bluuebunny/crossref_metadata_2025 huggingface dataset:
Carboplatin (Cb) clearance (Cl) in elderly and young patients with advanced non-small cell lung cancer (ANSCLC): An exploratory analysis of the Calvert’s formula
Authors: Merino M. , Maestu I. , Tallón M. , Almenar D. , Casabó V. G. , Muñoz J. , Jiménez N. V.
Published: March 2020

18047

Background: It seems that elderly lung cancer patients (p) respond better to combination chemotherapy than to single-agent therapy. Application of pharmacokinetic (pk) modelling to the routine therapeutic drug monitoring in elderly p help to individualize the dosage of anticancer drugs. The aim of this study was to explore the Calvert′s formula usefulness for calculating the Cb dose in elderly p by means of the predicted AUC/actual AUC ratio. Creatinine (Cr) Cl was calculated by Cockdroft-Gault equation. Methods: Between December 2005 and September 2006, 20 chemonaive ANSCLC p were included in two groups: 10 adults p ≤ 65 years and 10 aged p ≥ 75 years. Treatment consisted in Cb day 1 and gemcitabine 1250 mg/m2 days 1 and 8 every 21 days. Cb dose was calculated for a foreseen AUC = 5 in young adults and AUC = 4 in aged p. Three blood samples were collected at 1–2 hours(h), 3–5 h, 12–24 h postinfusion. Total and ultrafiltrated Cb was determined using a flameless atomic absortion spectrometer. For pk analysis non lineal effects models implemented in NONMEM program were used. Individual pk parameters were calculated and predictors in the structural model were analized. Results: Table 1 shows mean and variation coefficient of some biometric characteristics. Pk parameters analysis: ClAUC5 p = 137 mL/min; Clfactor (parameter for measuring Cl changes according to age) = 0.44; Cl AUC4 p = 59.7 mL/min. Cb Cl in elderly p was 43.55% with respect to younger p. In younger p estimated Cb Cl was 5.69% higher than Cb Cl calculated using the Calvert equation. In elderly p, the opposite effect was achieved, estimated Cb Cl was 26.85% lower than Cb Cl calculated Conclusions: The Cb Cl calculation by means of Calvert formula showed underestimation of the dose in younger p and upperestimation of the dose in elderly p. It is necessary to investigate the covariates which contribute to take away the strength of the Calvert equation, which could to affect the efficacy and toxicity of Cb.

[Table: see text]

No significant financial relationships to disclose.
Mutational analysis of EGFR and KIT in thymic epithelial tumor
Authors: Yoh K. , Nishiwaki Y. , Ishii G. , Goto K. , Kubota K. , Ohmatsu H. , Niho S. , Nagai K. , Ochiai A. , Saijo N.
Published: March 2020

18049

Background: Thymic epithelial tumor has been reported to express the epidermal growth factor receptor (EGFR), and thymic carcinoma has recently been described to have overexpression of KIT. We investigated the prevalence of EGFR and KIT mutations in patients with thymoma and thymic carcinoma to explore the potential for a targeted therapy with tyrosine kinase inhibitors. Methods: Genomic DNA was isolated from 41 paraffin-embedded tumor samples including 24 thymoma and 17 thymic carcinoma. EGFR mutations in exons 18, 19 and 21, and KIT mutations in exons 9, 11, 13 and 17, were analyzed by PCR and direct sequencing. Protein expressions of EGFR and KIT were also evaluated by immunohistochemistry. Results: We detected the EGFR mutation in 2 of 20 thymoma, but none of thymic carcinoma had mutation. All of the detected EGFR mutations were missense mutations in exon 21 (L858R and G863D, respectively). Expression of EGFR was seen in 71% of thymoma and 53% of thymic carcinoma. On mutational analysis of KIT, only one thymic carcinoma displayed a missense mutation in exon 11 (L576P). Expression of KIT was observed in 88% of thymic carcinoma and 0% of thymoma. Conclusions: Our findings indicate that a small number of patients with thymic epithelial tumor exhibit somatic mutations of EGFR or KIT although expressions of EGFR or KIT are present frequently in thymic epithelial tumor. Further investigations are warranted to determine their susceptibility to tyrosine kinase inhibitors in the treatment of thymoma and thymic carcinoma with EGFR or KIT mutations.

No significant financial relationships to disclose.
A systems pathology model for predicting overall survival in patients with refractory, advanced non-small cell lung cancer (NSCLC) treated with gefitinib
Authors: Donovan M. J. , Kotsianti A. , Bayer-Zubek V. , Verbel D. , Clayton M. , Hamann S. , Capodieci P. , Pang H. , Cordon- Cardo C. , Parums D. , Holloway B.
Published: March 2020

18065

Background: The abundant expression of the epidermal growth factor receptor (EGFR) in a variety of solid tumors including non-small cell lung cancer (NSCLC), head and neck, breast, colon and brain has made it an attractive target for various selective molecular therapeutics, including the tyrosine kinase inhibitor gefitinib. The recent evidence of activating mutations in EGFR combined with clinical - demographic features has suggested that subgroups of patients with NSCLC are most likely to respond to selective therapies. We sought to determine whether the integration of clinical variables, tumor morphometry and quantitative protein profiles using support vector machines could identify a set of features which predicts overall survival in patients with NSCLC treated with gefitinib. Methods: We analyzed tumor samples from 109 patients with advanced refractory NSCLC treated with gefitinib. Formalin fixed, paraffin embedded tissue samples were evaluated with the following assays: Hematoxylin and Eosin image morphometry, EGFR DNA mutation analysis, EGFR protein immunohistochemistry and quantitative immunofluorescence with the following antibodies: CK18, Ki67, Caspase 3 activated, cd34, EGFR, phosphorylated-EGFR, phosphorylated-ERK, phosphorylated-AKT, PTEN, Cyclin D1, phosphorylated-m-TOR, PI3-K, VEGF, KDR (VEGFR2) and phosphorylated KDR. A predictive model was developed using support vector regression for censored data. Results: 4 of 87 patients had tyrosine kinase domain mutations in exons 19, 20 or 21. Utilizing 51 patients with complete data profiles (i.e. clinical, image morphometry and immunofluorescence), a model predicting overall survival was developed with a concordance index of 0.74. Poor performance status, poorly differentiated histology by morphometry and increased levels of activated caspase 3, phosphorylated KDR (VEGFR2) and cyclin D1 were associated with reduced survival. Conclusion: The integration of clinical, imaging and biomarker data identified a set of features which were associated with a more aggressive disease phenotype and resulted in overall poor survival.

[Table: see text]
Phase II study of oral fluoropyrimidine (UFT) plus vinorelbine in the elderly (age > 70) with advanced non-small cell lung cancer
Authors: Suyama H. , Shigeoka Y. , Igishi T. , Matsumoto S. , Yasuda K. , Sugitani A. , Katayama S. , Yamamoto M. , Hitsuda Y. , Shimizu E.
Published: March 2020

18075

Background: Many pts with non-small cell lung cancer (NSCLC) are in elderly population. There are few pts who can receive standard treatment with platinum-based chemotherapy because of their poor organ functions. Thus, the development of a low-toxic and highly- effective regimen is needed for these populations. We have reported schedule-dependent synergism of vinorelbine and 5-FU against NSCLC cell lines. Furthermore, we have already conducted phase I study using vinorelbine and UFT, and have decided the recommended dose of this regimen. Methods: The objective of this prospective phase II study was to assess the efficacy and toxicity of this regimen in the elderly. Chemonaive NSCLC stage IIIB or IV pts, aged 70 or more, with performance status 0/1 were enrolled in this study. The pts received a treatment consisting of 20mg/m2 of vinorelbine on days 1 and 8, followed by 600mg of UFT orally on days 2–6 and 9–13 every 3 weeks for more than 4 cycles. Results: Until April 24, 2006, of 30 pts enrolled in this study, 29 pts were evaluable. Median age was 78 (range 71–86) and median cycles of chemotherapy were 4 (1–32). Objective response rate was 27% (95% CI; 10–44%), median time to progression was 150 days (15–470) and median over all survival time was 270 days (77–892). Treatment-related toxicity were neutropenia G3 33%, G4 7%; febrile neutropenia G3 4%; pneumonia G3 10%. Conclusions: This data points out vinorelbine and UFT as an active and tolerable regimen in the elderly with advanced NSCLC.

No significant financial relationships to disclose.
Dendritic cells loaded with XAGE-1b protein induce specific antitumor response against lung cancer
Authors: Zhou Q. , Wu Y. L. , Guo A. L. , Wang K. , Xu C. R. , Wang Z. , An S. J. , Yang S. Q.
Published: March 2020

18080

Background: Dendritic cells (DCs) are the most potent antigen-presenting cells for initiating cellular immune response. Cancer-testis antigens (CTA) are the biggest tumor antigens family expressing only in some tumors and genital system but not in normal cells. XAGE-1b gene is one of CTA which highly expresses in lung cancer and has strong immunogenicity. Our study was to examine whether DCs loaded with XAGE-1b protein could induce specific antitumor response against lung cancer cells in vitro. Methods: Tumor tissues and normal lung tissues were obtained by operation from 30 non-small cell lung cancer patients. Cancer cells and normal lung epithelium cells were cultured and saved as target cells. Total RNA were isolated and RT-PCR was done to determine XAGE-1b gene expression. XAGE-1b gene was cloned by constructing expression vector and recombinant protein was expressed and purified by using BL21 (DE3) E. coli and AKTA-FPLC. Peripheral blood monocytes were isolated from 20ml blood and cultured to be DCs in serum-free DCs Medium. DCs were loaded with XAGE-1b protein through coculture and induced T lymphocytes into XAGE-1b-specific cytotoxic T lymphocytes (CTLs). The cytotoxicity of CTLs was then measured by cytotoxic assay. Results: 12/30(40%) lung cancer tissues expressed XAGE-1b gene, most of which were adenocarcinoma (11/12, 91.7%). None of normal tissues expressed it. Gene sequencing and western blot confirmed the expression vector construction and recombinant protein expression. Immunofluorescence identification showed the accumulation of XAGE-1b protein in immature DCs. T lymphocytes were stimulated twice with XAGE-1b protein-loaded DCs. Cytotoxic assay showed that the CTL cytotoxicity was much stronger for XAGE-1b positive tumor cells than for XAGE-1b negative tumor cells and it was almost none for normal lung epithelium cells. Conclusions: Our study indicates that DCs loaded with XAGE-1b protein could induce specific antitumor effect against lung cancer cells in vitro and this model offers a new approach to the immunotherapy for lung cancer.

No significant financial relationships to disclose.
RNAi-based adjuvant therapy in a NSCLC mouse model prevents the development of distant metastasis
Authors: Müller-Tidow C. , Bulk E. , Hascher A. , Sargin B. , Vormoor J. , Hotfilder M. , Berdel W. E. , Serve H.
Published: March 2020

18089

Background: Surgery cures about 50% of the patients with early stage NSCLC. Although adjuvant chemotherapy improves outcome, a considerably fraction of patients still dies due to development of distant metastasis. Microarray analyses revealed that S100P expression is a strong adverse prognostic factor in early stage NSCLC. Methods: In a mouse NOD/SCID metastasis model based on subcutaneous xenotransplants of NSCLC cell lines we analyzed the effects of S100P expression on metastasis development after curative resection of the primary tumor. Tumors were resected 3–4 weeks after inoculation into the left flank after tumors reached a specified size. Adjuvant RNAi (shRNA based) therapy against S100P was i.v.-administered on the 5 days surrounding tumor resection. Results: S100P overexpression in HTB56 lung cancer cells led to more rapid tumor growth as xenografts. After tumor resection, metastasis developed in 14% (2/12) of the control mice but in 67% (8/12) of the S100P expressing tumors p<0.05. shRNA plasmids were developed and confirmed to be active in downregulating S100P. When these plasmids were i.v.-injected before resection, a significant decrease in S100P protein expression occurred. Control plasmid did not have any effect. The size of S100P-shRNA treated tumors decreased after 2 i.v.-applications. Metastasis developed in 69% (11/16) of the mice treated with the control plasmid. In S100P-shRNA treated mice only 28% (5/18) developed metastasis (p<0.05). After i.v.-injection of NSCLC cells with endogenous S100P expression, all mice (100% - 10/10) developed metastasis when adjuvant treatment was administered with control shRNA. However, when the mice were treated with S100P-shRNA in the first week after i.v.-injection of the tumor cells 33% of the mice (3/9) did not develop lung metastasis. Conclusion: Expression of S100P is a negative adverse prognostic marker in early stage NSCLC. S100P enhances metastasis formation in a mouse metastasis model. Adjuvant therapy with shRNA against S100P is feasible and effective in at least two murine NSCLC metastasis models. These findings suggest that S100P is a potentially important target to inhibit NSCLC metastasis and RNAi based therapy approaches might offer novel ways for targeted therapy in adjuvant situations.

No significant financial relationships to disclose.
A phase II study of XL999 in patients (pts) with NSCLC
Authors: March R. J. , Mirtsching B. , Modi S. , Wertheim M.
Published: March 2020

18112

Background: XL999 is a potent spectrum-selective inhibitor of receptor tyrosine kinases including VEGFR2/KDR, FGFR1/3, PDGFR-β, FLT3, RET, KIT, & SRC. A Ph 1 clinical study in pts w/advanced malignancies evaluating weight-based (0.2 - 6.4 mg/kg) & fixed dose (200 mg & 160 mg) XL999 administered by 4hr IV infusion on a wkly or every other wk schedule has shown preliminary evidence of anti- tumor activity (3 PRs & 10 pts w/SD lasting 3–26+ months). The safety profile was characterized by hypertension & cardiovascular changes including EKG, LVEF decrease &/or cardiac enzyme elevation following 1st dose administration. DLTs were cardiac failure & transaminase elevation. A dose of 2.4 mg/kg/wk was selected for phase II evaluation. Methods: The 1 objectives of this phase II study are to determine the RR & to further evaluate the safety & tolerability of XL999. Adult pts w/NSCLC (stage IIIB with malignant effusion, stage IV, or recurrent) & previously treated with no more than 2 prior systemic cytotoxic chemotherapy regimens, including a platinum-or taxane-containing regimen, & no more than one prior target agent targeting VEGF or EGFR, are eligible. Additional inclusion criteria include ECOG PS 0–1 & absence of known brain metastases. Pts with LVEF<50% or below lower limits of normal or with significant cardiovascular abnormalities are excluded. Tumor response is assessed every 8 wks by RECIST criteria. XL999 is administered wkly at 2.4 mg/kg as a 4hr IV infusion. Results: Nine pts received XL999. Three pts remain on study drug. One pt has a confirmed PR with complete resolution of a 2cm lung nodule. Another has a total reduction of 23% in multiple hepatic lesions (by RECIST). A third pt continues with SD for 3.5 months. Six pts with PD are discontinued. AEs reported in at least 2 pts were grade 1 diarrhea, fatigue, anorexia, & dizziness. Grade 3 AEs included 1 report each of N/V. No Grade 4 or 5 AEs or serious cardiac AEs have been reported. Conclusions: Wkly IV dose at 2.4 mg/kg appears generally well-tolerated & shows preliminary evidence of anti-tumor activity in advanced NSCLC pts refractory to multiple prior anti-cancer therapies.

No significant financial relationships to disclose.
Biweekly paclitaxel as second-line treatment in advanced non-small cell lung-cancer (NSCLC). A phase II study of the Lung Cancer Galician Group
Authors: Vazquez-Estevez S. , Fírvida J. , Huidobro G. , León L. , Lázaro M. , Salgado M. , Mel J. , Grande C. , Pérez E. , Campos B.
Published: March 2020

18120

Background: Paclitaxel is an active drug for NSCLC. Our purpose was to evaluate the efficacy and toxicity of biweekly administration of this drug in previously treated patients with advanced NSCLC. Methods: Patients with stage IIIB and IV NSCLC, which progressed after or during first-line chemotherapy, measurable disease, ECOG PS=0–1 and adequate organ function were included. Paclitaxel was administered at 150 mg/m2 iv, days 1 and 14, every 28 days, for a maximum of six cycles. Both, toxicity and efficacy analyses, were performed on the intent-to-treat (ITT) population. Results: Between September 2004 and November 2006, 42 patients (M/F, 39/3) were included, with median age 64 years (39–79). Tumor histology mainly included epidermoid (40.5%) and adenocarcinoma (35.7%). Tumor stage was IIIB (23.8%) and IV (76.2%). Median number of metastatic lesions was 1 (55%), located mainly in lymph nodes (30%), lung (25%), adrenal glands (16%) and bone (11%). Previous chemotherapy included platinum (76.1%), docetaxel (66.6%) and gemcitabine (52.4%). A total of 167 cycles (median 4, range 1–6) were administered. Median relative dose intensity was 94%. Toxicity: Grade III/IV hematologic toxicities per patient were neutropenia (2.5%) and anemia (2.5%). Grade III/IV non-hematologic toxicities were asthenia (2.5%), arthralgias/myalgias (2.5%) and peripheral neuropathy (2.5%). Efficacy: Of 39 ITT patients (3 patients have just begun chemotherapy), 7 achieved PR, 11 SD and 16 progressed, resulting in an ORR of 17.95% (95% CI: 5.9–30%). Five patients could not be evaluated for response due to early withdrawal (4 tumor-related exitus and 1 PS deterioration). Median TTP and OS were 174 days (95% CI: 115.52–232.48) and 332 days (95% CI: 261.18–402.82), respectively. Conclusions: Biweekly paclitaxel is an active and very well tolerated regimen in previously treated patients with advanced NSCLC.

No significant financial relationships to disclose.
Phase II trial of imatinib (I) and docetaxel (D) in recurrent non-small cell lung cancer (NSCLC)
Authors: Huang C. H. , Williamson S. , Van Veldhuizen P. J. , Hsueh C. T. , Smith H. , Mayo M. , Allen A. , Kelly K.
Published: March 2020

18132

Background: Second line monotherapy for NSCLC produces a response rate of 9% and a median survival of 7–8 months, regardless of the agent used. Emerging data suggest that combining an approved agent with an anti-angiogenesis inhibitor may improve efficacy in the salvage setting. Platelet Derived Growth Factor Receptor alpha (PDGFR-alpha) is involved in angiogenesis and its expression has been reported in 100% of adenocarcinoma (11/11) and 89% of squamous cell (16/18) lung cancer specimens in a small group sample. Preclinical models have shown that I inhibits PDGFR and may subsequently inhibit angiogenesis. In addition, I + D have additive anticancer activity. We initiated a phase II trial of I +D to evaluate the efficacy and safety of this combination regimen in recurrent NSCLC. Methods: Patients (pts)with pathologically confirmed NSCLC, measurable disease, no more than 1 previous platinum-based chemotherapy regimen, PS 0–1, clinically stable brain metastases and adequate organ function were eligible. Tumor samples, when available, were tested for PDGFR expression by immunohistochemistry. All pts received D 30mg/m2 intravenously weekly x 3 every 4 weeks and oral I 600mg daily for 4 cycles. Non- progressors after 4 cycles continued with I alone for a total of 12 months or until progression. Tumor response was assessed every 2 cycles. The primary endpoint was response rate. A Simon two-stage design was used with 16 patients in the first stage and accrual of a total of 32 patients planned. Results: Currently 15/16 patients for stage I of the protocol have been enrolled. A total of 24 cycles of combined I+D were given. Patient characteristics and toxicity data are described in the table below. Efficacy data is premature. Conclusion : I +D combination has been well tolerated in this relapsed population. A detailed toxicity, efficacy and PDGFR analysis will be presented.

[Table: see text]

No significant financial relationships to disclose.
Changes in high FDG-avid tumor volumes during radiation therapy differ from that of CT gross tumor volumes in patients with non-small cell lung cancer
Authors: Zhao L. , Ten Haken R. K. , Kong F.
Published: March 2020

18139

Background: To study whether changes in Fluorodeoxyglucose (FDG)-avid tumor volumes (VPET) correlate with changes in CT gross tumor volumes (CTGTV) during the course of radiation therapy (RT). Methods: Patients with stage I-III non- small cell lung cancer (NSCLC) were prospectively enrolled in this pilot study and were treated with fractionated RT based therapy with or without chemotherapy. FDG-PET/CT scans were acquired within 2 weeks prior to RT (pre-RT), after 45 Gy of irradiation (during-RT), and 3 months after completion of RT (post-RT). The scans were co-registered within our treatment planning system using the CT portion of each scan. Fused CTGTVs were delineated for each CT dataset. Fused VPETs were auto-contoured using 20%, 30%, 40% and 50% of maximum FDG activities within the tumors as threshold (VPET20, VPET30, VPET40, and VPET50, respectively) for each PET dataset. Paired T test and linear correlation were used for statistic analysis with all P values obtained using a 2-tailed test. Results are reported as Mean ± StDev. Results: Fifteen patients were enrolled in this pilot study. Pre-RT CTGTVs averaged 130.3 ± 194.7 cm3 and reduced to 91.7 ± 155.3 cm3 3 months after RT (P = 0.027). A mean PET threshold of 20.0 ± 10.6% matched best with the CTGTVs pre-RT. For the during-RT PET scans, the best-matched threshold increased to 30.0 ± 10.2% (P < 0.001). No significant correlation was found between changes of VPET and reduction of CTGTV during-RT. During-RT changes of higher FDG-avid VPET significantly correlated with the reduction of CTGTV Post-RT (P values were 0.735, 0.189, 0.022, and 0.029 for VPET20, VPET30, VPET40, and VPET50, respectively), but during-RT changes of CTGTV did not (P = 0.113). Conclusions: Changes of high FDG-avid tumor volumes during-RT differ in magnitude from CTGTV changes. High FDG-avid tumor volume changes (instead of CTGTV changes) during-RT are correlated with CTGTV changes Post-RT. Further study in a large number of patients is needed to verify these findings.

No significant financial relationships to disclose.
Phase II and pharmacokinetic (pk) study of induction docetaxel/cisplatin followed by pulsed docetaxel chemoradiation for stage III non-small cell lung cancer (NSCLC)
Authors: Chen Y. , Pandya K. J. , Smudzin T. , Strychor S. , Sidone B. , Zamboni W. C.
Published: March 2020

18142

Background: We have previously reported that docetaxel (Doc) demonstrates longer G2/M arrest and better synergistic effects with irradiation when compared with paclitaxel in human lung cancer cell lines. We designed a phase II clinical study targeting micrometastasis using upfront induction chemotherapy (CT) with Doc/cisplatin (CP) followed by sensitizing Doc chemoradiation (CRT) for patients (pts) with stage III NSCLC. Methods: Pts with inoperable stage III NSCLC were eligible. Induction CT consisted of Doc 75 mg/m2 and CP 75 mg/m2 on d 1 followed by rhG-CSF (150 ug/m2 sq on d 2 to 10). The CRT consisted of sensitizing Doc 12 mg/m2 twice per wk with daily RT (64.8 Gy to gross tumors and 45–57.6 Gy to subclinical disease). PK studies of Doc were performed during CT and CRT in each pt. The clearance (CL) and area under the plasma concentration versus time curve (AUC) were estimated. Results: 26 pts were enrolled and 16 completed study. Overall response rate was 69% [50% (8/16) PR and19% (3/16) CR]. 2-year survival was 57 %. During induction CT, primary grade (G) 3 toxicities were allergic reaction (10%), non-neutropenic infection (20%), nausea/vomiting (N/V) (10%), fatigue (10%), hypertension (5%) hyperglycemia (5%), dyspnea (5%) & fatigue (5%). There was no G3/4 hematologic toxicity. During CRT, 50% (4/8) of pts developed G3 esophagitis after Doc at 12 mg/m2. The next 8 pts received Doc at 10 mg/m2 with only 1 pt developing G3 esophagitis. Other G3 toxicities from CRT were N/V (28%), fatigue (14%), loss of appetite (14%), flushing (7%), chest pain (7%), & diarrhea (7%). No G3 or 4 pneumonitis or any G4 toxicity. Mean ± SD Doc CL at 75 and 10 mg/m2 were 20 ± 5 and 22 ± 10 L/h/m2, respectively. Ratio of Doc CL at 75 to 10 mg/m2 within a pt was 1.0 ± 0.4. Doc AUC at 75 and 10 mg/m2 were 3,933 ± 1,028 and 566 ± 257ng/ml·h, respectively. Conclusions: One-cycle full- dose Doc/CP with rhG-CSF followed by pulsed low-dose Doc CRT is associated with promising antitumor activity and low hematologic toxicity. Grade 3 esophagitis was associated with dose intensity of radiosensitizing Doc, and was minimized by dose reduction. Results suggest that this regimen should be further evaluated in pts with NSCLC. The PK disposition of Doc was similar at 75 and 10 mg/m2.

No significant financial relationships to disclose.
A phase II trial of weekly cisplatin and docetaxel in advanced non-small cell lung cancer (NSCLC)
Authors: Sovak M. A. , Lutzker S. , Guensch L. , Joyce M. , Schwartz S. , Wu Y. , Zheng L. , Aisner J.
Published: March 2020

18150

Background: Every 3-week cisplatin doublets used to treat advanced NSCLC carry a significant risk of renal and other toxicities and can be difficult for patients with co-morbidities. To reduce these toxicities, we conducted a phase II study to evaluate the efficacy and toxicity of weekly cisplatin and docetaxel in advanced NSCLC. Methods: Eligibility included patients with advanced or recurrent NSCLC, ECOG PS of 0–1, and no prior chemotherapy for metastatic disease. This Cancer Institute of New Jersey network, single stage phase II clinical trial was designed to give 3 weekly doses of cisplatin at 25 mg/m2 and docetaxel at 35 mg/m2, followed by 1 week of rest, for a total of 6 cycles of therapy. Toxicity was monitored weekly, and disease evaluation was performed every 2 cycles. The primary endpoint was response rate (RR); secondary endpoints included time to progression (TTP), median and 1-year survival. Results: From 12/03 to 11/06, 36 patients were enrolled so far. The median age of patients is 63 (range 47–78), the majority is white (n=33), 29 have stage IV disease, and half (n=18) are women. Fourteen have an ECOG PS=0 and 22 with PS=1. Histologic subtypes are: adenocarcinoma (n=24), NSCLC NOS (n=7), squamous (n=5). Eleven patients received = 4 cycles of therapy; median number of cycles delivered is 2.5. Reasons for treatment discontinuation include completion of therapy (n=5), progression of disease (n=16), adverse events (n=8), and patient preference (n=4). Three patients continue on therapy at this time. No complete responses were yet observed; 8 patients (22%) achieved a partial response; 10 patients had stable disease, 10 patients progressed, and 8 came off study before first disease evaluation. Median TTP was 3.1 months (mo) (95% CI 2, 5.5), median survival is 8.3 mo (95% CI 5,16.2) and 1-year survival is 39% (95% CI 20, 57). Most toxicities were mild but also included neutropenia (grade 3, n=1; grade 4, n=1), neutropenic fever (n=1), renal toxicity (grade 3, n=2), nausea (grade 3, n=1), fatigue (grade 3, n=3), diarrhea (grade 3, n=4) and metabolic abnormalities (grade 3, n=3). Conclusion: Weekly cisplatin and docetaxel is well tolerated with a low incidence of toxicity and demonstrates activity similar to every 3-week treatment in patients with advanced NSCLC.

No significant financial relationships to disclose.
IMRT and cetuximab in stage 3 non-small cell lung cancer: The NEAR trial (NCT00115518)
Authors: Jensen A. D. , Münter M. W. , Bischoff H. G. , Herpel E. , Haselmann R. , Timke C. , Haberkorn U. , Huber P. E. , Thomas M. , Debus J. , Herfarth K. K.
Published: March 2020

18168

Background: For stage 3 non-small cell lung cancer (NSCLC), RCHT is the treatment of choice with sometimes marked side- effect. Hence, patients with co-morbidities may not be eligible for combined treatment. Based on the results at other tumor sites, a combined- modality treatment with the EGFR antibody cetuximab and IMRT should be evaluated in a prospective phase II trial. Methods: Pts with inoperable stage 3 NSCLC ineligible for RCHT are included in the trial. Treatment consists of cetuximab weekly and concurrent IMRT with 50 Gy to CTV and subsequent boost to GTV to 66 Gy. Staging and f/u include CT, FDG-PET, and lung function prior to/after completion of treatment (response assessment) plus CT scans in 3 mo intervals. Overall treatment time is 4 months. Side-effects and efficacy were assessed. Results: So far, 17 of 30 pts (median 70 yrs; 57–82 yrs) have been enrolled. The median f/u from treatment start was 6 months (1–17). 3 pts are still being treated, 13 pts have completed, and one pt died prior to completion of treatment. Where available, EGFR staining yielded a median receptor score of 2 (0–3) in 12 pts. 3/12 pts showed strong (3+), 2/12 showed no EGFR expression. The treatment was well tolerated with only 1 treatment-related °3 morbidity (esophagitis). All pts showed acneiforme skin rash (°I), but no significant reduction of lung function. 2 pts with underlying heart disease developed thrombembolic complications (arterial & pulmonary embolisms). We observed PR in 10/13 and SD in 3/13 pts (RECIST). All pts showed a marked reduction of SUV in PET even if CT did not show PR. Conclusion: Preliminary results of IMRT combined with cetuximab suggest a reasonably safe treatment with only mild side-effects and encouraging local response. Addition of cetuximab does not seem to increase toxicity of RT.

[Table: see text]
Outcome of treatment with 2nd and 3rd generation platinum-based chemotherapy in advanced non-small cell carcinoma (NSCLC): A single institute experience
Authors: Khodadad K. , Malekzadegan M. R. , Hashemi N. , Azadi A. , Abdollah Shamshirsaz A. H. , Padyab M. , Emami H.
Published: March 2020

18169

Background: The cornerstone of treatment in patients with advanced NSCLC is chemotherapy. During past years 3rd generation cytotoxic drugs have replaced 2nd generation drugs in combination with platinum. Although some trials suggest that newer agents are less toxic and with better response rates compared to older ones, but overall survival outcomes are similar. Methods: Between 1999- 2005, 275 patients with advanced NSCLC (unresectable IIIA, IIIB and IV) have been treated in our center with either frontline 2nd (204 pts.) or 3rd (71 pts.) generation, platinum-based regimens. Retrospectively we analyzed the outcome of treatment (i.e. response rate and overall survival) in these patients according to the generation of chemotherapy regimen. Results: Male/female ratio was 3.6/1 and mean age 58.9. Pathology subtypes includes: adenocarcinoma (49.8%), squamous cell carcinoma (28%), undiff. NSCLC (21.8%) and large cell carcinoma (0.4%). The RR was higher with 3rd generation protocols compared to 2nd generations (47.9% vs 26.5%, P = 0.001) but the median OS in both groups was statistically non-significant (12.07 vs 10.57 m). Analyzing RR and OS in different pathology subtypes shows that in adenocarcinoma and squamous cell ca. the RR is higher with 3rd generation compared to 2nd generation (40.5% vs 20%, P=0.01 & 72.8% vs 27.3%, P=0.005 respectively), but the OS between these two generations was not statistically significant in both pathology subtypes. In undiff. NSCLC the outcome between 2nd and 3rd generation is non-significant in terms of OS and RR. The distribution of different stages in both study groups was statistically similar. Conclusions: Based on this study the 3rd generation protocols in the treatment of advanced NSCLC is superior to 2nd generation protocols in term of RR, although the median OS is statistically non-significant.

No significant financial relationships to disclose.
TGFBR1*6A germline deletion in gemcitabine (gem)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: Domine M. , Alberola V. , Muñoz-Langa J. , Muñoz-Quintana M. A. , Molina M. A. , Viñolas N. , Gonzalez-Larriba J. , López- Brea M. , Sanchez J. J. , Taron M.
Published: March 2020

18171

Background: An in-frame germline deletion variant (TGFBR1*6A) in the TGFBR1 gene results in loss of three alanines within the 9-alanine (*9A) repeat in the receptor. Compared with *9A, *6A is a less effective mediator of TGFB antiproliferative signals. Methods: We examined the germline deletion TGFBR1*6A in 107 gem/cis-treated stage IV NSCLC p. DNA was extracted from peripheral lymphocytes and deletion was analyzed by length analysis of fluorescently labeled PCR products. Results: Median age, 65 (range, 32- 81); male, 100 p (93%. Performance status (PS) 0, 39 p (37%); PS 1, 52 p (48.5%); PS 2, 26 p (24.5%). Adenocarcinoma: 56 p (52%). 71.6% of p had the *9A/*9A genotype; the remaining 28.4% had the *6A/*9A genotype. Response was observed in 37 p (34.5%). Overall median survival (MS) was 8 months (m). There were no differences in response or MS between p harboring the *9A/*9A genotype and those with the *6A/*9A genotype. There was a trend towards longer MS in p with PS 0 with *9A/*9A genotype (11 m) than in thoase with *6A/*9A (3 m) (P=0.06). Conclusions: Although the findings of this study do not identify significant differences between *6A and *9A, the fact that the shorter signal sequence could confer a tumor growth advantage merits further investigation.

No significant financial relationships to disclose.
Detection of prognostically distinct subpopulations in non-small cell lung cancer patients treated with epidermal growth factor receptor (EGFR) inhibitors
Authors: Stewart D. J.
Published: March 2020

18178

Hypothesis: In patient survival curves that follow 1st order kinetics, prognostically distinct subpopulations will be identified by inflection points in plots of log % survival vs time. Prognostically important dichotomous variables (present vs absent, or above vs below a threshold) will give inflection points while important continuous variables will shift curve slope without giving inflection points. Methods: For overall and progression-free survival curves from 35 published clinical trials of EGFR inhibitors, curve height at different times was measured manually and converted to % of height at time 0. Curve nonlinear regression analyses were performed using the Pharsight WinNonlin 5.0.1 program. Results: In assessments done to date, the most common survival curve pattern was conformity to a 2-compartment model, indicating a single inflection point and ≥ 2 prognostically distinct subpopulations. The second most common pattern was conformity to a 1-compartment model, suggesting that some populations are relatively homogenous. Only a minority of curves could be fit to 3-compartment models that would have indicated ≥ 3 distinct subpopulations. In different studies, EGFR inhibitors shifted some patients from poorer to better prognosis compartments compared to placebo, and/or decreased the slope (ie, increased the t1/2) of one or both individual compartments. Similarly, factors that have been found to be associated with prognosis in these studies were associated with formation of prognostically homogeneous groups or with alterations of relative compartment sizes or slopes. Conclusions: It is feasible to perform nonlinear regression analysis of log-linear survival plots to define prognostically distinct subpopulations. Preliminary assessments suggest that EGFR inhibitors and factors known to be important prognostically are associated with alteration of size and survival t1/2 of these subpopulations. Helpful data that could potentially be obtained from such analyses include minimum number, size and t1/2 of prognostically distinct subpopulations, and impact of a therapeutic modality or potential prognostic factor on each subpopulation.

No significant financial relationships to disclose.
Epidermal growth factor receptor mutations and stat3 phosphorylation in surgically resected non-small cell lung cancer
Authors: Yang F. , Zhou Z. , Wang J.
Published: March 2020

18180

Background: Somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene and EGFR downstream pathways in non-small-cell lung cancer (NSCLC) have generate enormous interest in the searching of biological predictors of EGFR inhibitor. Selective Akt and STAT3 pathways activation has been hypothesized from in vitro model. The goal of this study is to determine the association of EGFR mutations with phospho-STAT3 (p-STAT3) in resected lung adenocarcinoma samples. Methods: 94 consecutive lung adenocarcinoma specimens from Chinese patients were analyzed for activating EGFR mutations in exon 19 and 21 by direct sequencing and p-STAT3 expression by immunohistochemistry. Results: 18 (19%) samples harbored exon 19 deletions and 22 (23%) samples had exon 21 L858R mutaions. 46 (49%) samples were scored p-STAT3 positive defined as strong nuclear staining in more than 5% cancer cells. 25 (62%) cases with EGFR activating mutations showed positive p-STAT3 nuclear staining, compared with 21 (39%) p- STAT3 cases in the EGFR wild type group (p=0.024). Conclusions: Our data further support the hypothesis that EGFR mutations may selectively activate STAT3 pathway in NSCLC.

No significant financial relationships to disclose.
Preliminary results from a phase II study of celecoxib plus chemotherapy in patients with untreated advanced NSCLC
Authors: Wang J. , Liu X. , Yang L. , Guo Q. , Yang L. , Zhao J. , Wu M. , An T.
Published: March 2020

18188

Background: Preclinical studies indicated that cyclooxygenase-2(cox-2) inhibitor celecoxib may enhance antitumor efficacy of cytotoxics, and combination with chemotherapy had acceptable tolerability in a phase I trial. This phase II trial evaluated the efficacy and safety of the celecoxib plus platinum-based chemotherapy in advanced NSCLC as first-line chemotherapy. Methods: Patients: chemotherapy naïve, IIIB (w/malignant effusion) IV, PS 0–2; treated with platinum-based chemotherapy (Gemcitabine 1,200 mg/m2 d1, 2, Cisplatin 75 mg/m2 d1 Q3w or Docetaxel 35 mg/m2 d1,8,15, cisplatin 75 mg/m2 d1, Q4w), and plus celecoxib 400 mg p.o. bid., until evidence of disease progression or toxicity. Primary endpoint: median survival; secondary endpoints: response rate and toxicity. Results: From 3/05 to 6/06, 30 pts with cox-2 positive expression detected by ICH were treated; 27 evaluable for response and toxicity; M/F: 18/12; median age 64 (42–74); PS 0/1/2: 3/23/4; Path: adeno/squamous: 60%/40%; StageIII/IV: 35%/65%. Toxicity: Grade 3 or 4 neutropenia and thrombocytopenia were observed in 40% (11/27) and 30%(8/27) patients, respectively. One patient death was considered possible treatment related. Response: CR:0; PR: 14 (52%; 95% CI 32%-76%); SD: 6 (22%; 95% CI 14%-32%); PD:7 (26%; 95% CI 19%-36%). Median duration of response and stable disease: 6.4 (range 3.5–7.5) and 3.5 months (range 1.5–8.0), respectively. Survival is too early to evaluate. Conclusions: Celecoxib in combination with platinum-based chemotherapy appears to be well tolerated and demonstrates encouraging activity in patients with previously untreated advanced NSCLC. Accrual is continuing to 40 patients and updated response and survival data will be presented.

No significant financial relationships to disclose.
Combined treatment of patients with incompletely resected invasive thymoma: A retrospective analysis
Authors: Kowalski D. M. , Janowicz-Zebrowska A. , Krzakowski M. J. , Jaskiewicz P. , Zajda K. , Denisso T. , Lasota W.
Published: March 2020

18193

Background: Although surgery remains the mainstay of therapy for invasive thymoma, complete resection is feasible in only 60% of patients (pts) and adjunctive radiotherapy (RT) or/and chemotherapy (CT) is advocated. Multidisciplinary approach with chemotherapy (CT) and radiotherapy (RT) is an option for unresectable disease. The aim of our study was to evaluate retrospectively the outcome of pts with invasive thymoma submitted to postoperative RT or combined CT and RT. Methods: Pts in our analysis underwent either radical resection followed by RT or they had incomplete resection with subsequent CT and RT. Results: Between March 1996 and September 2005, 32 (18 women; 56.3% and 14 men; 43.7%) pts with invasive thymoma were treated. Median age was 47,8 years (range, 20–75). Clinical stage I, II, III or IVA was diagnosed respectively in 3 (9.4%), 12 (37.5%), 6 (18.7%) and 11 34.4%) pts. Pathologic types of invasive thymoma were as follows: A - 4 pts (12.5%), B - 9 pts (28.1%), AB - 8 pts (25%); pathological type was not specified in 1 pts (3.1%). Type C thymoma was diagnosed in 10 pts (31.3%). Complete resection was performed in 26 pts (81.3%), whereas 1 pt (3.1%) was irradiated only and 5 pts (15.6%) were treated with CT as single modality. Cisplatin-based CT was used in all pts. Twenty pts (62.5%) were irradiated, while RT was not used in 12 pts (37.5%). Median survival time (MST) for all pts was 54.5 months (range: 2–240 months), and median time to progression (MTTP) was 27.5 months (range: 1–221 months). MST for pts on CT was 46.3 months (range: 2–156) in comparison with 54.7 months (range: 2–240) in non-CT group. MTTP for CT group was 35.2 months (range: 2–144) and 51.0 months (range: 2–221) for no CT group. Tolerance of CT was acceptable. Conclusions: Postoperative RT is effective in reducing local recurrence rate and prolonging survival in pts with invasive thymoma. The role of postoperative CT is unclear and deserves further exploration.

No significant financial relationships to disclose.
A phase II study of docetaxel (D) plus imatinib (I) in patients with previously treated non-small cell lung cancer
Authors: White L. A. , Schmidt A. M. , Sjak-Shie N. N. , Greco A. O. , Cronin B. , Fisher K. L. , Eckardt J. R.
Published: March 2020

18200

Background: Docetaxel(D) has been shown to improve overall survival in pts with previously treated NSCLC. Pre-clinical data suggest synergistic activity with the combination of D and I. Paul Matthew; et al demonstrated the safety of this combination in pts with prostate cancer. Methods: This is a Phase II study of the combination of D and I in prev tx NSCLC to determine response rate, toxicity and assess overall survival. Pts must have received at least 1 prior regimen and have an ECOG PS of 2 or less. Prior tx with D was allowed. D was admin at 30 mg/m2 on a weekly schedule for 3 weeks followed by 1 week rest. I was admin at a starting dose of 600 mg/day throughout the study. Results: A total of 10 pts were enrolled. Seven male and 3 female with a median age of 66 years (range 58 - 74). A total of 26 cycles were delivered to 10 pts (mean = 3). Responses included 1 PR/3SD/2PD/4NE. One pt with a PR responded after cycle 4 but progressed after cycle 6. One pt maintained SD for 21 wks then expired due to an unrelated PE (h/o peripheral vascular disease). Grade 4 toxicity included periorbital edema (1 pt), pneumonia (2 pts), diarrhea (1 pt), dehydration (1 pt), dyspnea (1pt), anorexia (1 pt), pleural effusion (1 pt), and neutropenia (2 pts). Grade 3 toxicity included hyponatremia (1 pt), renal failure (1 pt), hypotension (2 pts), mental status changes (1 pt), anorexia (1 pt), azotemia (1 pt), dyspnea (1 pt), herpetic esophageal ulcer (1 pt), pneumonia (1 pt), neutropenia (2 pts), weakness & fatigue (1 pt), and anemia (1 pt). Four of 10 pts received only 1 cycle. (Three of those 4 suffered a fatal adverse event during cycle 1, not felt to be treatment related. The fourth developed herpetic esophageal lesions and was taken off study prior to tumor assessment.) Conclusions: The study was closed before the initial planned pts were enrolled due to low activity and unexpected high tox. Only 1 of 10 pts achieved a PR. Stable disease was observed in 3 pts but was of short duration in 2 of the 3. Despite supportive treatment, nausea, vomiting, diarrhea, and anorexia were difficult to control. Hematologic toxicity was encouragingly infrequent with only 2 pts experiencing Grade 4 neutropenia. Alternative dosing schedules would be recommended before pursuing this combination in NSCLC pts. Study supported by a grant from Novartis.

No significant financial relationships to disclose.
Stage III non small lung cancer (NSCLC): Docetaxel (D), gemcitabine (G), and cisplatin (C) as induction chemotherapy, an Italian phase I study
Authors: De Santis S. , Donato V. , Migliorino M. R. , Tedesco B. , Condo S. , De Marinis F.
Published: March 2020

18201

Background: Based on the several clinical trials, combined modality therapy became the standard of care for patients with stage III NSCLC “unresectable” with good performance status (Kathy S. Albain, Educational Book ASCO 2006, 453–461; Thomas E. Stinchcombe, Oncologist 2006, 11, 809–823). The most effective induction chemotherapy has yet to be determined. The objective of this prospective phase I study was to define the maximum tolerated dose (MTD), and to evaluate the activity and safety of one of the third generation triplets as a full dose neoadjuvant regimen in patients (pts) with unresectable Stage III NSCLC. Methods: In this study, chemotherapy-naïve pts with stage IIIA-N2 bulky and IIIB (except malignant pleural effusion) NSCLC were eligible. Inclusion into the trial and treatment decisions were done by multidisciplinary panel involving surgeons, medical oncologists and radiotherapists. All drugs were given intravenously on days 1 and 8, and repeated every 3 weeks up to 2 cycles followed by concurrent chemoradiation. D (30–35 mg/m2) was given first, followed by C (35 mg/m2) and G (1000 mg/m2). Results: From Jan ‘06 to Jul ‘06 twelve eligible pts were enrolled, 10/2 m/f gender; median age 63 (50–72), 1 patient with ECOG PS 0, 11 pts with PS 1; 5 pts with stage IIIA-N2 bulky, 7 pts with stage IIIB NSCLC; nine pts were smokers. All pts were evaluable for toxicity. Toxicity grade 3–4 by CTC criteria was: grade 3 neutropenia in 2/3 patients and grade 3 thrombocytopenia in 1/3 patients on the second dose level of chemotherapy (i.e. docetaxel 35 mg/m2), and was considered dose-limiting. Of 9 pts treated at the MTD (i.e. docetaxel 30 mg/m2), only 1 patient developed grade 4 neutropenia and 1 patient grade 3 thrombocytopenia; 3 patients (30%) had grade 2 neutropenia and grade 2 stomatitis. Of 12 evaluable pts for response, after induction chemotherapy eighty-three percent of patients (9/12 pts) had an objective response and 16,6% (2/9 pts) stable disease. Phase II is continuing for larger patient accrual. Conclusions: The recommended doses for further phase II studies are D (30 mg/m2) followed by C (35 mg/m2) and G (1000 mg/m2) every 3 weeks. This regimen is well tolerated and effective, and appears to be an excellent choice for stage III NSCLC.

No significant financial relationships to disclose.