CI 14–44%), and 23% had progressive disease. Grade 3/4 hematologic events included leukopenia (81%), neutropenia (96%), and thrombocytopenia (8%). Grade 3/4 non-hematologic events included hyponatremia (6%), anorexia (6%), fatigue (2%), and neuropathy (2%). Febrile neutropenia occurred in 2 patients, and one patient developed pneumonia. Conclusions: Meloxicam added to carboplatin plus docetaxel demonstrated acceptable tolerability with encouraging activity in advanced NSCLC patients.

No significant financial relationships to disclose.
Artificial intelligence, complex system analysis and simulation modeling for early detection of lung cancer
Authors: Kshivets O.
Published: March 2020

18127

Background: Early detection (ED) of non-small cell lung cancer (LC) is the key to the cancer problem solving and practically regulates effectiveness of surgery. We examined immunologic factors associated with early LC. Methods: In trial (1987–2006) the data of consecutive and monitored 94 LC patients (LCP) after lobectomies (age=58.3±0.8 years; tumor size=2.32±0.07 cm; m=80, f=14) with pathologic stage IA (T1N0M0) (squamous=36, adenocarcinoma=53, large cell=5; G1=32, G2=38, G3=24), 282 patients with lung non-malignant pathology (NMP) (m=188, f=94; pneumonectomies=5, lobectomies=179, segmentectomies=98; non-malignant tumours=100; abscess=112; tuberculoma=70) and 120 healthy donors (HD) (m=69, f=51) were reviewed. Variables selected for ED study were input levels of 64 immunity blood parameters, sex, age. Representativeness of samplings was reached by means of randomisation based on unrepeated random selection. Logistic regression, clustering, discriminant analysis, neural networks computing, structural equation modeling, Monte Carlo and bootstrap simulation were used to determine any significant regularity. Results: Logistic regression modeling displayed that ED of LC significantly depended on: CD8, CD4, CD16, neutrophils, monocytes (P=0.002–0.041). Neural networks computing, genetic algorithm selection and bootstrap simulation discovered relationships between early LC and blood lymphocytes (rank=1), T-lymphocytes (2), CD4 (3), CD16 (4), B- lymphocytes (5), CD1 (6), NST-A2 (7), CD8 (8), NST-SP (9), NST-A1 (10), monocytes (11), eosinophils (12). Conclusions: Correct recognition of LCP with stage IA (T1N0M0) from NMP and HD was 81.7% by logistic regression (odds ratio=6.39), 84.1% by discriminant analysis and 99.2% by neural networks computing (area under ROC curve=0.99; error=0.063).

No significant financial relationships to disclose.
12-Lipoxygenase is a potential therapeutic target in non-small cell lung cancer
Authors: Pidgeon G. P. , Gately K. , Lysaght J. , Cathcart M. C. , Campbell V. , Kay E. , O’Byrne K. J.
Published: March 2020

18129

Background: Platelet-type 12-LOX is an arachidonic acid metabolising enzyme resulting in the formation of 12(S)-HETE, which stimulates tumour cell adhesion, invasion and metastasis. We examined the expression of 12-LOX in NSCLC and its role in cell survival. Methods: A549 (adenocarcinoma), SK-MES1 (squamous cell lung carcinoma), H460 and H647 (large cell lung carcinoma) were grown in serum depleted media (0.5%) and screened for 12-LOX expression by RT-PCR and western blot analysis. Cells were treated with baicalein (10uM), a selective inhibitor of 12-LOX, or 12(S)-HETE (100ng/ml) and cell survival / proliferation determined by BrdU assay. Apoptosis was determined using the multi-parameter apoptosis kit and In-cell Analyser, and also by FACS. Gene alterations following 12-LOX inhibition in both A549 and SKMES-1 cells were assessed by quantitative PCR arrays and validated by RT-PCR. A panel of retrospective resected lung tumours were stained for 12-LOX expression by immunhistochemistry. Results: All lung cancer cells lines expressed moderate levels of platelet-type 12-LOX, which was reduced following treatment for 24h with the baicalein. Baicalein decreased lung cancer survival in all cell lines, while 12(S)-HETE increased cellular proliferation. Inhibition of 12-LOX induced apoptosis in a dose dependent manner, with decreased f-actin filaments and loss of mitochondrial mass potential. QPCR array data implicated a number of genes regulating these effects which were validated by RT-PCR, many of which control apoptosis and angiogenesis. The subset of genes downregulated included bcl-2, VEGF, integrin a2 and a4. 12-LOX expression was observed in a variety of human lung cancers with different histological subtypes. Conclusions: 12- LOX is a survival factor in NSCLC. 12-LOX inhibitors decreased NSCLC survival, inducing apoptosis through mechanisms including downregulation of the bcl family of proteins, integrin receptor and angiogenic growth factors. Expression of 12-LOX in fresh resected and retrospective tissue suggests that inhibition of this enzyme is a potential therapeutic strategy in the treatment of NSCLC.

No significant financial relationships to disclose.
N-cadherin, a potential novel therapeutic target in small cell lung cancer
Authors: Batus M. , Kaiser K. A. , Coon J. S. , Ahmed S. , Patel A. , Avery E. F. , Kemper M. A. , Kassar M. , Bonomi P. D.
Published: March 2020

18134

Background: New treatment ideas are needed in small cell lung cancer (SCLC). N-cadherin which is associated with increased tumor invasiveness is a potential novel therapeutic target. It seems reasonable to test recently developed cyclic peptide N-cadherin antagonists in tumors with high N-cadherin expression, and it seemed likely that high N-cadherin expression would occur more frequently in aggressive tumors like SCLC. Our objective was to determine the frequency and biological significance of N-cadherin expression in SCLC. Methods: We retrospectively analyzed 86 patients with small cell lung cancer, most of whom received treatment: chemotherapy with or without radiation. We reviewed their clinical charts and obtained: date of diagnosis, age, gender, performance status, treatment dates and treatment response (CR/PR, stable disease, progression), and death or last encounter date. We also analyzed their pathology specimens for frequency of expression of N-cadherin and grouped them into three categories: no expression, some expression of N-cadherin >1% but <35%, and strong expression 36–100%. Subsequently, we determined the correlation between the N-cadherin frequency groups and the overall survival for all 86 patients. We also determined the time to progression in a subset of 56 patients (with available treatment response data). Results: Out of the 86 patients, 18 (21%) did not express N-cadherin, 10 (11.6%) patients showed >1% but <35% expression of N- cadherin, and 58 (67.4%) had a strong expression >36%-100%. There was no association found between N-cadherin expression and overall survival using either the Log-Rank Test or the Wilcoxon Test. In the subset of 56 patients with available treatment response data there was no association between N-cadherin expression and progression free survival. Conclusions: N-cadherin was expressed relatively frequently in this group of SCLC patients, and these results suggest that phase II trials of the novel cyclic peptide N-cadherin antagonists are warranted in SCLC. N-cadherin did not appear to have prognostic value in our study.

No significant financial relationships to disclose.
Phase I/II trial of bortezimib and pemetrexed in patients with advanced non-small cell lung cancer
Authors: Natale R. B. , McKinley M. , Hilger J. , Myers T.
Published: March 2020

18145

Background: Bortezomib (Vc) is a novel proteosome inhibitor with activity in several malignancies including multiple myeloma, mantle cell lymphoma, and NSCLC. In NSCLC, Vc has additive activity combined with carboplatin and gemcitabine in first line and with docetaxel in second line treatment. Pemetrexed (P) is active in NSCLC and preclinical data suggests a pro-apoptotic synergy between Vc and P. Therefore, we initiated a phase I/II dose finding study of Vc + P in previously-treated patients (pts) with advanced or metastatic NSCLC. Methods: Fifteen pts have been accrued to 3 of 4 planned dose levels of Vc + P. Starting doses (and # pts treated) were Vc 1.4 mg/m2 day 1 & 8 + P 400 mg/m2 day 1 every 3 weeks (3 pts). The 2nd and 3rd dose levels were Vc 1.6 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (8 pts, 5 new + 3 from dose level 1) and Vc 1.8 mg/m2 day 1 & 8 + P 500 mg/m2 day 1 (7 pts). Results: 15 pts are evaluable for response and toxicity and include 8 males, 7 females, median age 67 (range, 55–82), PS 0/1 (3/12 pts), median of 2 prior therapies (range 1–3). Confirmed PRs occurred in 2 pts (13%) and stable disease in 5 (33%). Dose limiting toxicities consisted of grade 4 fatigue (1 pt) and neutropenia/fever (1 pt) at dose level 2, and grade 3 abdominal pain and fatigue (1 pt) and grade 3 diarrhea and vomiting (1 pt) at dose level 3. Conclusions: The above combination is safe at the doses tested thus far and active in pts with heavily pretreated, advanced NSCLC. We are currently exploring Vc 2.0 mg.m2 Day 1 & 8 + P 500 mg/m2 day 1 every 3 weeks to determine the MTD and plan a multi-site Phase II study to determine response rate and survival in a larger pt population.

No significant financial relationships to disclose.
Biweekly docetaxel and gemcitabine as first line chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: Gaspar E. , Firvida J. , Amenedo M. , Orts D. , Salgado M. , LLorca C. , Ramos M. , Perez E. , Cervera J. , Abal J.
Published: March 2020

18147

Background: The activity and tolerability of third-generation agents led many investigators to evaluate doublet combinations in the hope that platinum analogues could be eliminated from the treatment of advanced NSCLC. To improve the therapeutic index of this combination, we performed a study with biweekly gemcitabine and docetaxel. Primary objective was determination of objective response rate (ORR). Secondary objectives were time to progression, tolerability and overall survival. Methods: Patients histologically confirmed of non-small cell lung cancer, aged ≥ 18, ECOG PS 0–2, measurable lesion according RECIST criteria, adequate bone marrow, renal and hepatic function were included. Prior chemotherapy was not allowed. Patients received treatment with a combination of Docetaxel 50 mg/m2 and gemcitabine 20,00 mg/m2 each 15 days for a maximum of 8 cycles. Results: Fifty patients were included between July 2005 and October 2006.Now we present the results of the first 32 patients: 88% were male, median age was 62.7 years old, 69% had ECOG 0–1 and 81% of patients had stage IV. Histology was squamous cell carcinoma (53%) adenocarcinoma (31%) and large cell carcinoma (16%). A total 221 cycles were administrated . Over 30 patients evaluable for response, none achieved CR, 11 PR (36%), 7 SD (23%) and 12 PD, with an overall response rate of 36%. Median follow up of patients is 16 months, with a median overall survival of 9 months. Grade 3–4 toxicity per patient was: neutropenia (6%).Grade 1–2 toxicity per patient asthenia (75%), and nauseas (30%). Conclusions: These results suggest that biweekly schedule of gemcitabine / docetaxel is a safe and active regimen in first line advanced NSCLC patients.Updated results will be presented.

No significant financial relationships to disclose.
A phase II trial of pemetrexed (P) in patients (pts) with performance status (PS) 2 and 3 as first- and second-line treatment for advanced non-small cell lung cancer (NSCLC)
Authors: Zinner R. , Fossella F. V. , Kies M. S. , Herbst R. S. , Lu C. , Johnson F. M. , Bhat S. V. , Price J. S. , Cleeland C. , Wang X.
Published: March 2020

18149

P (Alimta) is approved as second-line therapy in pts with advanced NSCLC. In a phase III trial comparing P with docetaxel (D), median survival was 8.3 mos (P) vs 7.9 mos (D); P had a more favorable safety profile than D (Hanna, 2004). There are few data on pts with PS 3, and ASCO 2003 guidelines recommend that chemotherapy be reserved for pts with PS 0, 1 and possibly 2. Since P is well tolerated, PS3 pts may tolerate and benefit from it. In this trial, we treated 20 pts with stage IIIb/IV NSCLC and PS 2–3 who were chemo-naive or had received 1 prior regimen. Pts received P 500 mg/m2 IV D1 Q 3 wks. All pts received folic acid, vitamin B12 and dexamethasone prophylaxis. Serial blood samples were obtained to monitor inflammatory cytokines, and symptoms were monitored using the validated MDASI instrument. All pts were assessable for toxicity-symptoms, and 17 pts were evaluable for response (assessed after first cycle). Pt characteristics: 8 pts were PS 3 (4/8 first line) and 12 pts were PS 2 (6/12 first line). Median age was 69 for PS3 and 68 for PS2. 5/8 PS3 pts and 6/12 PS2 pts were men. 2/8 PS3 pts and 4/12 PS2 pts had stage IIIb. 4/8 PS3 pts and 6/12 PS2 pts were chemo-naive. Grade 3–4 toxicities for PS3/PS2 cohorts were: neutropenia 0/1 pt, anemia 1/2, fatigue 2/0, pneumonia 1/1, hypotension 1/1, neutropenic fever 0/1, atrial fibrillation 1/1. Response rates (RR) in PS3 pts were minor response (MR) 1/8, stable disease (SD) 5/8, progressive disease (PD) 2/8; RR in PS2 pts were partial response (PR) 1/12, MR 2/12, SD 3/12, PD 3/12, inevaluable 3/12. RR by line of therapy: first-line 6/10 SD, 2/10 PD, 2/10 inevaluable, and second-line, 1/10 PR, 2/10 MR, 3/10 SD, 3/10 PD, and 1/10 inevaluable. Reasons for PS3 pts coming off study were progression (4/8), constitutional toxicity (3/8), fatal pulmonary emboli (1/8); PS2 pts came off study due to progression (5/12), constitutional toxicity (2/12), and pneumonia (1/12). 4/12 PS2 pts are still on study. These preliminary data suggest that single-agent P is well-tolerated and has a promising RR in poor PS pts. Total planned accrual is 30 PS3 and 45 PS2 pts. Survival, symptom, cytokine data will be presented.

[Table: see text]
Irinotecan, carboplatin and etoposide regimen in extensive disease small cell lung cancer: Phase II trial
Authors: Syrigos K. , Katirtzoglou N. , Charpidou A. , Botsis T. , Karapanagiotou E. , Dilana K. , Gkiozos I. , Pantazopoulos K.
Published: March 2020

18153

Background: The prognosis for the patients with small cell lung cancer (SCLC) is very poor with metastases often present at the time of diagnosis. Despite the initial chemo-sensitivity the majority of the patients will relapse and die of their disease. Irinotecan, a topoisomerase I inhibitor, has been reported as an active new agent in SCLC. In combination with cisplatin, it has showed superiority in response rates and progression free survival over the standard regimen of cisplatin and etoposide. We conducted a phase II study in order to evaluate the efficacy and safety of Carboplatin, Irinotecan and Etoposide (CIE) combination in extensive-disease SCLC (ED-SCLC) Methods: Forty six chemo-naïve patients with ED-SCLC and PS 0–2 were enrolled. Forty of theme were men and 6 women. All of them were smokers and the median age was 59.6 years. We administered carboplatin AUC 5 on day 1, irinotecan 120 m2 on day 2 and etoposide 75 mg/m2 on days 1, 2, 3 in a 21 days repeated cycles. The treatment was continued for up to 6 cycles. Response assessments were performed after cycles 3 and 6 and every 2 months subsequently. The patients were evaluated for response, survival and toxicity. Clinical (as site of metastasis) and laboratory (such as LDH) parameters were tested as prognostic factors for survival. Results: Two hundred and two cycles were administered with an average of 4.5 cycle per patient. Overall response rate was 52.2% (partial and complete), mean overall survival was 16.3 months (CI: 95%: 13.0–19.7) and there was a 1 year survival rate of 43.47%. Patients with brain metastasis had worse prognosis (P:0.004). The three drug regimen was well tolerated. Only 1 patient had diarrhea grade II, 6 had grade III/IV and 1 patient was referred with abdominal pain. One was presented with fatal thrombocytopenia while two toxic deaths were reported. Nine patients (19.5%) had neutropenia grade III/IV, without being fatal, and 3 were presented with grade III anemia which need blood transfusions. Conclusions: CIE regimen is effective and well tolerated for the treatment of the poor prognosis group of ED-SCLC patients with responses and overall survival comperable to standard regimen (CE).

No significant financial relationships to disclose.
Randomized phase II trial of two sequential schedules of docetaxel (D) and cisplatin (C) followed by gemcitabine (G) in patients with advanced non-small cell lung cancer
Authors: Galligioni E. , Gebbia V. , Cartenì G. , Gamucci T. , Grossi F. , Ferraù F. , Nardi M. , Pollera C. , Rossi S. , De Marinis F.
Published: March 2020

18154

Background: C based doublets remain the cornerstone for first line treatment of advanced NSCLC but the role of sequential use of chemotherapy is still investigational. Aim of this study was to assess the activity and toxicity of 3 courses of C and D followed by 3 courses of single agent G, to reduce C exposure and sequentially administer 2 second generation cytotoxic drugs. The weekly D/C schedule was further investigated, to reduce toxicity. Methods: Chemotherapy naive stage IIIB or IV measurable NSCLC pts, aged 18–70 and PS 0–1, were stratified by stage (IIIB vs IV) and randomized, after local ethic committee approval and signed informed consent, to D and C (both 75 mg/m2 on day 1) q21 days for 3 cycles (Arm A), or to D and C (both 25 mg/m2 on days 1, 8, 15) q28 days for 3 (Arm B). Responding or stable pts of each arm, were treated with 3 additional cycles of G (1,200 mg/m2 on days 1, 8) q 21 days. Primary endpoint of the study was response rate (RECIST). Sample size was calculated of 42 pts per arm, considering worthy of further investigation a regimen with =14 objective responses. Results: Between May 2005 and October 2006, 88 pts were enrolled (Arm A/B: 43/45), with 69 evaluable so far (median age 63 yrs, median PS 0, and M/F ratio 53/16). Toxicity (NCI-CTG criteria) after 3 cycles, evaluable on 67 (32/35) pts, was mainly hematological, with grade 3/4 neutropenia in 17 pts (17/0), neutropenic fever in 1 (arm A), infections in 2 (arm B), grade 3/4 thrombocytopenia in 3 (1/2) and grade 3/4 anemia in 2 (arm A). Non-hematological grade 3/4 toxicity consisted of fatigue (4/1), diarrhea (4/1), pulmonary toxicity (1/4), pain (2/3), stomatitis (1/2) and alopecia (2/0). Fifty one pts (A/B: 29/22) are evaluable for response after 3 cycles, with 16 PR (55%) and 7NC in arm A and 1CR+6PR (32%) and 7NC in arm B. Objective responses after 6 cycles, available only in few pts so far, show 1CR+10PR in arm A and 2PR in arm B. At a median FU of 6.5 months, 60/85 pts are alive (33/27) and 25 are dead (8/17), with 3 pts, never treated, lost to f. up. Conclusions: From these preliminary results, CD combination appears active and manageable while the activity of G, cannot be defined yet. Data collection is continuing and analysis will be completed and mature, by the time of the meeting.

[Table: see text]
A preliminary report of a phase II trial of single-agent vinflunine as second-line treatment of advanced non-small cell lung cancer
Authors: Joppert M. , Boccia R. , Dakhil S. , Steis R.
Published: March 2020

18156

Background: In preclinical and early clinical trials, single-agent vinflunine (a novel microtubule inhibitor) has shown activity in a variety of tumors, including non-small cell lung cancer (NSCLC). The purpose of this phase II, single-arm study is to evaluate the safety and efficacy of vinflunine administration every 3 weeks to patients with advanced NSCLC who have progressed after prior treatment with a platinum-based doublet. The primary endpoint is 1-year survival rate. This report presents preliminary safety information demonstrating the safety and tolerability of this combination. Methods: Patients = 18 years with confirmed advanced NSCLC (stage IIIB with malignant pleural effusions or stage IV) that have progressed after receiving a platinum-based doublet as first-line therapy, received vinflunine (320 mg/m2) as a 20-minute IV infusion on Day 1 of each 21-day cycle. Results: At the time of analysis, 36 patients (of a planned total of 75) have received study treatment. Patient characteristics include: gender male/female, 24/12; median age 68.5 years (range 42–86); ECOG performance status 0/1, 10/26; and race Caucasian/Black, 34/2. The median number of cycles administered was 2 (range 1–9). Fourteen patients are still on study. The most common toxicities (NCI CTC version 2), regardless of causality, were Grade 3 fatigue (14.3%), asthenia (8.6%), neutropenia (8.6%), constipation (5.7%), cough (5.7%), dehydration (5.7%), vomiting (5.7%), dyspnea (5.7%), and ileus (5.7%). Grade 4 toxicities were neutropenia (22.9%) and change in mental status (5.7%). There were 5 deaths (2 from progressive disease, 1 from respiratory distress, 1 from coronary artery disease, and 1 case of sepsis possibly related to study drug). Conclusions: These preliminary results suggest that vinflunine has a manageable safety profile when used as a single agent for second-line treatment of patients with advanced NSCLC. Supported by Bristol-Myers Squibb.

[Table: see text]