bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutathione pathway genes predict quality of life (QOL) in lung cancer patients: A NCCTG-97–24–51 based study
Authors: Yang P. , Mandrekar S. , Hillman S. , Allen K. , Jett J. , Perez E. , Adjei A.
Published: March 2020

18037

Background: Platinum compounds are major chemotherapeutic agents in lung cancer and are metabolized by the glutathione pathway enzymes. We reported that genotypes of glutathione-related enzymes, especially GCLC, may be host factors in predicting survival of patients with stage IIIB/IV non-small cell lung cancer who were stable or responding from prior platinum-based chemotherapy (Yang et al., ASCO 2006). NCCTG investigators previously correlated allelic variants in 5-FU metabolizing genes with QOL in colorectal cancer patients (Sloan et al., ASCO 2004). We sought to evaluate the role of glutathione pathway genotypes on QOL. Methods: DNA samples were analyzed using 6 polymorphic DNA markers in the glutathione metabolic pathway. The contrasting genotypes in the analysis were GSTM1 and GSTT1 (null vs. present), GSTP1-I105V (AA vs. GA/GG), GSTP1-A114V (CC vs. CT/TT), GPX1 (CC vs. TT/TC), and GCLC (homozygous repeat 77 vs. heterozygous 7*). Forty-six patients completed the FACT-L and the UNISCALE QOL questionnaires at baseline and week-8, and we have results for all 6 genotypes. A clinically significant decline (CSD) in QOL was defined as a 10% decrease from baseline to week-8. A multivariate logistic regression model was used to evaluate the association of all 6 genotypes with a CSD in QOL. Results: Patients carrying the GPX1-CC genotype had a CSD in the UNISCALE (Odds Ratio (OR): 10.0; p=0.02), total FACT-L score (OR: 7.9; p=0.03), the FACT-L physical well being construct (OR: 13.7; p=0.02), and the FACT-L functional well being construct (OR: 5.3; p=0.05). Other constructs, i.e., emotional, social and family, and additional concerns were not significantly associated with the genotypes. Conclusions: Genotypes of glutathione-related enzymes, especially GPX1 may be inherited factors in predicting patients’ QOL after platinum-based chemotherapy. Further investigation to define and measure the direct or indirect effects of these genes on QOL is critical, particularly, via drug responses, toxicities, and disease recurrence. (This work was partly supported by NIH grants CA77118, CA80127, and CA84354.)

No significant financial relationships to disclose.
Gefitinib (G) plus interleukin-2 (IL-2) in previously treated patients with advanced non-small cell lung cancer (NSCLC)
Authors: Tomasello G. , Buti S. , Bosio G. , Stifani I. , Maestrelli M. , Brighenti M. , Porzio R. , Lazzarelli S. , Negri F. , Longarini R. , Passalacqua R.
Published: March 2020

18042

Background: Previous studies in patients with NSCLC treated with IL-2 reported relatively long survival (Cancer 1994;73:1353–60) and a recent study indicated that lymphocytes are activated by G treatment (J Cancer Res Clin Oncol. 2006;132:719- 725.). In this study we explored the possible synergism between IL-2 and G in terms of response rate, survival and toxicity. Methods: From September 2003 to November 2006, 70 consecutive chemotherapy treated patients with advanced, progressive NSCLC received oral G 250 mg daily in a compassionate use program at a single institution. The first 39 patients included in the study received only G, the others 31 also received subcutaneous IL-2: 1 MUI/m2 twice a day on day 1 and 2, once a day on day 3, 4, 5 every week for 4 consecutive weeks with 4 week rest period. This is a phase II trial combined with a cohort design each having a different outcome event. All the evaluations were made using Recist criteria and according to the intention to treat principle. Results: The main patients characteristics and results are showed in the table below. Fifty-one (73%) patients received one prior chemotherapy regimen, while 17 (24%) received = two prior lines of treatment. *Median, months ±95% CI. §p value<0.05 Cox’s regression analysis, including PS, gender, smoke, skin toxicity, histology and use of IL-2, revealed that only skin toxicity [p<0.001; HR 0.29;CI 95% 0.16–0.54] and use of IL-2 [p<0.001; HR 0.33;CI 95% 0.18–0.60] were significantly associated with improvement in OS. Patients treated with IL-2 also showed grade 2–3 fever in 46%, fatigue in 21%, arthralgias in 13%, besides the known G- related toxicity. Conclusions: In this consecutive, non-randomized, series of patients, the use of IL-2 seems to increase the efficacy of G. Further randomized studies of TK inhibitors with IL-2 are warranted.

[Table: see text]

No significant financial relationships to disclose.
Exclusions to use of bevacizumab in elderly veterans with advanced non-small cell lung cancer (NSCLC)
Authors: Merza T. , Howard L. M. , Junagadhwalla M. , Gajra A.
Published: March 2020

18046

Background: Bevacizumab (BEV) is a monoclonal antibody against VEGF approved for treatment of advanced NSCLC in the 1st line setting. BEV is being evaluated in other settings in NSCLC (2nd line, adjuvant). BEV is associated with a distinct toxicity profile including hemorrhage, delayed wound healing, viscus perforation, hypertension (HTN), and thrombosis which limits its use. At the VA medical center, we noticed poor accrual to trials with BEV. We retrospectively studied all patients diagnosed with NSCLC in the past 3 years to identify the factors that would exclude patients from participating in clinical trials with BEV. Methods: Patients were identified from our tumor registry and clinical data was reviewed. We used the exclusion criteria as per ECOG 4599 and an open industry sponsored trial (erlotinib ± BEV for 2nd line NSCLC) as listed in the table below. Results: A total of 106 male veterans with stage 4 NSCLC were identified with a median age of 72 years. Patients with squamous predominant histology (n=26) were excluded. Of the remaining 80 patients evaluated for use of BEV, 72 patients (90%) met 1 or more exclusion criteria. The following table displays the breakdown of exclusion criteria both non-specific and specific to BEV. Conclusions: Elderly veterans with NSCLC have multiple co-morbidities precluding use of cytotoxic chemotherapy. Use of BEV is further limited in this population. There is a need for agents with a favorable toxicity profile in the treatment of NSCLC. Clinical trials specific to the needs of this group of patients with poor PS and multiple co-morbidities are needed to improve participation and to offer newer therapies to the elderly veteran with lung cancer.

[Table: see text]

No significant financial relationships to disclose.
Expression of cyclin D3 confers resistance to erlotinib
Authors: Petty W. J. , Voelzke W. R. , Memoli V. A. , Dragnev K. H. , Urbanic J. J. , Rigas J. R. , Dmitrovsky E.
Published: March 2020

18054

Background: Transcriptional repression of cyclin D1 occurs during responses to erlotinib (E) both in vitro and in vivo. Cyclin D3 has overlapping function with cyclin D1 but has distinct transcriptional regulation. Methods: The expression of cyclin D3 was compared in E sensitive cell lines (H358, H441) and an E resistant cell line (A549). Cyclins D1, D2, and D3 were independently overexpressed in E sensitive NIH 3T3 cells by plasmid transfection. Biopsy tissues from a proof-of-principal clinical trial of E were assessed for cyclin D3 expression. Results: A549 cells were resistant to E and expressed high levels of cyclin D3 RNA and protein compared to E sensitive cell lines. Overexpression of cyclin D1 and cyclin D3 conferred partial resistance to E in NIH 3T3 cells while cyclin D2 had no significant effect. Comparison of cyclin D3 immunostaining in tumor biopsies from patients before and after treatment with E revealed an increase in the percentage of cyclin D3 expressing cells following treatment with E. Conclusions: Cyclin D3 confers resistance to E in vitro and in vivo. Drugs such as retinoids and rexinoids that target cyclin D3 expression may prove useful for enhancing sensitivity to E.

No significant financial relationships to disclose.
Phase I dose escalation, toxicity and dynamic contrast-enhanced (DCE) MRI imaging biomarker study of first line treatment with imatinib (I) and cisplatin (C) plus docetaxel (D) in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Vlahovic G. , Foster T. L. , Andrews C. H. , Herndon J. E. , Sporn T. , Kelley M. J. , Dewhirst M. W. , Vujaskovic Z.
Published: March 2020

18056

Background: Imatinib (I) inhibits activated PDGF-Rβ and down-regulates VEGF resulting in decreased angiogenesis and improved blood flow favoring enhanced tumor drug delivery in lung cancer xenoagrafts. Objectives: 1) determine the MTD for the combination of I and C plus D in NSCLC pts, 2) describe non-dose limiting toxicities (non-DLT), 3) evaluate for feasibility and changes in blood flow/permeability measurement by DCE-MRI after treatment with I, and 4) explore the relationship between measured DCE-MRI parameters and proangiogenic plasma tumor markers PDGF-BB, VEGF, PAI1, ANG2, OPN, and MMP1. Methods: Eligibility: NSCLC with tumor expression of p-PDGF-Rβ. DCE-MRI was performed before and after 7 daily doses of I alone (lead-in) followed by C plus D on day 1, every 3 weeks. Once daily I was given with each C plus D cycle, on days -5 to +2. Standardized hemodynamic parameters (Ktrans, Ve, Kep) were acquired from DCE-MRI. Enrolled patients’ plasma was analyzed by ELISA to determine plasma tumor markers’ level. Results: 14 enrolled pts (9 M, 5 F) were evaluable for toxicity and 13 for response. Six pts were treated at dose level 1 (C+D 60/60 mg/m2, and I 300 mg); one DLT (febrile neutropenia) was seen; there were no DLTs in cohort 2 (60/60 mg/m2 and I 400 mg; n=3), and two DLTs were observed in cohort 3 (70/70 mg/m2 and I 400 mg; n=5) - febrile neutropenia and grade 4 diarrhea. For all cohorts, grade 3 and 4 toxicities were: fatigue (7%), nausea (14%), neutropenia (14%), elevated creatinine (7%), and dispnea (7%). Two pts (15%) had partial response, and 6/13 pts had stable disease as their best response. DCE-MRI demonstrated trend in decrease of Ve after 7-day treatment with I (p=0.088). Exploratory analysis revealed a significant correlation of: both ANG2 and OPN with Ve (p=0.02 and 0.05 respectively), MMP1 with Kep (p=0.03), and VEGF with Ktrans (p=0.02). Conclusions: MTD for I and C plus D in chemo naïve NSCLC pts is 400 mg and 60/60 mg/m2, respectively. More, DCE-MRI is feasible in NSCLC pts. Phase II study is open and currently enrolling with continues exploration of DCE-MRI as a predictive imaging biomarker, collectively with tumor proangiogenic markers.

No significant financial relationships to disclose.
Correlation of gefitinib efficacy and detection of new EGFR mutation variants in pre-treated patients (pts) with advanced non- small cell lung cancer (NSCLC)
Authors: Pallis A. , Voutsina A. , Kalikaki A. , Koutsopoulos A. , Souglakos J. , Christophylakis C. , Kentepozidis N. , Giassas S. , Mavroudis D. , Georgoulias V.
Published: March 2020

18062

Background: The efficacy of tyrosine kinase inhibitors (TKIs) of EGFR is associated with well characterized mutations on the exons 18, 19 and 21 of EGFR gene. Less common mutations could be detected in these exons but their relationship with the clinical efficacy of TKIs has not been established yet. Methods: Genomic DNA was extracted from microdissected formalin-fixed paraffin-embeded tumor tissue from 86 pts enrolled in a gefitinib expanded access program. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Results: Classical EGFR mutations (CM) were detected in 9 (10.4%) pts and other mutations variants (MV) in 19 (22%) pts. Eight (42.1%) MV were observed in exon 18, 3 (15.8%) in exon 19 and 8 (42.1%) in exon 21. Tumor Growth Control (TGC) was achieved in 88.9% (3PR and 5SD) pts with CM, 63% (2PR and 10SD) pts with MV and in 45.9% (3PR and 25SD) pts with wild type EGFR gene (WT). There was no clear association between the presence of EGFR MV and the sex, histology or smoking history. The median TTP was 64 weeks (range:4- 80+), 20 weeks (range:6–140) and 16 weeks (range:4–176+) in pts with CM, MV and WT, respectively. Nine (47.3%) pts with EGFR MV had a TTP >24 weeks. The median survival was 78 weeks (range:5–94+), 70 weeks (range:10–142) and 36 weeks (range:4–176+) in pts with CM, MV and WT, respectively. Three patients bearing mutations in exons 18, 19, and 21 progressed despite gefitinib treatment suggesting that these mutations could be related to resistance to gefitinib. Conclusions: EGFR mutation variants could be associated with response or resistance to TKIs but their low incidence requires their evaluation in a largest cohort of patients.

No significant financial relationships to disclose.
Subgroup analysis of African American patients from a randomized phase 3 trial of gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to P plus Cb in advanced (stage IIIB, IV) non-small cell lung cancer (NSCLC)
Authors: Treat J. , Gonin R. , Edelman M. , Belani C. P. , Socinski M. , Catalano R. , Marinucci D. , Ansari R. , Comis R. , Obasaju C.
Published: March 2020

18066

Background: A relationship between race and prognosis in patients with NSCLC has been suggested with African Americans (AA) having higher incidence and lower survival rates compared to whites (W) with a similar stage of disease. However, due to under representation of AA in clinical trials there is little data to substantiate this hypothesis. To investigate the possibility of a race effect on the efficacy and safety of standard chemotherapy doublet regimens in AA pts, we conducted a retrospective subgroup analysis of our Phase 3 randomized trial comparing 3 regimens for advanced NSCLC (Treat, et al: Abst#7025, Proc ASCO 2005). Methods: A Phase 3 study in advanced (stage IIIB/IV) NSCLC chemonaive patients with ECOG PS <2 was designed to compare the efficacy of a G-containing platinum regimen GCb (G 1000 mg/m2 IV D 1, 8 plus Cb AUC 5.5, D 1) to a nonplatinum G doublet GP (G 1000 mg/m2 IV D 1,8 plus P 200 mg/m2, D 1) and a reference regimen of PCb (P 225 mg/m2 plus Cb AUC 6.0, D 1). Outcome and toxicity data of AA pts vs. W pts were compared. Survival (OS) was the primary endpoint with secondary endpoints being response rate (RR), time to progression (TTP) and toxicity. Data from all 3 arms were pooled for this analysis. Results: A total of 128 AA and 906 W pts were analyzed. There were no significant differences in the OS or TTP distributions in AA compared to W pts ( Table 1 ). The incidence and grade of hematologic toxicity in AA vs. W pts were comparable. AA demonstrated slightly lower incidences of Grade 3–4 constitutional (5.1% vs. 9.0%), hemorrhage (1.4 % vs. 2.5 %), and metabolic (4.4% vs. 7.0%) toxicities compared with W pts. Conclusions: Use of standard chemotherapy doublets as first-line chemotherapy in AA pts with advanced NSCLC demonstrated similar efficacy and safety compared to W pts treated under similar conditions.

[Table: see text]

No significant financial relationships to disclose.
Tumor specific antibodies for the early diagnosis of lung cancer
Authors: Pedchenko T. V. , Mernaugh R. , Massion P. P.
Published: March 2020

18068

Background: The survival rates in lung cancer vary significantly by stage, the earlier the better. However, only 16% of patients are diagnosed at stage I. This implies an urgent need to identify a panel of biomarkers for the early detection of lung cancer in order to offer an improve chance for cure. We hypothesized that a unique phage-display recombinant antibody library approach will allow us to capture from serum and evaluate cancer antibodies as novel diagnostic biomarkers of non-small cell lung cancer. Methods: Immunoglobulins G (IgG) were purified from 3 groups of pooled serum: 10 diagnosed with adenocarcinoma, 10 squamous carcinomas, and 10 controls. A naïve rodent scFv (single chain fragment variable) phage-displayed recombinant antibody library (∼2.9 x 109 members) was used to select scFv specific for cancer human IgG. Individual bacterial colonies obtained after two rounds of subtractive biopanning on purified normal IgG and cancer IgG were picked and induced to express soluble E-tagged ScFv antibodies. An ELISA was used to screen ScFv for binding activity to pooled normal and cancer serum IgG. Single scFv clones that showed preferential binding to cancer IgG in ELISA were further validated for binding specificity by dot blot. ScFv were assayed against individual serum samples obtained from 120 normal, 60 adenocarcinoma, 56 squamous carcinoma, and 35 other, non-small cell, lung cancers. Dot blot signal intensity was quantified using Typhoon 8600 imaging system. Results: Seventy-five individual bacterial clones produced scFv that, by ELISA, distinguished purified normal from cancer IgG from pooled serum samples. Selected scFv antibodies show significantly higher binding activity to cancer-related IgG as compared to normal IgG. Twenty-five scFv were further validated for binding activity in individual human serum samples by dot blot assays. Ten scFv clearly differentiated cancer immunoglobulins from normal in human serum by dot blot, with preferential binding either to adeno- or squamous carcinoma. Conclusions: In this preliminary dataset, we identified scFv antibodies that interact with immunoglobulins present in human cancer serum samples. We show that this is a feasible and promising approach to discover cancer-specific immunoglobulins as candidate diagnostic biomarkers.

No significant financial relationships to disclose.
Gemcitabine plus conventional-dose epirubicin versus gemcitabine plus cisplatin as first-line chemotherapy for stage IIIB/IV non-small cell lung carcinoma: A randomized phase II trial
Authors: Hsu C. , Cheng A. , Shih J. , Yu C. , Kuo S. , Lin C. , Huang T. , Yang P. , Yang C.
Published: March 2020

18072

Background: Epirubicin is active for treatment of non-small cell lung carcinoma (NSCLC) but its optimal dose was undetermined. This study was designed to evaluate the efficacy and safety of gemcitabine plus conventional-dose epirubicin for stage IIIB/IV NSCLC. Methods: Patients with histological or cytological diagnosis of stage IIIB/IV NSCLC who had not received prior chemotherapy were eligible. Patients were randomized to GE (gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 and epirubicin, 70 mg/m2 on day 15) or GC (gemcitabine, 1,000 mg/m2 on days 1, 8, and 15 and cisplatin, 80 mg/m2 on day 15). Treatment cycles were repeated every 4 weeks. Objective tumor response and toxicity were evaluated by using the World Health Organization criteria. Results: No significant difference in baseline characteristics between patients randomized to GC (n=41) and GE (n=39) arms were found. The objective response rate was 31.0% (95% C.I. 16.4% to 45.5) for GC and 37.2.0% (95% C.I. 22.2% to 52.3%) for GE. The median time-to-treatment-failure and overall survival were 6.1 months (95% C.I. 4.9 to 7.4 months) and 13.2 months (95% C.I. 8.9 to 17.5 months) for GC and 6.2 months (95% C.I. 5.2 to 7.2 months) and 21.2 months (95% C.I. 14.6 to 27.8 months) for GE, respectively. More grade 3/4 neutropenia (71.8%) was noted in GE than in GC (43.9%). Febrile neutropenia was also more common in GE (4 patients) than in GC (1 patient). However, delay of protocol treatment due to leukopenia was similar between the 2 arms. Data on the expresssion of the excission repair cross-complimentation 1 (ERCC1), evaluated by immunohistochemical study for patients with available tumor tissue, will be presented. Conclusions: Gemcitabine plus conventional-dose epirubicin is an effective and well-tolerated regimen for patients with stage IIIB/IV NSCLC.

No significant financial relationships to disclose.
Phase I trial of vorinostat (V) in combination with pemetrexed (Pem) and cisplatin (CDDP) in patients with advanced cancer
Authors: Chen L. , Vogelzang N. J. , Blumenschein G. , Robert F. , Pluda J. M. , Frankel S. R. , Sharma S.
Published: March 2020

18088

Background: Pem and CDDP are active agents in many tumor types, and the combination is approved as first line therapy in malignant pleural mesothelioma (meso). Vorinostat (V), an orally active histone deacetylase inhibitor, was shown to induce PR in 2 meso patients (pts) (Krug 2006, Kelly 2005). A Phase I trial was undertaken to determine the safety and maximum tolerated dose (MTD) of Pem+CDDP+V. Methods: Pts with advanced solid malignancies, adequate organ function, ECOG PS = 2, = 1 prior chemotherapy, >18 yrs of age, and at least 6 months from prior treatment with Pem+CDDP were eligible. Patients were treated on 21 day cycles. V was started 2 days before standard doses of CDDP (75 mg/m2) and Pem (500 mg/m2) and was given on 4 schedules: dose levels were: I-200 mg BID for 14/21 d, II- 300 mg BID for 3/7 d wk1, 2 wk rest, III-300 mg QD for 7/21 d, and IV- 400 mg QD for 7/21 d. Results: Twenty-two pts were treated: median age was 60 (range 31–81); 13M: 9F. Tumor types were NSCLC 8, meso 5, bladder 3, colorectal 2, other 4. Nineteen of 22 patients were evaluable for investigator determined response: 1 CR (5.3%), 1 PR (5.3%), 11 SD (57.9%), 6 PD (31.6%). Conclusions: Dehydration and fatigue were common DLTs on different schedules of Pem+CDDP+V. V 300 mg x 7 days was tolerable in this combination. Hints of clinical activity were observed in bladder cancer and sarcoma patients, and stable disease was seen in three mesothelioma patients. Alternative dose schedules of Pem + V are under investigation.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of vinflunine in patients with relapsed small cell lung cancer
Authors: Peyton J. D. , Spigel D. R. , Hainsworth J. D. , Yardley D. A. , Burris H. A. , Vazquez E. , Farley C. , Porter L. , Lunin S. , Greco F. A.
Published: March 2020

18091

Background: Vinflunine (VFL) is a novel microtubule inhibitor of the vinca alkaloid class which has demonstrated significant preclinical activity in a small cell lung cancer (SCLC) model and antitumor activity in several other tumor types. This multicenter community- based trial was designed to examine the role of VFL in patients (pts) with relapsed SCLC. Methods: The primary endpoint is objective response rate (ORR). Eligibility criteria: previously treated SCLC (sensitive or refractory relapsed pts; limited to 1 prior platinum or non-platinum therapy for limited- or extensive-stage disease), ECOG PS 0–2, measurable disease, and informed consent. Treatment: VFL 320 mg/m2 IV over 20 minutes day 1 every 21 days for up to 6 cycles. Pts were restaged every 6 weeks. This 2-stage trial was designed to achieve a 20% ORR in platinum-sensitive pts (per RECIST criteria). Results: 29 pts were enrolled from 3/06 to 12/06 (trial ongoing, n=41 planned). Data are available for 16 pts in this analysis. Baseline characteristics: median age 64 years; male/female, 63%/37%; ECOG PS 0/1/2, 25%/50%/25%; and sensitive relapse, 50%. 3 partial response have been observed (ORR 19%, 95% CI 4%-46%). 3 pts (19%) had stable disease and 7 pts (44%) had progressive disease. 3 pts were not evaluable due to: treatment-related toxicity (sepsis; constipation); declining PS, 1 pt each. With a median follow-up of 5 months, the median progression-free survival and overall survival are 1.7 months and 3.6 months, respectively. Grade (G) 3/4 non-hematologic toxicity occurring in more than 1 pt: constipation, dyspnea, fatigue, and hyponatremia (13% each). G3/4 hematologic toxicity: leukopenia (44%), neutropenia (38%), and thrombocytopenia (6%). There have been no treatment-related deaths. Conclusions: VFL appears active as second-line treatment for SCLC. Additional assessment of myelosuppression is needed to better assess VFL’s role. Completion of accrual is anticipated by 4/07.

No significant financial relationships to disclose.
Costs associated with intravenous (IV) chemotherapy administration in patients with lung cancer
Authors: Skarin A. T. , Duh M. S. , Weiner J. R. , Lefebvre P. , Neary M. P.
Published: March 2020

18092

Background: The IV method of chemotherapy administration imposes not only a time burden on patients and facilities, but also has cost implications for payers. This study aims to assess the costs associated with the IV administration of chemotherapies for patients with all forms of lung cancer and for a subset of patients with small cell lung cancer (SCLC) in a large employer-payer claims database. Methods: Using medical claims data from 5.5 million beneficiaries between 01/01/1998 and 01/31/2006, we identified 8,605 patients with lung cancer (ICD-9 codes 162.3–162.9, 176.4, or 197.0) receiving IV chemotherapies. We then identified a subset of 942 patients likely to have SCLC by selecting those receiving chemotherapy regimens primarily used to treat SCLC and excluding patients receiving procedures and treatments often associated with NSCLC. Average total costs per day of IV chemotherapy administration (including drug, administration costs, etc.) were computed for all patients and for the SCLC subset based on the actual amount paid. Costs were also computed separately for: IV chemotherapy drugs, IV chemotherapy administration procedures, and other drugs and services such as IV administration of other drugs to treat side effects of chemotherapies, evaluation and management, and laboratory tests. Results: Average total cost per day of IV chemotherapy administration for all patients was $1,112, with $652 (59%) attributable to IV chemotherapy drugs, $85 (8%) to IV chemotherapy administration procedures, and $375 (34%) to other drugs and services. Among patients with SCLC, average total daily cost was $815, with $423 (52%) attributable to IV chemotherapy drugs, $89 (11%) to IV chemotherapy administration, and $303 (37%) to other drugs and services. Conclusions: IV chemotherapy administration procedures and other visit-related services accounted for 42% and 48% of total costs in patients with all forms of lung cancer and those with SCLC, respectively. The increased availability and use of oral chemotherapy drugs in lung cancer should provide savings to payers by avoiding the costs associated with IV administration.

No significant financial relationships to disclose.
Prognostic serum markers in malignant pleural mesothelioma: Epidermal growth factor and platelet-derived growth factor
Authors: Betta P. , Libener R. , Orecchia S. , Salvio M. , Schillaci F. , Filiberti R. , Puntoni R. , Paganuzzi M. , Marroni P.
Published: March 2020

18097

Background: While no previous data has so far shown any difference between the efficacy of serum platelet-derived growth factor (PDGF-AB) and serum epidermal growth factor (EGF) in distinguishing MPM from benign pleural diseases, some pilot studies have shown the potentiality of both these markers in the prognosis of MPM patients. This study investigates this capacity by analyzing survival in a series of MPM patients. Methods: Using an ELISA method, EGF (ng/ml) baseline serum was determined in 83 newly diagnosed MPM patients, and in 62 cases PDGF-AB serum levels were also measured. After a median follow-up time of 11.8 months (range 0.4–52.1 months), the log-rank test was used to compare the survival curves, and Cox’s regression analysis was also performed. Results: Median serum values were 0.56 ng/ml (range 0.09–2.05) for EGF and 43.0 ng/ml (range 0.1–145) for PDGF-AB. Patients with EGF levels higher than the median level of 0.56 ng/ml had an average survival time of 9.4 months (95%CI: 5.7–13.2), while the average survival time of patients with below-median EGF levels was 13.2 months (95%CI: 10.6–15.8); a statistically significant difference (p=0.005). For patients with PDGF-AB levels higher than an assumed cut-off of 49.8 ng/ml, (above 75th percentile of MPM marker concentration) average survival was 7.9 months (95%CI: 4.5–11.3) as against the 14.9 months (95%CI: 10.3–18.7) in patients with below cut-off marker levels, again statistically significant (p=0.02). Cox’s regression analysis was performed on 42 patients in whom data on age, sex, histology, stage and platelet count were available. EGF and PDGF-AB levels higher than the selected cut-offs were confirmed as independent predictors of poor survival (HR=1.49; 95% CI: 1.04–2.13; p=0.03 and HR=1.96; 95% CI: 1.23–3.13; p=0.005, respectively). Conclusions: Our data suggest that circulating PDGF-AB and EGF levels are promising markers for clinical monitoring of MPM patients.

No significant financial relationships to disclose.
Hormone replacement use, age, and prognosis for women with non-small cell lung cancer
Authors: Robinson A. , Ayeni M.
Published: March 2020

18099

Background: Lung cancer is the leading cancer cause of mortality in women. A recent report by Ganti et al, presented at ASCO, suggested that women who had been taking hormone replacement therapy (HRT) had significantly decreased survival after a lung cancer diagnosis. In addition, in women fit enough to be enrolled on randomized controlled trials in advanced lung cancer, younger women (under age 60) may have a worse prognosis than older women. The purpose of this current study was to do an institutional review on women diagnosed with lung cancer to determine whether these novel prognostic factor results could be duplicated. Methods: All female patients who were diagnosed with lung cancer between January 1999 and December 2003 were reviewed for age at diagnosis, stage, treatment, smoking history, hormonal therapy, performance status, weight loss, age at menopause, and overall survival. Patients were excluded if they had small cell lung cancer, were unknown primary, or had previous or synchronous non-lung, non-skin, cancers. Statistics were performed using Chi- Squared tests for categorical variables, while the Kaplan-Meier method and Cox-Regression models were used for univariate and multivariate analysis of overall survival. Results: Of 397 patients, the majority (68%) were stage 3 or 4. There were very few never smokers (5%). Twenty-nine percent of patients had prior HRT, with no effect on overall survival, with median survivals of 13 months in the non- HRT group and 14 months in the HRT group. The most powerful predictors of overall survival were: Stage, Performance Status, and Weight Loss. Patients aged 60–75 did as poorly as younger patients (median survival 10 months for stage 4 disease). Conclusions: Stage, performance status, and weight loss, are the most powerful predictors of survival for women with lung cancer. Patients with prior HRT use do not have inferior outcomes compared to non-HRT users. In a non-clinical trial population, patients under age 60 have similar outcomes as women aged 60 to 75.

No significant financial relationships to disclose.
Preoperative docetaxel and gemcitabine in resectable non-small cell lung cancer: A phase II trial of the Minnie Pearl Cancer Research Network
Authors: Thompson D. S. , Spigel D. R. , Greco F. A. , Yardley D. A. , Burris H. A. , Vazquez E. , Erland J. , Shipley D. L. , Spremulli E. , Hainsworth J. D.
Published: March 2020

18100

Background: Preoperative chemotherapy may improve outcomes for patients (pts) with resectable non-small cell lung cancer (NSCLC) compared with surgery alone. This multicenter community-based phase II trial examined the role of preoperative gemcitabine (G) and docetaxel (D) in pts with resectable NSCLC. Methods: The primary endpoint was to assess the pathologic response rate of G/D in pts with potentially resectable clinical stages IB, II, and selected III NSCLC [T3N1, T1–3N2 (1 nodal station = 2 cm), T4N0, T4N1 excluding vascular, tracheal, esophageal, vertebral disease, or malignant effusions]. Additional eligibility criteria: measurable disease, ECOG PS 0–1, and informed consent. Treatment: G 1,000 mg/m2 and D 30 mg/m2 days 1, 8 every 21 days x 3 cycles. Pts were restaged after treatment and resected 3–6 weeks later. If pts were inoperable, had incomplete resections, or N2 disease, D 20 mg/m2, carboplatin AUC=1.5 weekly x 7, and radiation to 63 Gy were administered. Analysis was by intent to treat. Results: Between April 2004 and September 2005, 75 pts were enrolled. Median age was 62 years. 92% of planned preoperative therapy was administered and 38 pts (51%) underwent resection. The clinical objective response rate was 30% (95% CI 20%-42%). No pathological complete responses were observed. 26 pts went on to receive chemoradiotherapy. Median progression-free survival was 9.8 months (95% CI 5.9–13.9). Median overall survival was 18 months (95% CI 14.8- 21.3). 71% of pts were alive at 1 year. Grade 3/4 hematologic toxicity with preoperative therapy included neutropenia (28%), anemia (4%), and thrombocytopenia (7%). Grade 3/4 non-hematologic toxicity was limited. Conclusions: G/D is a well tolerated preoperative regimen for pts with resectable NSCLC, however did not result in pathologic complete responses. There is no suggestion that G/D is more active than other tested combined modality regimens. The role of preoperative therapy in NSCLC remains undefined. Additional studies comparing preoperative and adjuvant treatment are warranted.

No significant financial relationships to disclose.
A pilot study of weekly docetaxel and daily trofosfamide as metronomic second-line chemotherapy in the treatment of metastatic non-small cell lung cancer (NSCLC)
Authors: Gorn M. , Habermann C. , Thom I. , Schuch G. , Andritzky B. , Brandl S. , Burkholder I. , Hossfeld D. K. , Bokemeyer C. , Laack E.
Published: March 2020

18105

Background: An emerging notion for the treatment of advanced solid malignancies in adults is to manage it as a chronic disease and aim to keep tumor burden and associated symptoms at the lowest possible level. One of the most promising strategies to achieve this is to target the tumor vasculature using modified, “metronomic”, dosing schedules. We conducted a pilot study of weekly docetaxel in combination with daily trofosfamide as a metronomic second-line regimen in patients (pts) with metastatic non-small cell lung cancer (NSCLC). Methods: From March 2003 to November 2005, 21 pts with stage IV disease who had one prior chemotherapy were enrolled. Pts received docetaxel 25 mg/m2 on days 1, 8 and 15, every 4 weeks plus trofosfamide 50mg per day. Results: Median age: 60 years; gender: 18 male (85.7%), 3 female (14.3%); median Karnofsky PS: 80%; histologic subtypes: 8 squamous cell carcinomas (38.1%), 7 adenocarcinomas (33.3%), 6 large cell carcinomas (28.6%); previous chemotherapy: platinum-based in 15 pts (71.4%), platinum-free in 6 pts (28.6%). A total of 62 chemotherapy cycles were administered. The median number of cycles per pt was 3 (range 1 - 8). The intent-to-treat overall response rate was 19% (95% CI 5.5 - 41.9) 1 CR (4.8%), 2 PR (14.3%), 9 SD (42.9%), 8 PD (38.1%). The median overall survival from onset of second-line therapy was 6.9 months (95% CI 5.0 - 13.9 months), the median progression-free survival 2.9 months (95% CI 1.58 - 6.28 months), the 1-year survival rate 28.6% (95% CI 14.5 - 56.2%), and the 2-year survival rate 7.1% (95% CI 1.26 - 40.6%). Hematological and non-hematological toxicities were mild. No grade 4 toxicity was observed. Conclusions: To the best of our knowledge, this is the first trial that combines docetaxel and trofosfamide for the treatment of NSCLC. Our results suggest that the concept of metronomic chemotherapy is a valuable addition to the treatment of NSCLC. The combination of docetaxel and trofosfamide is active and well tolerated as second-line therapy in pts with metastatic NSCLC.

No significant financial relationships to disclose.
Renal safety of sustained pemetrexed (P)/platinum treatment for advanced malignant mesothelioma (MM)
Authors: Karthaus M. , Hornych K. , Wiegand U. , Pfeil N. , Baysal F. , Trapp M. , Tagizadeh K.
Published: March 2020

18106

Background: MM is a very rare and aggressive neoplasm with a short life expectancy. Standard care of MM is P + cisplatinum (DDP). The optimal duration of chemotherapy(ctx) for MM is undetermined. The feasibility of maintenance with P/DDP has not been reported. A major obstacle to sustained P/DDP for MM is renal safety beside neurotoxicity. At present, there are no data regarding renal safety in pts receiving ≥ 6 cycles of P/DDP in MM. Methods: We evaluated long term renal function of P(500 mg/m2)/DDP(75 mg/m2) for MM prospectively. Ctx on d1 was repeated on d22 until disease progression or toxicity. Pts with impairment of renal function (creatinine-clearance <60 ml/min) switched to P/carboplatin (CP) AUC 5 for further ctx. P ctx was stopped if creatinine-clearance (CrCl) <45 ml/min. Routine folinic acid and vitamine B12 was administered to prevent AE. Study endpoint was long term renal function for sustained therapy of P/DDP followed by P/CP and/or P-mono. Results: Between 12/02 and 05/06 86 consecutive MM pts were treated. Staging revealed peritoneal MM in 19, and pleural MM in 67 pts. Five pts did not receive ctx. First-line ctx was P/DDP in 66 pts (prior s-crea 0.85; SD 0.17) given a mean of 4.9 cyles (range 1–11) for a mean of 120 d (21–397 d) and a mean of 138 mg DDP/cycle. 28 pts received CP/P sequentially for further maintenance up to 27 cycles (mean 6.4). A change from P/DDP to P/CP was necessary due to a worsening renal function in all of those pts. Mean s-crea/CrCl prior to DDP ctx in those pts was 0.87 mg/dl (SD 0.17)/96.0 ml/min (SD 26) and 1.01 mg/dl (SD 0.29)/73.4 ml/min (SD 22) at the end of P/DDP. Mean given CP dose was 425 mg/cycle (range 175 - 725 mg). Pts subsequently receiving P/CP had a s-crea of 1.16 mg/dl (CrCl 73.4 ml/min) prior to ctx that did not change during P/CP (1.13 mg/dl/CrCl 73.2 ml/min). 13 pts received P- mono with a mean of 8 cycles (1–26) subsequently. Renal function showed a s-crea(CrCl) of 1.13 mg/dl (71.2 ml/min) prior and 1.11 mg/dl (70.8 ml/min) at the end of P ctx. Conclusions: Long term maintenance P/DDP of MM is limited by renal impairment due to DDP, while subsequent P/CP or P-mono was feasible and not associated with further deterioration of renal function. Further trials with sustained P/CP or P ctx for MM are warranted to evaluate the efficacy of maintenance for advanced MM.

No significant financial relationships to disclose.
Possible correlation between SOCS1 methylation and EGFR exon 19 mutation but not exon 21 mutation in Chinese NSCLC patients
Authors: Lee S. , Mok T. , Li H. , Yim A. , Wan I. , Lam K. C. , Chan A. , To K. F. , Tao Q.
Published: March 2020

18113

Background: Suppressor of cytokine signaling-1 (SOCS1) and -3 (SOCS3) interact with the epidermal growth factor receptor (EGFR) to bring about the ubiquination and degradation of the receptor. Silencing of SOCS1 and SOCS3 by methylation was postulated to regulate the IL-6R/JAK-mediated STAT3 activation. Its relationship to EGFR and EGFR mutations in lung cancer remains unclear. Here, we examined the relationship between EGFR mutations and methylation of SOCS1 and SOCS3 in Chinese NSCLC patients. Methods: EGFR mutations were assessed in DNAs from microdissected tumor cells. PCR products were purified and sequenced using the BigDye Terminator Cycle Sequencing Kit (Applied Biosystem) and the ABI 3100 Genetic Analyzer. For methylation analyses of SOCS1 and SOCS3, DNAs were extracted from paraffin sections of tumor tissues, bisulfite treated and analyzed by methylation- specific PCR (MSP). Results: Data is available from 9 lung cancer cell lines and 20 tumor samples. Five EGFR-wild type cell lines had methylation for SOCS1. We found EGFR exon 19 mutation in 5 (25%) tumors, exon 21 mutation (L858R) in 2 (10%) tumors, and 1 (5%) tumor had double mutations. Four of 5 (80%) tumors with exon 19 mutation and none (0%) of the tumors with exon 21 mutation had SOCS1 methylation, comparing to only 2 of 12 (17%) EGFR-wild type tumors had SOCS1 methylation. SOCS3 methylation was not detected in any of the primary tumors or cell lines. Conclusions: Our preliminary findings suggest that SOCS1 methylation might be positively correlated with EGFR exon 19 mutation but exclusive from exon 21 mutation. A following study with larger sample size is currently under way. SOCS1 methylation may explain the better tumor response associated with EGFR exon 19 mutation.

No significant financial relationships to disclose.
Disease stabilization (SD) as a surrogate end-point in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib (E) or gefitinib (G)
Authors: Pronzato P. , Loprevite M. , Brianti A. , Defferrari C. , Catania G. , Grossi F.
Published: March 2020

18115

Background: One retrospective study (Hotta K, Ann Oncol 2005), investigating the prognosis of patients (pts) obtaining SD as best response with G treatment, has demonstrated that both progression-free survival (PFS) and survival (S) were significantly longer than those in pts with progressive disease (PD). The aim of this retrospective study was to compare the PFS and S outcome in pts with advanced NSCLC who achieved SD or partial response (PR) after treatment with E or G. Methods: Pooled data from 62 pts, entered into an open label phase II program of E (n=31) and a compassionate-use program of G (n=31), were retrospectively analyzed. E and G were given orally at 150 and 250 mg per day respectively and were continued until disease progression, development of unacceptable toxicity or patient’s refusal. Results: Pts characteristics: median age 69 years (42–85); females= 21 pts (34%); never/former smokers= 16/38 pts (26/61%); adenocarcinoma/BAC= 35/10 pts (56/16%); PS 0/1= 18/38 pts (29/61%). In 16 pts (26%) E or G were given as first-line therapy; 21 pts (34%) had received =2 prior lines of chemotherapy. Six pts (10%) achieved a PR and 18 pts (29%) obtained SD. TTP and OS in pts obtaining PR and SD were comparable: 7 vs 5.5 and 9.7 vs 9.1 months respectively. In progressing pts median TTP and OS were 1.7 and 3.7 months. Conclusions: Our findings indicate the importance of achieving disease control with both E and G treatment. Pts obtaining SD had a similar PFS and S compared with those having PR. An analysis of the role of mutational status and other biomarkers in predicting clinical outcome is currently underway.

No significant financial relationships to disclose.
Clinical significance of altered expression of the retinoid acid receptors alfa and beta (RAR a and b) and the cellular retinol binding protein (CRBP-1) in stage I non-small cell lung cancer
Authors: Pallotta M. G. , Mauro L. , Beguelin G. Z. , Dallurzo L. M. , Smith D. , Lastiri J. M. , Vasallo B. , Val De Kier Joffé E. , Puricelli L.
Published: March 2020

18117

Background: Retinoids, a group of natural and synthetic Vitamin A analogues, are known to play a major role in regulating growth, differentiation and apoptosis of many cell types. Its role as prognostic factors in non-small cell lung cancer (NSCLC) is poorly known. Methods: Patients who underwent a successful surgical resection for stage I NSCLC were elegible. Antigen expression was analyzed by immuno histochemistry on histological samples of the tumor to investigate the expression pattern of RARa, RARb and CRBP-1. 51 NSCLC patients stage I (18 Stage Ia and 33 Stage Ib) were tested . A case was considered positive when more than 10% of cells presented specific staining for the antigen. Prognostic evaluation was performed with the Log-Rank test and the multivariate proportional hazard model. Results: About 40% of cases were positive for RARa. In the case of RARb 58.3% NSCLC showed cytoplasm staining, while only 18% showed nuclear immunopositivity. Taken together, the 81.5% of NSCLC tumors expressed at least one RA receptor (RARa or RARb or both). CRBP-1 staining was observed in 52% of the lung tumors. No relationship was found between the number of cells expressing the studied molecules and clinical pathological features, including sex, T stage, histopathology, adjuvant therapy, smoking habit or the presence of tumor cells in the pleural fluid. The only exception was that a higher percentage of adenocarcinomas were positive for RARa as compared with epidermoid tumors (50.0 vs 14.3%, p=0.05). On the other hand RARb was expressed preferentially in epidermoid tumors (81.3% vs 42.9 %, p<0.05). Univariate analysis showed a significant association between positive expression of RARb with shorter overall survival (log-rank test 3.7, p<0.05). However, the multivariate study indicated that RARb expression was influenced by other clinical pathological parameters, suggesting that this antigen would not be able to predict cancer-specific survival in an independent way. Conclusions: A high number of stage I NSCLC express RARs and CRBP. This suggests that retinoid expression could harbour relevant prognostic information at an early stage of the disease.

No significant financial relationships to disclose.
Clinical predictive factors for mutations in epidermal growth factor receptor (EGFR) exon 19 and 21 in Japanese patients with lung cancer
Authors: Goto K. , Kim Y. , Yoh K. , Niho S. , Ohmatsu H. , Kubota K. , Nishiwaki Y. , Saijo N.
Published: March 2020

18131

Background: It has been reported that lung cancer with activating mutations of EGFR are highly sensitive to gefitinib or erlotinib. Furthermore, the incidence of EGFR mutations is significantly higher in adenocarcinoma, female, never-smoker, Japanese patients. However, it is difficult to take sufficient amount of biopsy specimen of lung cancer with advanced disease for mutation analyses in clinical practice. Therefore, in this study, clinical predictive factors for EGFR mutations in Japanese patients with lung cancer were clarified. Methods: EGFR exon 19 and 21 mutation status was determined in 284 tumor samples using direct sequencing, polymerase chain reaction. To identify clinical independent predictive factors for EGFR mutation, the logistic regression analysis was performed. Results: 131 tumors of them could be analyzed for mutations in EGFR exon 19 and 21. EGFR mutations were detected in 38 tumors (29%). Median age of patients with EGFR mutations was 62 years (rage 43–84); 19 male and 19 female; 18 stage I, 15 stage II, and 5 stage III disease. Cigarette- smoking history of patients with EGFR mutations included non-smoker in 20 patients, light smoker (< 10 pack-years smoker) in 4, and heavy smoker (> 10 pack-years smoker) in 14. Multivariate analyses showed that non-smoker or light smoker (p=0.007) and adenocarcinoma (p=0.044) were the significant predictive factors contributing to EGFR mutations. Gender, serum CEA level, and clinical stage were not associated with EGFR mutations. Seventy patients treated with gefitinib and 25 PR were observed, and the overall response rate was 36%. The response rate to gefitinib in patients with and without EGFR mutations were 76% and 7%, respectively. In addition, EGFR mutations were detected in 51% (19/37) of patients with adenocarcinoma and light smoker, and the response rate to gefitinib of them was 49% (18/37). Conclusions: In Japanese patients with lung cancer, non-smoker or light smoker and adenocarcinoma were significant predictive factors for mutations in EGFR exon 19 and 21.

No significant financial relationships to disclose.