bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of amrubicin (AMR) for recurrent or refractory small cell lung cancer (SCLC)
Authors: Kudoh S. , Yoshimura N. , Kimura T. , Mitsuoka S. , Hirata K.
Published: March 2020

17053

Background: AMR, a totally synthetic 9-amino-anthracycline, demonstrated excellent single-agent activity for previously untreated extensive stage SCLC (Yana et al., Proc. ASCO, 1998, abstr.No.1734). The aim of this trial was to evaluate clinical activity of AMR in the treatment of patients with recurrent or refractory SCLC. Methods: Eligibility criteria were patients having histologically or cytologically proven measurable SCLC, had relapsed after one or two previous systemic chemotherapies, an Eastern Cooperative Oncology Group performance status (PS) of 0–2 and adequate organ function. AMR (40 mg/m2) was administered on days 1–3 every 3 weeks. This study, with a planned sample size of 25, had 80% power to support the hypothesis that the true response rate was >30%, and 5% significance to deny the hypothesis is the true RR was <10%. Results: Between July 2003 and October 2005, 19 patients were enrolled with the following characteristics: male/female, 15/4; median age, 66 years (range 47–78); PS 0/1/2, 0/16/3; sensitive relapse/refractory case, 7/12. Median number of treatment cycles was 3. A total of 59 courses were assessable for safety. The principle toxicity was myelosuppression. Grade 3/4hematologic toxicities were leukopenia (53/32%), neutropenia (32/53%), thrombocytopenia (32/0%) and anemia (42/0%). Non-hematologic toxicities weremild with no grade 4 toxicities; grade 3neutropenic fever (16%), infection (11%), diarrhea (5%), constipation (5%), and AST/ALT (11%) were observed.Responses included 7PR (3 sensitive cases and 4 refractory cases) and 8SD; for an objective RR of 37% (95% CI 16–59%). Conclusions: AMR is well tolerated and promising for treatment of recurrent or refractory SCLC. This regimen warrants further evaluation in a phase III trial.

No significant financial relationships to disclose.
Epidermal growth factor receptor mutations and gene amplification in Japanese non-small cell lung cancer patients treated with gefitinib
Authors: Kawaguchi T. , Sasaki H. , Kawahara M. , Takeuchi H. , Iuchi K. , Matsumura A. , Isa S. , Kubo A. , Kitaichi M. , Kasai K. , Takada M.
Published: March 2020

17063

Background: To evaluate relationship between epidermal growth factor receptor (EGFR) gene status and clinical outcome in patients with non-small-cell lung cancer (NSCLC) treated with gefitinib. Also, to examine an involvement of human papilloma virus (HPV) in EGFR status of these patients. Methods: Twenty seven patients with NSCLC who had relapsed after surgery and received gefitinib were included. Genomic DNA was extracted from the 12 paraffin and the 15 frozen surgical specimens. PCR and sequencing for genotyping were done for EGFR (exon 18–21) and ERBB2 (exon 19–22) and KRAS (exon 1). Gene amplification for EGFR was analyzed by quantitative real-time PCR. HPV was detected by PCR and in-situ PCR. Results: Nine patients (33%) had EGFR mutations; seven patients had deletion mutations in exon 19, one patient had missense mutations (L858R) in exon 21. Two patients had missense mutations (G719S, exon 18 and L838P, exon 21) No mutations were identified in ERBB2 and KRAS. EGFR copy number in the tumor cells ranged from 1.1 to 9.7, and increased EGFR copy numbers (≥3) were observed in six patients ( 22.2%). Two patients (7%) had HPV, and had no mutation and no amplification. Response rate (67% {six of nine patients} v 18% {three of 17 patients}; p = 0.012) was significantly better in patients with EGFR mutations than in patients with wild-type EGFR. Overall survival (median 17 v 9 months) was better in patients with EGFR mutations than in patients with wild-type EGFR. EGFR copy number and presence of HPV were not associated with clinical outcome. Conclusions: EGFR mutations were significantly associated with better clinical outcome in gefitinib treated NSCLC patients.

No significant financial relationships to disclose.
Bexarotene improves median survival (MS) in untreated, advanced NSCLC, when given in combination with carboplatin/paclitaxel
Authors: Bordoni R. , Saleh M. , Khanwani S. , Page T. , Auerbach M. , Steinbaum F. , Ghalie R.
Published: March 2020

17070

Background: Bexarotene (bex) is a subclass specific, synthetic rexinoid analogue, that preferentially binds and modulates the expression of RXR subclass of receptors α, β, and γ. It induces concentration-dependent repression of multiple genes (cyclin D1/D3, total EGFR, pEGFR) inhibiting cell growth, angiogenesis, invasion and metastasis, inducing differentiation, and apoptosis in tumor cells. Several phase-I/II trials suggested increased survival in patients with advanced NSCLC. Methods: Stage-IIIB with pleural effusion & Stage-IV chemo-naïve patients, ECOG 0–2, were enrolled and treated with carboplatin IV AUC-6 d-1 and paclitaxel IV 100 mg/m2 d-1, 8, 15, every 28-d for 4 cycles. Pts were randomized using a 1:1 design to bex PO 400 mg/m2/d either concurrent (C) from Day 1 or sequential (S) at the completion of chemo, for up to a year. Results: 56 patients were enrolled; median age 62.3 (range 41–86), 48 TNM Stage IV, 38 males, 50 ECOG PS 0–1. Of 51 pts evaluable for response, 30 (58%) achieved PR (C: 15 and S: 15); 16 (31%) showed SD (C: 8 and S: 8), and 5 (9.5%) had PD (C: 3 and S: 2). Thirty-two (63%) patients have expired as of 12/31/05. Based on ITT, 40 evaluable pts showed a median TTP of 169 days (C: 166.5 and S 172); The MS for the entire group is 342 days (11.42 mo (C: 12.8 and S: 10.53). Currently, 10 pts are still alive between 407 to 1036 days from registration on the trial. The treatment was well tolerated; overall, AEs were reported in 48% of pts in the S arm and 51% in the C arm. The incidence of Gr 3–4 AEs, regardless of the treatment arm, was < 5%. There were no treatment-associated deaths. Conclusions: Our data suggests a better ORR, TTP, and improvement in MS, when bex is added to carboplatin/ paclitaxel, regardless of concurrent or sequential administration, compared with chemo alone. ORR was not compromised by bex administration and in fact it was above average reported for similar phase-II & -III studies. Toxicity is easily managed.

[Table: see text]
Expression of CEACAM1 in pulmonary adenocarcinoma cells and their metastases
Authors: Laack E. , Schult-Kronefeld O. , Burkholder I. , Görn M. , Andritzky B. , Kugler C. , Edler L. , Bokemeyer C. , Schumacher U. , Thöm I.
Published: March 2020

17071

Background: The cell adhesion molecule CEACAM1 is involved in intercellular adhesion and is expressed in a variety of normal human tissues such as mammary gland, colonic mucosa and prostate. In cases of malignant transformation of these tissues a down regulation or loss of CEACAM1 has been shown. In contrary, CEACAM1 is not expressed in normal lung tissue or melanocytes and it has been demonstrated that a expression in these tissues is associated with the development of metastatic disease. The aim of the present investigation was to analyze a possible association between the expression of CEACAM1 in pulmonary adenocarcinoma cells and their lymph node and hematogenous metastatic cells. Methods: CEACAM1 expression was immunhistochemically evaluated in primary tumor cells, cells in lymph nodes and in distant metastases of 96 patients with metastatic adenocarcinoma of the lung who had undergone surgery between 1999 and 2002. Results: An expression of CEACAM1 has been shown in 78 of 96 primary tumors. We found a significant positive correlation between the CEACAM1 expression on the cells of the primary tumor and the lymph node metastases (p<0.005) and the hematogenous metastases (p<0.05). Conclusion: As shown before, CEACAM1 is not expressed in normal lung tissue but in most primary adenocarcinomas of the lung. We are the first to demonstrate, that its expression is preserved in the lymph node and hematogenous metastases in metastatic disease implicating that its expression is of functional significance of both metastatic sites.

No significant financial relationships to disclose.
The Ets transcription factor Esx regulates expression of metastasis-associated genes in non-small cell lung cancer (NSCLC)
Authors: Mitas M. , Graham A. , Khoors A. , Chen Y. , Lewin D. , Davoodi P. , Mikhitarian K. , Montero A. , Cole D. , Wallace M.
Published: March 2020

17077

Background: The overall 5-yr survival for the treatment of lung cancer patients is less than 20% due to the inability to control metastatic disease. Methods: To identify genes that promote the development of metastases in NSCLC and other solid tumors, we first performed three separate microarray analyses using Affymetrix U133A chips whereby expression values of a pool of normal lymph nodes was compared to: lung cancer cell lines (n = 4), and metastatic lymph nodes from breast (n = 3) and pancreatic (n = 3) cancer patients. Separate lists of the 35 most highly overexpressed genes for each cancer type were compiled. Results: We observed that each list contained EpCAM, XAG, CK19, and CK8 (p = 1.1E-18). To search for genes that might regulate expression of these four genes, we queried the CGAP NCI60 gene expression database with the 87 genes contained on the three lists and constructed a connectivity map such that the presence of a gene on the map required: 1) high correlation (p < 8.0E-6) with at least two other genes, and 2), direct or indirect contact to EpCAM or XAG. The map contained two gene clusters (XAG cluster = 6 genes; EpCAM/CK19/CK8 cluster = 7 genes) that were connected to, and potentially regulated by, the Ets transcriptional factor Esx. Genes from both clusters, as well as Esx, were highly overexpressed in metastatic mediastianal lymph nodes obtained from NSCLC patients. To investigate whether Esx might regulate expression of one or more genes in the two clusters, we transfected an NSCLC cell line derived from lymph node metastases with siRNA to Esx and observed: 1) a reduction in expression of EpCAM (4-fold), XAG (7-fold), and the orphan nuclear receptor ESRRα (1,000-fold), and 2), an inhibition of cell growth. Conclusions: Based on our ability to simultaneously inhibit cell growth and expression of multiple metastasis-associated genes with a single siRNA, we conclude that Esx is a major regulator of lymph node metastasis.

No significant financial relationships to disclose.
Phase I study of OGX-011, a second generation antisense oligonucleotide (ASO) to clusterin, combined with cisplatin and gemcitabine as first-line treatment for patients with stage IIB/IV non-small cell lung cancer (NSCLC)
Authors: Laskin J. J. , Chi K. N. , Melosky B. , Sill K. , Hao D. , Canil C. M. , Gleave M. , Murray N.
Published: March 2020

17078

Background: The clusterin gene is frequently expressed in NSCLC and encodes a cytoprotective chaperone protein that promotes cell survival and is upregulated in response to apoptotic stimuli such as chemotherapy. OGX-011 is an ASO that binds to clusterin mRNA thus potently regulating expression and chemosensitizing cancer cells. Previous Phase I studies of OGX-011 identified biologically active doses of 480mg to 640mg. The objective of this multi-center Phase I study was to define the Phase 2 dose of OGX-011 in combination with standard chemotherapy. Methods: Patients (pts) with chemotherapy-naive advanced stage IIIB/IV NSCLC were potentially eligible. OGX-011 is given as a 2hr IV infusion weekly after 3 loading doses (days -7, -5, and -3). OGX-011 dose escalation was planned to a maximum of 640mg. Cisplatin was given at 75 mg/m2 IV day 1 and gemcitabine 1250mg/m2 IV days 1 and 8, on a 21-day schedule up to 6 cycles. Pharmacokinetic profiling was done in cycle 1. Results: Between Jan 2004 and Apr 2005, 10 patients were enrolled. Median age 62 yrs (49–75); 4 female. ECOG 0/1: 3/7. Stage IIIB/IV: 1/9. 9 of 10 pts completed at least one cycle; 1 withdrew after one dose of OGX-011 due to progressive disease (PD). Of the 9 pts, 6 received ≥ 5 cycles and 3 received 2–4 cycles (2 patients discontinued due to PD and 1 at the pts request). Median follow-up: 5.0m (1.6 - 6.7m). As of Jan 2006, 2 pts had a PR; 5 had SD; 2 had PD. 4 pts had 5 serious adverse events: elevated creatinine, hypoxia, pneumonia, pleural effusion, and febrile neutropenia. 3 pts had Gr 3 hyponatremia. Gr 3/4 hematological toxicities in 10–40% and 10–20%, respectively. No dose-limiting toxicities noted; 7 pts received OGX-011 at 640 mg. A proportional increase in OGX-011exposure (Cmax and AUC0-inf) from 480 to the 640 mg was noted with no apparent effect on GEM/CIS. Conclusions: OGX-011 was well tolerated and can be given at biologically active doses (640 mg) with standard GEM/CIS chemotherapy for patients with advanced NSCLC. A multicenter Phase II trial of this combination is underway. Sponsored by OncoGenex Technologies, Inc. with Isis Pharmaceuticals Inc.

[Table: see text]
Risk of severe radiation pneumonitis in gemcitabine (GEM) based consolidation chemotherapy after concurrent chemo-radiation (C-RT) in stage III non-small-cell lung cancer (NSCLC)
Authors: Mok T. , Zhang L. , Liao M. , Boyer M. , Yang J. , Wu Y. , Zhou C. , Zee B. , Lee J.
Published: March 2020

17079

Background: Recent phase II study (S9504) showed that 3 cycles of consolidation docetaxel after C-RT is associated with prolonged survival but 6 pts (7%) had severe (≥gr 3) radiation pneumonitis and 2 (2.4%) died.(None at S9019) LCRG, a multinational Asian study group, designed a randomized phase II study aiming to assess the treatment outcomes of consolidation GEM or GEM/Carboplatin (CAR) after C-RT. GEM is a potent radiation sensitizer with known recall phenomena, thus we evaluated the risk of severe radiation pneumonitis with GEM-based consolidation chemotherapy after C-RT in this interim report. Methods: Enrollment criteria: Histologic proven NSCLC; attained CR/PR/SD after C-RT (Cisplatin-based chemotherapy between 25 mg/m2 and 40 mg/m2 per week or 60 mg/m2 to 100mg/m2 every 3 to 4 weeks; fraction dose not more than 2.0 Gy; total dose not less than 54 Gy and not higher than 64 Gy); ECOG PS 0–1; adequate hematologic/renal/liver function. Patients were screened for eligibility within 6 weeks after C-RT. Eligible patients are randomized to receive GEM 1250mg/m2 day 1,8 q21days with or without CAR 5XAUC day 1. Results: Between 3/04 and 9/05 we screened 51 patients and excluded 19. Six (31.5%) were excluded due to radiation pneumonitis.(gr 1=5 and gr 3 = 1). C-RT induced toxicity was the main reason for difficulty with accrual to this trial. We enrolled 32 patients (m:f 29:3; mean age 58 (40–78); adeno:scc:other 14:16:2; IIIa:IIIb 4:28) Median RT fraction and dose was 30 (27–32) and 60 Gy (54–64), respectively. 19 pts received GEM and 13 received GEM/CAR. Severe (≥gr 3) radiation pneumonitis was reported in 3 pts (9.3%) and 1 (3.1%) died from the complication. Another 10 and 6 pts had grade 1 and 2 radiation pneumonitis, respectively, but without significant clinical compromise. Conclusions: Radiation pneumonitis is common after C-RT with or without consolidation chemotherapy. However, severe radiation pneumonitis is relatively uncommon in pts who received GEM based consolidation chemotherapy after C-RT. A possible explanation is that we have screened out the high risk pts prior to enrollment.

[Table: see text]
Intratumoral injection of oncolytic adenovirus H101 in combination with vinorelbine/cisplatin chemotherapy in patients with advanced non-small cell lung cancer
Authors: Zhou C. , Xu Y. , Ni J. , Zhou S. , Xu J.
Published: March 2020

17082

Background: Chemotherapy is main treatment for advanced NSCLC. But its efficacy is quite small with improvement of 1–2 months in median survival. New strategy against NSCLC is needed. Oncolytic adenovirus H101 is found to be effective against NSCLC. This trial is desigened to investigate efficacy and toxicity of intratumoral injection of H101 in combination with chemotherapy in the treatment of NSCLC. Methods: The NSCLC patients confirmed cytologically or pathologically were randomized to intratumoral injection of adenovirus H101 (1.5 × 1012 viral particles) plus NP chemotherapy (arm A) or NP chemotherapy (arm B). Objetive response was evaluated every two cycles and time to progression (TTP) and overall survival were followed up. Results: Out of 18 evaluable patients in Arm A, 4 patients showed partial response (PR),3 minor response(MR), 7 stable disease (SD) and 4 disease progression (PD), while in Arm B 16 evaluable patients showed 3 PR, 4 MR, 3 SD and 6 PD. At the first time of response evaluation, there was 1 PD in Arm A,but in Arm B there were 5 of PD. Failure rate in Arm B was significantly higher than in Arm B. Survival curves between the two arms were similar. Six month, 9 month and 1 year survival rates were slightly higher in Arm B and median TTP was also prolonged in Arm A. Except non-infectious fever, Arm A was similar in other toxicities to Arm B. there was only 2 patients developing mild pneumothorax. Conclusions: Intratumoral injection of H101 1.5 × 1012 viral particles in combination with NP chemotherapy was feasible, effective and safe in treatment of advanced NSCLC.

No significant financial relationships to disclose.
Cytokines modulation and activity in non-small cell lung cancer (NSCLC) by chemotherapy and indinavir
Authors: Bearz A. , Simonelli C. , Talamini R. , Sgadari C. , Monini P. , Ensoli B. , Spazzapan S. , Vaccher E. , Berretta M. , Tirelli U.
Published: March 2020

17094

Background: Our aim was to evaluate the activity of chemotherapy (CT) and indinavir, a protease inhibitor affecting matrix metalloproteases (mmps) of tumors, according to in-vitro studies (Sgadari, Nat Med 2002), in NSCLC patients (pts). Methods: All consecutive pts with NSCLC, IIIB and IV, underwent a platin-gemcitabine treatment. All pts with stable disease or partial remission after 3 courses were given 3 more courses plus indinavir 800 mg tid p.o, till progression. For each pt serum samples were collected before CT and every month till end of the study. Results: We enrolled 24 pts, with the same prognostic factors (age <70 years; PS 0 and IV stage disease). Clinical data are available for 18 pts. Up to now we did not find any clinical benefit with indinavir as maintenance therapy: median time to treatment failure (TTF) is 2.75 mos (±1.0) and median overall survival (OS) is 16 mos (±4.5), not significantly different from literature data. For 11 pts, biological data are available. Using a paired T-test to compare differences at different times, we did not find any variation in VEGF, TNF-α, ICAM, neopterine, γ-IFN, mmps by CT. VEGF decreases in comparison with basal time, but not significantly, mean value 326 pg/mL (±79). Indinavir induces an increase of mmp2, before Indinavir 68.8 pg/mL (±9.18), after 97.09 (±10.21), p = 0,04. Analyzing by response, all pts with a RP at CT had a progressive decrease of serological VEGF; pts with SD or PD had an increase of VEGF. Pts with longer OS had a decrease of TNF-α, even at the time of progression. Conclusion: In our pts TNF-α and VEGF seem to have different pathways. TNF-α is related with OS, while VEGF is related with response to treatment. VEGF is a good marker to follow the clinical response and TNF-α is a better prognostical marker for OS. All our pts showed mean serum VEGF values lower than the previously reported values as cut-off level for prognostic value (Laack E. Lung Cancer 2005); in fact we selected pts in SD or RP after the third course of CT. In our pts VEGF is related with tumor response to therapy (i.e. tumor volume) while TNF-α drives their outcome. Modulation of TNF-α and his pathway may improve pts outcome.

No significant financial relationships to disclose.
Phase II randomized study of gefitinib alone or plus vinorelbine every 2 weeks’ treatment in patients with adenocarcinoma of the lung who failed at least two regimens
Authors: Chen Y. , Perng R. , Tsai C. , Whang-Peng J.
Published: March 2020

17095

Background: To assess the feasibility and the efficacy of adding chronic intermittent low-dose vinorelbine to gefitinib (Iressa) treatment for lung cancer patients with adenocarcinoma who failed 2 previous regimens of chemotherapy. Methods: Patients who had adenocarcinoma and failed at least 2 regimens, including taxanes and platinum, were enrolled and randomized into 2 arms: oral Iressa 250 mg daily (I) or vinorelbine 15 mg/m2 intravenous infusion day 1 and oral Iressa 250 mg daily from day 2 to 14, every 2 weeks (IV). From August 2004 to October 2005, 48 patients were enrolled. Results: Twenty-four patients were randomized into Iressa plus vinorelbine treatment. However, 3 patients refused vinorelbine treatment and received Iressa treatment only. Thus, 27 patients received I treatment and 21 patients received IV treatment. Objective response rates were 55.6% in I and 57.1% in IV. Any grade of leukopenia, neutropenia, and fatigue sensation was significantly higher in the IV arm (p=0.035, 0.001, 0.012, respectively). All the toxicities in both arms were generally mild and no toxic death occurred. However, many patients in the IV arm stopped V treatment before disease progression, including port-A occlusion in 4 patients (after 2, 5, 20, and 23 injections, respectively), mucositis in 1 (after 4 injections), and fatigue sensation in 1 (after 7 injections). After a median follow-up of 8 months, median time to disease progression was higher in IV than I (longer than 12 months vs. 7.1 months, p = 0.0271), more than half of the patients in each arm were still alive (p = 0.2269), and more than 9 patients in each arm survived longer than 1 year. Conclusions: Iressa is highly effective in ethnic Chinese patients with adenocarcinoma of the lung who have failed previous platinum and taxane treatment. The addition of low-dose V every 2 weeks produced a signiificantly better progression-free survival. Replacement of intravenous V with oral V should be considered to prevent the early termination of V treatment.

No significant financial relationships to disclose.
Yttrium-90 microsphere treatment for liver dominant hepatic metastases from lung cancer
Authors: Murthy R. , Oh Y. , Tam A. , Gupta S. , Madoff D. C. , Glisson B.
Published: March 2020

17122

Background: Hepatic metastases are a common manifestation of primary lung malignancies; the primary and other extrahepatic sites are often less responsive to systemic therapy. A new method of regional therapy for hepatic metastases, called SIR-Spheres, a 32μ resin sphere incorporating a pure Beta emitter, Yttrium - 90, has advantages to older forms of regional hepatic therapy, used to treat colorectal liver metastases. The effectiveness and relatively response durability suggests a favorable alternative to chemotherapy for patients with liver-dominant metastatic lung cancers. We report our experience using SIR-Spheres in this setting. Methods: 6 patients (2 well differentiated carcinoid, 2 well & 1 poorly differentiated adenocarcinoma, 1 poorly differentiated small cell carcinoma) with unresectable hepatic metastases were treated with 8 infusions of SIR-Spheres after failing systemic chemotherapy, radiofrequency ablation or arterial embolization were included in the study. SIR-Spheres were administered as 2nd-6th line therapy. Median interval from diagnosis to SIR-Spheres treatment was 20.5 months (6–51 m). Results: Abdominal visceral arteriography demonstrated vasculature conducive for SIR-Spheres delivery in all patients. The median dose of 36.1 mCi (12.9–54 mCi) was delivered. SPECT - CT fusion Bremsstrahlung scans post therapy confirmed preferential deposition of SIR-Spheres within metastases. Responses to therapy included a decrease in the size of the hepatic metastases in one patient and stable disease in two patients. One patient had a mixed response and two patients had progression of disease. One Gr. III and one Gr. IV hepatic toxicity occurred. All patients experienced transient Gr. 1 or 2 fatigue. Time to progression of liver disease ranged from 3 to 9 months. Conclusion: SIR-Spheres is a feasible alternative to systemic therapy for patients with liver dominant metastases from lung cancers. Although serious hepatotoxicity was noted in patients with advanced liver metastases, the treatment was tolerated with only reversible fatigue in the majority of patients. When the treatment was effective, the duration of local disease control after one treatment equaled or exceeded what would be expected with chemotherapy.

[Table: see text]
Choice of chemotherapy (CT) for advanced/metastatic lung carcinoma, WHO types I - III - IV (NSCLC)
Authors: Bollina R. , Beretta G. , Belloni P. , Toniolo D. , Cozzi C. , Brigida S. , Beretta G. A.
Published: March 2020

17132

For NSCLC optimal CT has not been established so far, while many equivalent moderately active schemes are used. The present 40-month study randomized 71 consecutively accrued patients (pts) with parametrable disease between platinum(P)-based three-weekly combinations and non-P monoCT (weekly gemcitabine, vinorelbine or taxane). 68 evaluable pts characteristic were well balanced between treatments: median age 67 years (r. 40–82y), median P Status < 2 WHO scale (r. 0–2),male predominant 82.3%, ratio of IIIb/IV = 1.34 and squamous/non squamous histotype = 1.19, pathologies 26% (only mild to moderate, not contraindicating CT). Objective/subjective response (RECIST/MILAN criteria, JNCI 92:180; P.ASCO 19:642a) after poliCT (PCT) or monoCT (MCT) are reported in the descriptive table . Tolerance was good for both treatment, MCT resulting less deeply toxic and more easily accepted by the majority of pts. This study is still ongoing to achieve the total pts accrual in order to explore statistical significant in the principal determinant subgroup, to determine the subjective response to CT, and to confirm a possible difference in survival. The role of a programmed second line CT vs supportive care alone, and the impact of adding new biomolecular therapies (combined with CT) are the short-term challenges of the second part of this prospective study for advanced NSCLC.

[Table: see text]

No significant financial relationships to disclose.
Enhanced diagnosis in suggested malignant pleural effusion using combined modality of genetic and biochemical tumor markers
Authors: Chang J.
Published: March 2020

17137

Background: Cancer is influenced by oncogenes and tumor suppressor genes. Several tumor markers have been applied clinically in malignancy. A malignant pleural effusion may be an initial presentation of cancer and the presence of malignancy is confirmed by pleural cytology and biopsy. However, other diagnostic modalities are limited and not defined clearly, especially in cases of negative results from traditional diagnostic tool. Here, I investigated p53 and FHIT mutations and microsatellite alterations(MA) in the pleural effusion associated with malignancy(ME). Also, the diagnostic values of CEA, NSE, and CYFRA 21–1 as markers of malignant pleural effusion in lung cancer were assessed together. Methods: The genetic analyses of pleural fluid were done in 40 patients with ME and in the pleural fluid of 17 patients with tuberculous pleurisy(TB) as a control group. Levels of CEA, NSE, and CYFRA 21–1 were measured by immunoassay in the serum and pleural fluid of 34 patients with primary lung cancer and of 16 patients with TB. Results: p53 mutations were detected in 13% of ME and 0% of TB, and FHIT mutations were detected in 18% of ME and 12% of TB. Among 4 microsatellite markers; D3S1234, D3S1285, D9S171, and TP53, loss of heterozygosity(LOH) and microsatellite instability(MI) were observed for each group. MA including LOH and MI in at least one marker was seen 63% of ME cases vs. 35% of TB cases. Patients with lung cancer were found to have significantly higher serum and pleural fluid levels of CEA and CYFRA 21–1 than patients with tuberculous pleurisy. Using cut-off values of 5 ng/ml, 20 ng/ml, and 45 ng/ml for pleural fluid CEA, NSE, and CYFRA 21–1, the sensitivities and specificities were as follows: CEA; 82% and 94%, NSE; 36% and 94%, and CYFRA 21–1; 61% and 81%. A combination of pleural fluid CEA and NSE increased sensitivity and specificity. Conclusions: Although still limited in terms of sensitivity and specificity, this study shows that the determinations of CEA and NSE in pleural fluid enhance diagnostic yield better than all the other combination of tumor markers in malignant pleural effusion, especially in lung cancer and molecular diagnostic strategies including microsatellite alterations are possibly applied for the diagnosis of malignant effusion.

No significant financial relationships to disclose.
Palliative treatment with gefitinib (G) in advanced and heavy pre-treated non-small cell lung cancer (NSCLC)
Authors: Tamburini E. , Nicoletti S. , Papi M. , Fantini M. , Possenti C. , Pasquini E. , Nicolini M. , Fabbri P. , Fattori P. , Tassinari D. , Ravaioli A.
Published: March 2020

17139

Background: G has demonstrated to be active in patients with advanced NSCLC pretreated with chemotherapy. We report our experience about activity and safety of G in patients with advanced, heavily pre-treated NSCLC or chemotherapy-naive patients with a low performance status. Methods: The records of the patients treated with G were reviewed; all the patients pre-treated with at least one course of a platinum-containing regimen or with low performance status were considered eligible and enrolled in the trial. All the patients were treated with G 250 mg/die until progression of the disease or intractable toxicity. All the patients were evaluated every 21 days for toxicity and every 2 months for survival. Primary end point was time to progression (TTP); secondary ones were overall survival (OS) and safety. Results: Till today 56 patients were considered eligible and enrolled in the trial; the results are summarised in the table . *: using Kaplan-Meyer test. No significant differences in OS were observed between the patients chemotherapy-naive with low performance status or pre-treated with one line of chemotherapy vs heavily pretreated ones (respectively 170 days vs 120 days, p = 0.85 using the Log-Rank test). Toxicity was mild with no haematological side effects and grade IV diarrhoea in 1 patient (1.7%). Conclusions: G seems to represent an interesting option in patients with NSCLC with low performance status or heavily pre-treated with chemotherapy. Our data seem to confirm that G is an active and safe treatment in such a subset of patients, opening a novel dimension in the treatment of pre-treated NSCLC (supported by IOR).

[Table: see text]

No significant financial relationships to disclose.
Outcome of non small cell lung carcinoma patients receiving chemotherapy in Kartal State Hospital, Turkey
Authors: Kocak M. , Mayadagli A. , Ozkan A. , Gumus M. , Marti A. , Demir O. , Parlak C. , Aliustaoglu M.
Published: March 2020

17142

Background: Lung cancer has been the leading cause of cancer deaths in men worldwide, and is the second most common cause of cancer deaths in women. Non-small cell histology comprises about 70–80% of every diagnosis of lung cancer. Despite advances in the detection and treatment, the long-term survival of patients with advanced non-small cell lung cancer (NSCLC) remains poor, with a 5-year survival of less than 5%. We conducted this trial to determine the influence of treatment with docetaxel given in combination with cisplatin on survival and time to progression, and to evaluate its tolerability in chemotherapy naive patients with metastatic NSCLC. Methods: Patients with histological or cytological confirmed stage IV NSCLC who met the following criteria were eligible for the study: suitable for first-line chemotherapy with no previous chemotherapy, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, an objective measurable disease, an adequate bone marrow reserve, a normal hepatic and renal function. Cisplatin and docetaxel were delivered to the patients at one dose level through the courses repeated every 3 weeks for 4–6 cycles. Each patient received docetaxel at the doses of 75 mg/m2/day and cisplatin at the doses of 75 mg/m2/day both on day 1. Results: Fifty eligible patients with stage 4 NSCLC were enrolled into the study from June 2003 to September 2005. Median follow-up time was 6 months (1–21). Median age was 61.5 (39–75). Forty eight patients (96%) were male, and 2 patients (8%) were female. Histological type was squamous cell carcinoma in 21 patients (42%), adenocarcinoma in 11 patients (22%) and undifferentiated histologies in 18 patients (36%). The median overall survival time was 16 months (95%CI: 8–24). One-year survival rate was 56.3%. Overall response rate was 44% with 40% partial (PR), 4% complete response (CR). Twenty eight percent of patients had stable disease, and 28% of patients showed disease progression. The median time to progression was 4 months (95%CI: 2.4–5.5). Conclusion: Docetaxel/cisplatin demonstrated efficacy comparable to other platinum agent doublets.

No significant financial relationships to disclose.
The docetaxel (DOC) and gemcitabine (GEM) combination as adjuvant chemotherapy in patients with non-small cell lung cancer (NSCLC): A multi-institutional phase II trial
Authors: Kawamura M. , Eguchi K. , Izumi Y. , Kobayashi K. , Sakaguchi H. , Koike T.
Published: March 2020

17157

Background: As clinical phase II studies with non-platinum doublet for adjuvant chemotherapy after complete resection of NSCLC has been scarcely reported, this clinical study was designed to evaluate the toxicity profile and the efficacy of the adjuvant chemotherapy with non-platinum doublet of DOC+GEM. Methods: Eligibility criteria included: completely resected NSCLC, pathological stage II and IIIA, younger than 76 years old, and performance status 0–1. Patients treated preoperatively were excluded. Treatment consisted of DOC, 60 mg/m2, on day 8, and GEM, 1000 mg/m2, on day 1, 8, and 15 every 4 week (4 cycles). Dose of GEM was decreased to 800 mg/m2 after the initial 21patients because interstitial pneumonitis (IP) occurred in 3 among them. Results: Between August 2000 and August 2002, 35 patients (M/F: 21/14) were enrolled. The median age was 62 years (range 47–74) were enrolled with 5 patients (14.3%) over the age of 70. 34 patients had ECOG PS of 0. 28 patients had adenocarcinomas, 6 had squamous cell carcinomas, and one had adenosquamous carcinoma. Pathological stages were stage IIA in 5 patients, stage IIB in 1 and stage IIIA in 29 (82.9%). All patients received at least one cycle of chemotherapy. 29 patients received 3 cycles of chemotherapy and 23 (66%) completed 4 cycles. The main grade 3/4 toxicity (according to WHO scale) consisted of leukocytopenie (n = 19, 54.3%), thrombocytopenia (n = 3, 8.6%), appetiteloss (n = 4, 11.4%), dyspnea (n = 3, 8.6%), and vomiting (n = 1, 2.9%). IP, which caused dyspnea in these 3 patients, were well treated with steroid and suspension of chemotherapy. There was no treatment related death. Median follow-up period was 52 months. The 4 year recurrent free survival rate was 42.9% and the 4 year survival rate was 65.8%. Conclusions: Non-platinum doublet regimen with DOC+GEM as adjuvant chemotherapy for the NSCLC patients with complete resection was feasible and showed good compliance besides IP.

No significant financial relationships to disclose.
Combination of local tumor invasiveness (LTI) and International Prognostic Index (IPI) provides better predictive value in extranodal NK/T-cell lymphoma, nasal type (NTCL)
Authors: Kim T. , Lee S. , Kim D. , Lee S. , Im S. , Kim T. , Kim C. , Bang Y. , Heo D.
Published: March 2020

17503

Background: In contrast to B-cell lymphomas, NK/T-cell lymphomas have unique clinical pattern (local invasiveness; Blood. 2005;106:3785). Prognostic factors were evaluated according to IPI as well as LTI and compared with the other prognostic model (Lee J, et al JCO 2006). Methods: 176 patients diagnosed with NTCL between 1992 and 2004 were analyzed. Overall survival (OS) and progression-free survival (PFS) were compared according to IPI, IPI combined with LTI, and the other model. LTI was briefly defined as follows: bony invasion or perforation or skin invasion (upper aerodigestive tract); serosal invasion or perforation (gastrointestinal tract); tumor more than 5cm or invasion of deep extradermal structures (skin); and neurovascular or bony invasion (muscle). Results: After a median follow-up period of 80 months, 5-year (y) OS and PFS were 33% and 25%, respectively. The IPI risk group was predictive of OS and PFS (5-y OS 52%, 23%, 10%, and 4%, respectively, P < .0001; 2-y PFS 47%, 31%, 5%, and 4%, respectively, P < .0001) but failed to show survival differences between the high-intermediate and high risk groups (P = .0737). However, once both IPI and LTI are combined, there were significant differences in OS and PFS between the IPI score 0–2/LTI-, IPI score 0–2/LTI+, IPI score 3–5/LTI-, and IPI score 3–5/LTI+ groups (5-y OS 60%, 14%, 7%, and 4%, respectively, P < .0001; 2-y PFS 53%, 21%, 9%, and 4%, respectively, P < .0001). OS and PFS were also affected by the other prognostic model but this model failed to show survival differences among the risk groups (P = .1382). Conclusions: Combination of local tumor invasiveness and International Prognostic Index provides better predictive value in extranodal NK/T-cell lymphoma, nasal type.

No significant financial relationships to disclose.
Renal toxicity associated with zoledronic acid and pamidronate in multiple myeloma patients: A retrospective study
Authors: Nickolas T. L. , Chen L. , Markowitz G. , Green J. , Wintfeld N. , Neary M. , Duh M.
Published: March 2020

17515

Background: Patients (pts) with multiple myeloma (MM) are at an increased risk of renal impairment as part of disease progression. Herein we compared rates of renal toxicity in MM pts treated with zoledronic acid (ZO), pamidronate (PA), and no bisphosphonate (BP) treatment (NT). Methods: Medical and pharmacy claims and laboratory data were reviewed from >35 managed care plans between 01/2000 and 12/2004. Inclusion criteria were ≥2 claims for MM, no gap in health coverage, and serum creatinine readings before and after first ZO or PA infusion. MM pts who received NT served as a separate reference group. Observation periods extended from initial BP infusion to health plan disenrollment (BP monotherapy) or BP switch. Renal impairment was defined as a ≥25% decrease in glomerular filtration rate (GFR,abbreviated MDRD formula) from baseline. Andersen-Gill model, adjusted for demographics and baseline comorbidities, was used to analyze multiple events in a given pt, as physician practice patterns indicate that administration of both BPs continues even after the development of a first renal event. Results: The study population comprised 122 ZO-treated pts, 90 PA-treated pts, and 213 NT pts. Baseline characteristics of ZO and PA groups were similar except the ZO group had a significantly better baseline GFR and higher previous nephrotoxic drug use (both p < 0.01). After treatment, ZO and PA groups had similar renal impairment rates that were significantly higher than the NT group and increased with treatment duration (ZO 21.7%, PA 22.9%, NT 17.0% in pts treated for <6 months; increasing to ZO 53.8%, PA 50.0%, NT 33.7% in pts treated for ≥18 months). Mean renal impairment events per person-year were significantly higher for ZO than PA (1.83 vs 0.78, p < 0.001). Multiple-event analysis found a 2.6 times risk of renal impairment for ZO than PA (p < 0.0001). Compared with PA, ZO-treated pts had a steeper decrease in mean GFR from baseline by 8.5% (p = 0.03). Conclusions: This retrospective observational study suggests that in MM patients, both ZO and PA are associated with a similar higher risk of renal impairment than NT, but ZO-treated pts are significantly more likely to experience multiple impairment events upon repeated administrations.

[Table: see text]
The autologous hemopoietic stem cell transplantation in adult patients with lymphoma: Turkish Bone Marrow Transplantation Registry Results
Authors: Turkish T.
Published: March 2020

17517

Background: Turkish bone marrow transplantation registry (TBMTR) was established in 1995. Since 1992, data of adult lymphoma patients from fifteen transplant centers were collected and analyzed by TBMTR. Methods: A total of 437 adult lymphoma patients (185 Hodgkin’s and 252 non-Hodgkin’s lymphoma) undergoing autologous hemopoietic stem cell transplantation (HSCT) were registered by TBMTR from 1992 to 2002. Results: Peripheral blood was used in 94% of the transplantations as a source of stem cells. Non-TBI conditioning regimens were administered in 88% of the cases. The 100-day transplant related mortality was 11% in relapsed and in primary refractory Hodgkin’s lymphoma patients; while transplant-related mortality (TRM) was found to be 9% and 30% in non-Hodgkin’s lymphoma patients in first remission and in primary refractory cases, respectively. Infection was the most common cause of TRM. Overall (long-term) survival rates were 50% and 49% in relapsed cases and primary refractory cases with Hodgkin’s lymphoma, respectively; while in non-Hodgkin’s lymphoma patients the survival rates were 65% in cases in first remission, 50% in sensitive relapse, 0% in resistant relapse and 24% in primary refractory cases. Conclusions: In conclusion, TBMTR results are comparable to EBMT and IBMTR results. Therefore, autologous HSCT may provide long-term survival in patients with Hodgkin’s lymphoma as well as in patients with non-Hodgkin lymphoma in first remission and in sensitive relapse. Contributing authors and centers: F. Arpaci1, S. Ataergin1, G. Gurman2, S. Cagirgan3, M. Arat2, A. Ozet1, M. Ayli4, M. Ozcan2, A. Unal5, T. Soysal6, Y. Koc7, A. Buyukcelik8, A. Ozturk9, E. Ovali10, H. Goker11, B. Sahin12, S. Kalayoglu Besisik13, M. Bayik14, Z. Bolaman15, S. Bavbek16, M. Turan1 1GATA; 2Ankara University Hematology; 3Ege University; 4Numune Hospital, Ankara; 5Erciyes University; 6Cerrahpasa University; 7Hacettepe University Institute of Oncology; 8Ankara University Medical Oncology; 9GATA Haydarpasa; 10Karadeniz University; 11Hacettepe University; 12Cukurova University; 13Istanbul University Hematology; 14Marmara University; 15A.Menderes University; 16Istanbul University Institute of Oncology.

No significant financial relationships to disclose.
Serum LDH predicts response rate, response duration, and survival of patients (pts) with relapsed/refractory non-Hodgkin’s lymphoma (NHL) treated with 131I-tositumomab (131I-Tab) or 90Y ibritumomab tiuxetan (90Y-Iab) radioimmunotherapy (RIT)
Authors: Taylor Diangi Y. , Andreadis C. , Svoboda J. , Nasta S. D. , Tsai D. E. , Luger S. M. , Stadtmauer E. A. , Downs L. H. , Dadparvar S. , Alavi A. , Schuster S. J.
Published: March 2020

17520

Background: Although both 131I-Tab and 90Y-Iab are approved for treatment of pts with relapsed or refractory low-grade, follicular, or transformed NHL, a prospective randomized comparison of these two forms of RIT has not been performed. We retrospectively reviewed our experience using either agent in pts with NHL. Methods: Sixty-one pts with NHL who were treated with a single course of 131I-Tab (N = 22) or 90Y-Iab (N = 39) between 1999 and 2005 were included in this analysis. The median age was 61 y (range 21–83 y) and the median number of prior therapies was 5 (range 1–13). Overall, 27 pts had indolent NHL (20 follicular grade 1/2, 4 small lymphocytic, and 3 marginal zone), while 34 pts had aggressive NHL (22 diffuse large cell, 10 mantle cell, and 2 follicular grade 3). Among pts, 75% had stage III/IV disease, 52% had an elevated serum LDH, and 38% had bulky disease (>5 cm). These characteristics were similar for pts receiving either 131I-Tab or 90Y-Iab, with the exception of elevated serum LDH (64% vs. 33%, p = 0.02). Median follow up was 21 mos (range 3–55). Results: The overall response rate (ORR) was 44% with complete response (CR) in 21% of pts. The median time to progression (TTP) was 5 mos for all pts, 9 mos for responders, and 14 mos for CRs (range 4–55). Patients with indolent NHL had no difference in ORR, CR, or TTP from pts with aggressive NHL, but had a significantly longer OS (HR 0.37, p = 0.01). Elevated LDH was the only significant predictor of ORR (31% vs. 57%, p = 0.04). In multivariable analysis, elevated LDH was adversely associated with TTP (HR 2.0, p = 0.02) and OS (HR 2.7, p = 0.02) among both subgroups of NHL. We did not discern a difference in ORR, CR, TTP, or OS between 131I-Tab and 90Y-Iab, even when stratifying for serum LDH. Conclusions: RIT produced high response rates in heavily pre-treated pts with indolent or aggressive NHL. Elevated LDH is the most significant prognostic factor for ORR, TTP and OS in this population. Patients with an elevated LDH should be considered for alternative treatment approaches or clinical trials, including RIT in combination with chemotherapy or transplant.

[Table: see text]
Safety analysis of a phase II study of cyclophosphamide, vincristine, non-pegilated liposomal doxorubicin (Myocet), and prednisone + rituximab in biweekly regimen (R-COMP-14) as primary treatment of non-Hodgkin lymphoma
Authors: Garcia Arroyo F. R. , Herrero J. , Provencio M. , Gómez-Codina J. , Rueda A. , Llanos M.
Published: March 2020

17532

Background: Gold standard treatment of CD20+ aggressive B-cell non-Hodgkin lymphoma, R-CHOP, has been suggested to improve outcome when administered as dose-dense regimen supported with G-CSF. The non-pegylated liposomal doxorubicin (Myocet) has an improved safety profile compared to standard formulations of doxorubicin. Standard R-CHOP regimen has been modified replacing doxorubicin with Myocet, administered on a biweekly basis (R-COMP-14) looking for an increase in efficacy without impairing tolerability Methods: Single arm, multicentric, 2-step (Simon design) phase II trial. Newly diagnosed, diffuse large B-cell lymphoma, stages III, IV or I, II with IPI ≥ 1, CD20+, eligible patients (Pt) were treated with Myocet 50 mg/m2, cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (max. 2 mg), rituximab 375 mg/m2 and prednisone 100 mg/d d1–5 in biweekly cycles. Pegilated filgastrim (Neulasta™) was administered on day 2 of the cycle. Response was assessed after 3 cycles, and patients with PR or CR received 5 additional cycles. A safety analysis was planned by protocol with data of first patients included Results: The median age of the 13 Pt included was 59 (range 28–64). At baseline 53.9% Pt had III-IV stage and 41.7% had extraganglionar involvement. Median basal LVEF was 66% (range 44–79). A median of 7 cycles of R-COMP were administered. The median relative dose intensity per week for Myocet was 94.9%. 6.2% of the cycles were delayed and 8.6% of the cycles were dose reduced. There were 2 episodes of febrile neutropenia. G3 asthenia, G3 neurotoxicity and G3 related infection were found in one cycle each. One patient had G3 hepatic toxicity resolved with dose reduction. At the end of treatment the median LVEF was 65.52% (range 52–76), there was no cardiac event related to the treatment. 84.6% of Pt had complete or partial response (7 RC, 2 uRC, 2 PR, 1 SD, 1 PD) at the end of the study Conclusions: In this small safety group of Pt that received the dose-dense regimen, the preliminary results suggest that R-COMP-14 supported with Neulasta is a well tolerated and effective regimen. Recruitment will proceed as planned (75 Pt).

No significant financial relationships to disclose.