bluuebunny/crossref_metadata_2025 huggingface dataset:
IFCT0401-bio trial: Predictive biological markers for disease control (DC) of patients with non-resectable, adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC) treated with gefitinib
Authors: Wislez M. , Antoine M. , Poulot V. , Morere J. F. , Perol M. , Souquet P. J. , Lebitasy M. P. , Zalcman G. , Coulet F. , Cadranel J.
Published: March 2020

7653

Background: A French prospective multicentric phase II trial (IFCT0401) evaluated gefitinib as first-line treatment in non- resectable ADC-BAC. Tissue samples were collected for central pathological review and molecular analysis in attempt to identify biological markers associated with DC by gefitinib. Methods: Tumor samples were classified as BAC variants or ADC-other types according to the 2004 WHO histological classification and as non-mucinous or mucinous/mixed according to cytology. Immunohistochemistry was performed using antibodies against TTF1, Ki67, phosphorylated AKT, erbB2, and EGFR. Polysomy/amplification was examined for EGFR and erbB2. EGFR 18–21 and K-ras 2 exons were amplified and sequenced. Results: Tissue specimen were collected from 65 of the 88 eligible participants. This subgroup did not differ from the overall trial population in terms of sex ratio, proportion of non-smokers and DC rate. DC was achieved in 22/64 patients (DCR=34.4%, CI=[22–41]). 81% were BAC variants (n=50) and 19% ADC other types. Of the 50 BAC variants, half were non-mucinous and half mucinous. EGFR high polysomy/amplification was present in 6/40 samples (15%). EGFR exon 19, 20 and 21 mutations were detected in 6/57 (10.5%), 1/49 (2%) and 0/58 samples, respectively and K- ras mutation in 11/53 (20.7%). Expression of TTF1 (p<0.0001) and EGFR (p=0.04) as well as polysomy/amplification of EGFR (p=0.04) were significantly higher in the non-mucinous than in the mucinous type. There was also a trend for more frequent detection of EGFR mutations among non-mucinous than mucinous type (p=0.08). DC with gefitinib was significantly associated with female gender (p=0.02), non- smoker status (p=0.03), non-mucinous subtype (p=0.006), high TTF1 expression (p=0.02) and EGFR mutation (p=0.0003). K-ras mutation was associated with progression (p=0.04). Conclusions: Among patients with histologically proven ADC-BAC who received gefitinib, female gender, non-smoker status, non-mucinous subtype, high TTF1 expression, and EGFR mutation are associated with DC, while K-ras mutation is associated with disease progression. Multivariate analysis will be released at ASCO meeting.

No significant financial relationships to disclose.
Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer
Authors: Saintigny P. , Besse B. , Callard P. , Vergnaud A. , Czernichow S. , Colombat M. , Girard P. , Validire P. , Breau J. , Bernaudin J. , Soria J.
Published: March 2020

7655

Background: The role of erythropoietin (EPO) and its receptor (EPO-R) in tumor biology is under active investigation. This study was designed to evaluate the prognostic impact of EPO and EPO-R expression in stage I non-small cell lung cancer (NSCLC) patients. Methods: EPO and EPO-R expression in 158 tumor samples from resected stage I NSCLC was evaluated using immunohistochemistry and tissue-array technology. Disease specific survival time was calculated from the date of surgery to death from cancer-related causes. Results: EPOR and EPO were highly expressed in 20.9% and 35.4% of the tumors respectively. High EPO-R compared to negative or low level of expression was associated with a poor 5-year disease specific survival (60.6% versus 80.8%, logrank test: p=0.01). High EPO compared to negative and low level of expression was associated with a trend toward a poor 5-year disease specific survival (69.6% versus 80.4%, logrank test: p=0.13). High level of EPO-R and EPO coexpression compared to other groups of patients was associated with a poor 5- year disease specific survival (50.0% versus 80.0% of survival at the end of follow-up, logrank test: p=0.005). In multivariate analysis for disease specific survival, high level of EPO-R and EPO coexpression was an independent prognostic factor for disease specific survival (HR 2.214, 95% CI: 1.012–4.848, p=0.046). Conclusions: These results establish for the first time the pejorative prognostic value of EPO and EPO-R expression in early stage resected NSCLC and suggest a potential paracrine and/or autocrine role of endogenous EPO in NSCLC aggressiveness.

No significant financial relationships to disclose.
Lack of consensus on post-operative radiotherapy (PORT) fields used in non-small cell lung cancer (NSCLC)
Authors: Senan S. , Le Péchoux C. , Spoelstra F. O. , Ishikura S. , Casas F. , Ball D. , Price A. , DeRuysscher D. , van Sörnsen de Koste J. R.
Published: March 2020

7658

Background: Survival in patients with a completely resected stage III-N2 NSCLC may be improved by PORT. LungART is a phase III trial for patients with resected N2 disease who will be randomized to between PORT and no PORT, irrespective of the use of chemotherapy. LungArt target volumes are based upon the post-surgical findings in each patient, and on the surgical literature. A ‘dummy run’ was performed to study PORT volumes used internationally and to evaluate the LungART protocol. Methods: A CD-rom based contouring program containing the planning CT scans of 2 patients (post-lobectomy and pneumonectomy, respectively) were mailed to 17 thoracic radiation oncologists from 4 continents. Relevant clinical, radiological and pathological reports were provided in order to allow clinicans to contour their ‘routine’ clinical target volumes (CTV). Contours were saved onto a CD-rom and mailed to the study center. The LungART protocol was then provided and ‘protocol’ CTVs were generated. Contours of each case were transferred to a template CT dataset of that patient, and nodal CTVs were jointly generated by two clinicians using published definitions. An optimised treatment plan was generated for all CTV's. Results: For each case, a total of 10 routine CTVs were received. Both routine and protocol CTVs were provided for each case by 6 clinicians. The routine CTVs varied up to 3-fold between clinicians and this was significantly decreased by use of the protocol (F test, p=0.00003 and p=0.00002 for cases 1 and 2, respectively). Coverage of nodal stations 2R and 4R improved when CTVs were defined using the protocol. Risks of lung toxicity, as defined by the lung volumes treated to 20 Gy and 5 Gy, varied between the smallest and second largest routine CTVs. For the post-lobectomy case, the V20 (range) was 11.8–19.3% and a V5 of 33.8–57.9%. The corresponding V20 and V5 values were 1.5–2.1% and 31.6–39.7% for the post-pneumonectomy case. Both cardiac volumes receiving 45 Gy and spinal doses were similar for both CTVs. Conclusions: The variations in PORT volumes generated by experts led to important differences in the risk of radiation-induced lung toxicity. Standardized target definitions are needed in order to optimize the survival benefits from PORT, and the LungArt protocol may serve this purpose.

No significant financial relationships to disclose.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a biomarker for the effect of PTK787/ZK 222584 (PTK/ZK) as second-line mono-therapy in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC)
Authors: Morgan B. , Horsfield M. A. , Stattaus J. , Khalil A. , Gauler T. C. , Gounant V. , Fischer B. , Laurent D. , Krissel H. , Eberhardt W. E.
Published: March 2020

7676

Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival. PTK/ZK (PTK/ZK) is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R1–3). DCE-MRI measures early changes in tumour-associated vasculature in response to treatment and has been successfully used as a biomarker for biological activity of PTK/ZK in liver metastases from colorectal cancer. Methods: This is a prospective, multi- centre, phase-II study of PTK/ZK in pretreated patients with advanced stage NSCLC. 54 patients (pts) received 1,250 mg PTK/ZK once daily (qd), followed by 58 patients receiving 1,250 mg (500 am + 750 mg pm) PTK/ZK twice daily (bid). Response evaluation was based on RECIST. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. DCE-MRI was performed 2- 4 hours after PTK/ZK administration, on day 2 and at day 28. Contrast enhancement for the whole tumour was assessed by calculating the transfer constant (Ktrans) using a two-compartment model. Results: DCE-MRI was performed successfully in 35 pts in the qd cohort on day 2 and 29 pts in the qd cohort at day 28. There was a statistically significant mean reduction in Ktrans at day 2 of 35.2 % (p<0.0001, N=35, paired ‘t’ test) and at Day 28 of 38.1% (p<0.0001, N=29). 32 pts with day 2 DCE- MRI were evaluable for response assessment with 10 (31%) achieving SD at 12 weeks and 22 (69%) with progressive disease (PD). Both the SD group and the PD group had significant mean reductions in Ktrans at day 2 (39.4% and 37.1%, respectively). However, the difference between SD and PD was not statistically significant. Data for the bid cohort will be presented at the meeting. Conclusions: PTK/ZK causes statistically significant reduction in tumour vascular parameters of lung tumours. Ktrans has previously been shown to correlate with clinical outcome. However, for the qd cohort, no correlation could be demonstrated. This may be due to the limitation of the sample size as well as the heterogeneity of the targeted lesions selected for this study.

[Table: see text]
Liposomal cisplatin and paclitaxel versus cisplatin and paclitaxel in advanced NSCLC
Authors: Stathopoulos G. P. , Michalopoulou P. , Antoniou D. , Dimitroulis J. , Giamboudakis P. , Marosis K. , Stathopoulos J. , Tsoukalas G. , Grigoratou T.
Published: March 2020

7684

Background: A new liposomal formulation of Cisplatin has been tested in a phase I and phase II trial in advanced solid tumors as a single agent or in combination with Gemcitabine or paclitaxel. It is a non-myelotoxic and non-nephrotoxic agent. Effectiveness has been shown, in particular when it is combined with a second agent. Objectives, comparison of toxicity, efficacy of liposomal cisplatin (lipoplatin) versus cisplatin both combined with paclitaxel for non-small cell lung cancer patients. It is a preliminary report of the study which is on-going. Methods: From April 2006 till December 2006, 61 patients were recruited. 54 are evaluable for response and toxicity. Were all untreated. Median age 65 (42–80). They were randomized in two arms A and B. Arm A patients -27- were treated with lipoplatin-paclitaxel and Arm B patients -27- with cisplatin-paclitaxel. Arm A: 24 male, 3 female, histology: 10 squamous, 10 adenocarcinomas, 7 undifferentiated. Stage: IIIa 4 patients, IIIb 11 pat., IV 12 pat. Arm B: 25 males, 2 female, histology: 11 squamous, 11 adenocarcinomas, 5 undifferentiated, stage IIIa 2 pat., IIIb 14 pat., IV 11 pat. Arm A Chemotherapy: Lipoplatin 200 mg/m2 Paclitaxel 135 mg/m2 administered on day 1 repeated every 2 weeks. Lipoplatin infused for 8 hours in 5% dextrose 1 lt. Arm B: cisplatin 75 mg/m2 (hydration of 2 lt) and paclitaxel 135 mg/m2, every two weeks. Each day treatment was 1 cycle and the plan was to give 9 cycles per patient unless disease progression was detected before 9th cycle. Results: Response: Arm A: PR: 48.15% SD: 37.03% PD: 3.7% and clinical benefit 11.11%. Arm B: PR 44.44% SD 44.44% PD: 3.7% and clinical benefit 7.41%. Toxicity: Arm A: Renal toxicity in 1 pat. (3.70%) neurotoxicity grade I-II in 7 pat. (25.92%) Nausea-vomit in 5 patients (18.52%) Myelotoxicity Grade I-II in 10 pat. (37.04%). Arm B: Renal toxicity in 7 pat. (25.92%), Neurotoxicity Grade I-III in 12 pat. (44.44%) Nausea-vomit in 7 pat. (25.92%) Myelotoxicity Grade I-III in 17 pat. (62.96%). Conclusions: Preliminary results showed liposomal cisplatin compared with cisplatin each one combined with paclitaxel, the response rate was similar but toxicity and in particular nephrotoxicity, neurotoxicity, and myelotoxicity was significantly lower in liposomal cisplatin arm.

No significant financial relationships to disclose.
Role of ERCC1, XRCC3, Aurora A and TGFBR1 single-nucleotide polymorphisms (SNP) and CHFR and 14–3-3σ methylation in a customized cisplatin (cis) trial based on ERCC1 mRNA levels in stage IV non-small cell lung cancer (NSCLC) patients (pts)
Authors: Taron M. , Cobo M. , Isla D. , Massuti B. , Montes A. , Sanchez J. , Botia M. , Domine M. , Sanchez-Ronco M. , Rosell R.
Published: March 2020

7687

Background: The primary aim of this trial was response. In both the control arm and in the genotypic arm with low tumor ERCC1 mRNA levels, pts received docetaxel (doc)/cis; in the genotypic arm with high tumor ERCC1 mRNA levels, pts received doc/gemcitabine. Response was significantly higher in the genotypic arms. We examined 324 pts for genetic markers that could influence response, including ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 (Thr to Met), Aurora A 91 T>A, Aurora A 169G>A, a SNP within intron 7 of the TGFBR1 gene (Int7G24A), and an in-frame germline deletion (TGFBR1*6A). Methylation of 14–3-3s and CHFR were also analyzed. Methods: DNA from peripheral lymphocytes was used for genotyping (Taqman assay) and methylation-specific PCR was used for 14–3- 3s and CHFR in pretreatment serum DNA. Results: There were no differences in clinical characteristics among the different SNP types, except that pts with Aurora A 91 AA had higher tumor ERCC1 mRNA levels (P=0.005). No relationship was found between ERCC1 SNPs and tumor ERCC1 mRNA levels. A strong correlation was found between the Int7G24A and XRCC3 241 SNPs (P=0.03). The Int7G24A GA type had a higher odds ratio (OR) of response (OR 2.32) than the AA type (OR 3.15) (P=0.02). XRCC3 241 MetMet had a lower probability of response (OR 0.23) (P=0.04). No other differences in response were observed according to any of the other SNPs or methylation. In the multivariate model, the best response was observed in pts with performance status (PS) 0, low ERCC1 levels, and XRCC3 241 SNP ( Table ). Conclusions: Further research is warranted to define the role of theTGFBR1 Int7G24A gene in customized treatments.

No significant financial relationships to disclose.

[Table: see text]
Phase II trial of oxaliplatin, pemetrexed, and bevacizumab in previously-treated advanced non-small cell lung cancer (NSCLC)
Authors: Heist R. S. , Fidias P. , Huberman M. , Temel J. , Sequist L. , Lynch T. J.
Published: March 2020

7700

Background: Single agent chemotherapy is standard for second and third line therapy of NSCLC. Combination therapy has to date not proven to be superior to single agents –often adding additional toxicity without any additional efficacy. We investigated whether the combination of oxaliplatin, pemetrexed, and bevacizumab was an active and tolerable regimen in the pre-treated advanced NSCLC setting. Methods: In this two-stage phase II trial, patients received pemetrexed (500 mg/m2), oxaliplatin (120 mg/m2), and bevacizumab (15 mg/kg) on day 1 of every 21 day cycle, for a total of 6 cycles or until disease progression. Eligibility criteria included PS 0–1, non-squamous histology, and at least one prior chemotherapy regimen. Patients with treated brain metastases were allowed on this trial. The primary endpoint was response rate, with secondary endpoints of TTP, PFS, and OS. Results: 36 patients were enrolled on this study. Patient characteristics for 32 for which data is available were: 16 (50%) women, 16 (50%) men, 26 (81%) adenocarcinoma, 6 (19%) large cell or NSCLC, 6 (19%) treated brain metastases. Of the 31 patients evaluable for tumor response, 0 had CR, 8 (25%) had PR, 14 (44%) had SD, and 9 (28%) had PD. One patient experienced Grade V hemoptysis after cycle 2 before restaging. Nine patients experienced a Grade III/IV serious adverse event. These Grade III/IV toxicities included: cardiac ischemia (1), sensory neuropathy (1), dyspnea (1), anemia (1), constipation (1), fatigue (1), colitis (1), face pain (1), hyperglycemia (1), elevated ALT (1). Among the 6 patients with treated brain metastases, there was 1 PR, 2 SD, 2 PD, and one patient with Grade V hemoptysis whose response could not be assessed; there were no brain hemorrhage events. Data for PFS and OS are preliminary; estimated median PFS is 5.8 months (95% CI 3.8 - 8.9 mo), and estimated OS is 10.9 mo (95% CI 6.4 - 20 mo). Updated data will be presented at the time of the meeting. Conclusions: This data suggests that the combination of pemetrexed, oxaliplatin, and bevacizumab is tolerable and has a promising response rate. Updated data will be presented at the meeting.

No significant financial relationships to disclose.
Up-regulation of inflammatory and thrombotic mediators in lung cancer and their modulation by oral anticoagulantion
Authors: Fareed J. , Ciftci A. , Demir M. , Hoppensteadt D. , Altiay G. , Tobu M. , Iqbal O. , Fareed D. , Bick R. , Sheikh A.
Published: March 2020

7705

Background: Venous thromboembolic events (VTE) are associated with lung cancer and significantly contributes to the increased mortality in these patients. While the increased prevalence of VTE is fully recognized in lung cancer, its pathogenesis is not fully understood at this time. Even the patients undergoing therapeutic interventions are at high risk to develop VTE. Profiling of surrogate markers of thrombosis and inflammation provides an opportunity to understand the pathogenesis of thrombosis in these patients. Methods: In a prospective, randomized, controlled study patients with inoperable lung cancer (n=100) were randomized to receive chemotherapy, radiation and warfarin (INR 1.5–2.5) or chemotherapy, radiation without warfarin (n=50). Blood samples were drawn prior to and after the second treatment cycle with warfarin. All samples were analyzed for such inflammation markers as the tumor necrosis factor alpha (TNF a), CD 40 ligand (CD 40L), C-reactive protein (CRP), interleukin 1 beta (IL-1β), asymmetric dimethylarginine (ADMA) and nitric oxide (NO). In addition, prothrombin fragment F1.2 (F1.2) and thrombin antithrombin complex (TAT) were also measured. Results: The results are summarized in the following table . All of the surrogate markers of inflammation showed a decreased trend (13–50%) in the warfarin treated group, whereas the non-warfarin treated group exhibited an increase (18–46%) in all markers except CRP and ADMA. The markers of thrombin generation were down regulated in the warfarin treated group. Conclusions: The levels of various inflammatory markers are upregulated in lung cancer suggesting a pathogenic role of this process in lung cancer. Warfarin down regulated the inflammatory and thrombogenic processes in contrast to the non-warfarin treated group. The clinical relevance of these observations require additional analysis.

No significant financial relationships to disclose.

[Table: see text]
Impact of induction chemotherapy and adjuvant radiation therapy on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma
Authors: de Perrot M. , Feld R. , Anraku M. , Bezjak A. , Burkes R. , Roberts H. , Cho J. , Visbal A. , Leighl N. , Keshavjee S. , Johnston M.
Published: March 2020

7708

Background: Examine the results of tri-modality therapy for malignant pleural mesothelioma (MPM). Methods: Protocol consisted of induction cisplatin-based chemotherapy, followed by extrapleural pneumonectomy (EPP) and adjuvant hemithoracic radiation therapy (RT) to 54 Gy. Results: A total of 60 patients were suitable candidates for tri-modality therapy between 01/2001 and 01/2007. Induction chemotherapy was administered to 56 patients; 4 patients underwent EPP without induction chemotherapy because of patient refusal (n=2), previous chemotherapy (n=1) and sarcomatoid MPM (n=1). Chemotherapy included vinorelbine/cisplatin (n=26), pemetrexed/cisplatin (n=26) and gemcitabine/cisplatin (n=4). EPP was performed in 47 patients; 13 patients did not undergo EPP because of tumor progression during chemotherapy (n=2), extensive chest wall involvement at surgery (n=6), or involvement of mediastinal lymph nodes at mediastinoscopy (n=5). Three patients (6%) died within 30 days of surgery. Pathological stage was II (n=6), III (n=35), and IV (n=6). Adjuvant RT was administered postoperatively to 36 patients and is ongoing in 5 patients; 6 patients did not receive adjuvant RT because of fatigue (n=5) or previous RT (n=1), and 4 patients did not complete RT up to 54 Gy. Overall survival for the 23 patients who completed the tri-modality therapy was 37% at 3 years with a median survival of 15 months. Eleven of the 23 patients had recurrence after a median of 8 months (range, 2–13 months). Recurrences were locoregional (n=2), in contralateral chest (n=3), abdomen (n=3), contralateral chest and abdomen (n=2), or pericardium (n=1). Among patients undergoing EPP, disease-free survival was longer in patients undergoing adjuvant high dose hemithoracic RT (p=0.07), in epithelial tumors (p=0.03), and in early stage (p=0.07). Overall survival was influenced by histology (p=0.007) and stage (p=0.05), but not by adjuvant high dose hemithoracic RT (p=0.5). The type of chemotherapy had no impact on disease-free and overall survival. Conclusions: Aggressive tri-modality therapy is feasible in selected patient with MPM. Adjuvant high dose hemithoracic RT can improve disease free survival and achieve good local control.

No significant financial relationships to disclose.
Effect of family history on lung cancer outcomes
Authors: Ganti A. , Loberiza F. R. , Kessinger A.
Published: March 2020

7711

Background: Risk factors for development of lung cancer includes a family history of the disease, especially if younger and multiple family members are affected. The effect of family history on lung cancer outcomes is unknown. A study was conducted to investigate this question. Methods: The following data were abstracted from the medical records of patients with lung cancer seen in the Medical Oncology clinic by one of the authors (AK, AG) between 1999 and 2006: age, gender, smoking history, family history, stage, treatment and survival. χ2 test and Wilcoxon test were used for univariate comparisons based on family history of lung cancer. Cox Proportional Hazards regression analysis was used to evaluate the adjusted risk of death by family history. Univariate probability of survival was computed using Kaplan Meier estimate and compared using the log rank test. Results: Two hundred and eighty-nine of the 560 patients studied (51%) were male and 519 (93%) had a smoking history. Median age at diagnosis was 63 years (range: 16 - 89 yrs). Of the 148 patients (26%) with a family history of lung cancer, 115 had an affected first degree relative. The histology of the patients’ malignancy was: adenocarcinoma - 227 (41%), squamous cell - 103 (18%), small cell - 93 (17%) and other non-small cell carcinoma - 137 (24%). There was no effect of family history on histology or stage at diagnosis. Median survival in patients with a family history was 53 months compared to 58 months in patients without such a history (p = 0.06). On multivariate analysis, after adjusting for age, histology, stage at diagnosis, and smoking history, patients with a family history of lung cancer had a relative risk of death of 1.65 (95% CI: 1.07 - 2.56) (p = 0.02) compared to those without a family history ( Table ). This risk was especially increased in those who had an affected first degree relative (RR: 1.72; 95% CI: 1.08 - 2.75, p = 0.02). Conclusions: Lung cancer patients who have a first degree relative with lung cancer appear to have a worse outcome than those without a family history of lung cancer.

No significant financial relationships to disclose.

[Table: see text]
Activated Src kinase is expressed in malignant pleural mesothelioma tumors; dasatinib inhibition leads to cytotoxicity, cell cycle inhibition, and prevention of invasion and migration
Authors: Tsao A. S. , He D. D. , Saigal B. , Liu S. , Lee J. , Bakkannagari S. , Ordonez N. , Hong W. , Wistuba I. , Johnson F.
Published: March 2020

7713

Background: Malignant pleural mesothelioma (MPM) is a lethal disease with few effective therapeutic options. We sought to determine whether Src, a non-receptor tyrosine kinase, could be a new therapeutic target in MPM and to establish the potential therapeutic use of pharmacologic Src inhibitors in this disease. Methods: We analyzed four MPM cell lines (MSTO-211H, NCI-H28, NCI-H2052, and NCI- H2452) for immunohistochemical (IHC) expression of total and phosphorylated Src (Tyr 419, Tyr 530). These cell lines were treated with dasatinib, a Src inhibitor, and evaluated for apoptosis, cell cycle analysis, and migration and invasion. Downstream signaling events were studied by Western blot analysis. We also conducted IHC analyses with total Src, phosphorylated Src Tyr 419 (p-Src Tyr 419), and phosphorylated Src Tyr 530 on 46 archived MPM tumor specimens and correlated the biomarker results with the clinical outcome. Results: All four MPM cell lines expressed total and activated Src (p-Src Tyr 419). Three of the four cell lines were sensitive in vitro to cytotoxicity by dasatinib with inhibition of migration and invasion, cell cycle inhibition, and apoptosis. Treatment with dasatinib inhibited several pathways downstream of Src. In the archived MPM tumor specimens, Src protein was highly expressed on IHC analysis in tumor cells, but that expression did not correlate with overall or progression-free survival. However, expression of activated Src (p-Src Tyr 419) on the tumor cell membrane was higher in patients with stage 4 disease; the presence of metastasis correlated with higher membrane (P = 0.03) and cytoplasmic (P = 0.04) expression of p-Src Tyr 419. MPM nodal involvement at N1 was associated with the highest membrane expression of inactive Src (p-Src Tyr 530) (P = 0.02), whereas N2 disease was associated with the lowest expression. No gene mutations in Src exon 12 were found in the cell lines or tumor specimens. Conclusions: Activated Src may have an important role in survival, metastasis, and invasion in MPM, and targeting Src may be an important therapeutic strategy.

No significant financial relationships to disclose.
Clinical outcomes of adjuvant treatments for invasive thymoma: Dose chemotherapy influence prognosis?
Authors: Jeong S. , Cho B. , Jung J. , Im C. , Kim Y. , Choi H. , Park M. , Kim S. , Chung K. , Kim J.
Published: March 2020

7715

Background: The aim of this study was to evaluate therapeutic outcomes and to validate prognostic factors, including adjuvant chemotherapy, in resected thymoma patients who received adjuvant treatment. Methods: One hundred thymoma patients who received post-surgical adjuvant therapy from 1995 to 2005 were retrospectively reviewed. 55 patients received only radiotherapy for the adjuvant therapy, while 45 patients received both radiotherapy and chemotherapy. The total radiation dose was 45–63 Gy, with a median dose of 50.4 Gy. The chemotherapy consisted of 6 cycles of doxorubicin, cisplatin, vincristine, and cyclophosphamide. Treatments were applied every 3–4 weeks. The median follow-up duration was 65 months (range, 5–200 months). Results: The 5-year overall survival (OS) and disease- free survival (DFS) rates were 75.7% (89.2% in stage II, 67.9% in stage III, and 52.1% in stage IVA) and 70.3% (83% in stage II, 62.4% in stage III, and 33.6% in stage IVA) respectively. According to multivariate analysis, the prognostic factors for OS were age, WHO histology, Masaoka stage, and recurrence, while pleural involvement and WHO histology had statistically significant impacts on DFS. Higher radiation dosage, positive resection margins, and adjuvant chemotherapy did not influence survival outcomes. The most common relapse site was the pleura (15 patients, 53.6%). The toxicity from chemotherapy and radiotherapy was manageable, with no deaths due to toxicity. Conclusion: The prognosis of invasive thymoma was poor despite adjuvant treatments with radiotherapy and chemotherapy. In addition to WHO histology, pleural involvement was the most important prognostic factor for recurrence. The pleura was the most common relapse site. Therefore, new modalities to reduce pleural recurrence are warranted.

No significant financial relationships to disclose.
Comparison of melphalan-prednisone-thalidomide (MP-T) to melphalan-prednisone (MP) in patients 75 years of age or older with untreated multiple myeloma (MM). Preliminary results of the randomized, double-blind, placebo controlled IFM 01–01 trial
Authors: Hulin C. , Virion J. , Leleu X. , Rodon P. , Pegourie B. , Benboubker L. , Doyen C. , Dib M. , Guillerm G. , Moreau P.
Published: March 2020

8001

Background: The MP-T combination has been shown to be the standard treatment in newly diagnosed MM patients (pts) aged 65 to 75 years (Facon et al; JCO 2006; 24, A1). However, no specific therapeutic recommendation exists for pts older than 75 years regarding the benefit of adding Thalidomide to MP. Methods: The IFM 01–01 trial was initiated in 04/2002. Patients > 75 years with untreated MM were randomized to receive MP (Melphalan 0.2mg/kg/d + Prednisone 2 mg/kg/d day1–4, 12 courses at 6-weeks intervals) + placebo (MP-placebo) vs MP + daily Thalidomide 100mg/d (MP-T). No anti-VTE prophylaxis was given. The primary end-point was overall survival (OS). Secondary end points were progression-free survival (PFS), response to treatment and toxicity. A first interim analysis was performed after the inclusion of 150 patients and a data safety monitoring board recommended a second analysis after the accrual of 200 patients. We here present the preliminary results of this analysis. Results: At the reference date of November 1, 2006, 232 pts were randomised. In all, 200 pts were analysed (100 per group), with 33.5% of pts >80 years (median age, 78.4 years). There were no differences between the 2 groups regarding baseline characteristics. Data were analysed on an intent-to-treat basis. After the completion of therapy the rates of partial response and very good partial response were 31% and 8% respectively with MP-placebo vs 61% and 22% respectively with MP-T. The median PFS time was 19 months (95%-CI 14.6–21.5) with MP-placebo vs 24.1 months (95%-CI 19.4–29.7) with MP-T (p=0.004 log-rank test). In the MP-T arm, 43/100 pts stopped treatment due to toxicity (10 due to neuropathy) versus 11/100 in the MP-placebo arm. Toxicity (Grade 2–4) included peripheral neuropathy (18%), somnolence (7%) and DVT (7%) with MP-T, vs 6%, 6% and 1% respectively, with MP-placebo. Final results including OS data will be presented at the meeting. Conclusion: MPT is an effective combination with acceptable toxicity in patients with MM = 75 years of age, with a significant improvement in PFS.

No significant financial relationships to disclose.
Bortezomib (BTZ) prior to and as maintenance therapy after autologous stem cell transplant (ASCT) in multiple myeloma (MM): Long-term follow-up of a phase II study
Authors: Goyal S. D. , Uy G. , DiPersio J. F. , Vij R.
Published: March 2020

8044

Background: BTZ and immunomodulatory drugs have emerged as active therapeutic options for MM. However, the optimal method of incorporating these agents in the ASCT paradigm remains unclear. Data is available on thalidomide induction and post ASCT maintenance therapy. However, there are no published data on BTZ used in this manner. Methods: Following induction therapy, BTZ 1.3 mg/m2 was administered on d 1, 4, 8, and 11 q21d × 2 cycles. ASCT with melphalan 200mg/m2 was performed using G-CSF mobilized PBSC. Maintenance BTZ 1.3 mg/m2/d was administered weekly for 4 of 5 weeks × 6 cycles starting 90–120 days post-transplant. Results: 39 patients completed pre-transplant BTZ: 23M/16F, median age 56 years (range 38–69), IgG (28), IgA (10), light chain only (1), Durie-Salmon stage I (1) II (12) III (26), induction anthracycline/thalidomide-based regimen (37). 37 patients underwent ASCT. Pre-transplant treatment with BTZ did not adversely affect stem cell yield or engraftment (Uy et al, Blood, 2005;106(11): abstr 2926). The ORR /CR+VGPR were 92%/53% at d90–120 post-transplant. With a median follow up of 897 days, the median PFS was 806 days and Kaplan-Meier estimate of 3-year PFS is 41% (95% CI, 31–63%). Median OS has not been reached with 3-year OS estimate of 79% (95%CI, 63–94%). 14/39 (36%) patients experienced varicella zoster virus (VZV) reactivation at a median of 200 days post-enrollment. 12/39 patients had grade (Gr) 1 neuropathy at enrollment. Gr 3/4 neuropathy emerged in 2 patients preventing initiation of maintenance BTZ. Gr 3/4 neuropathy emerged in 3 patients during maintenance BTZ requiring drug discontinuation in two and dose reduction in one patient. No grade 3/4 hematologic toxicity was observed during maintenance BTZ. Conclusions: This is the first trial reporting on sequential administration of BTZ prior to and as maintenance therapy post ASCT in MM. Impressive CR/VGPR, PFS and OS were observed and a high rate of VZV reactivation was seen.

No significant financial relationships to disclose.
The benefit of reduced intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) as salvage treatment for relapsing multiple myeloma (MM)
Authors: Mohty M. , De Lavallade H. , Chabannon C. , Stoppa A. , Faucher C. , El-Cheikh J. , Furst S. , Gastaut J. , Blaise D.
Published: March 2020

8045

Background: The role of RIC allo-SCT in MM is still controversial. This single centre study aimed to evaluate RIC allo- SCT for relapsed MM, using a genetic randomization through a donor vs. no donor comparison. Methods: Between 2002 and 2005, 32 patients with relapsed or refractory MM, and with an identified sibling, were referred to our centre for HLA typing. In all, 19 patients (59%; donor group) had an HLA-identical sibling donor, while the remaining 13 pts (41%; no donor group) had no HLA-identical sibling donor. There were no significant differences between these two groups that were comparable as for demographic, disease and prognosis factors. All pts had previously failed auto-SCT. Results: Among the 19 pts from the donor group, 18 (95%) could proceed to allo-SCT. With a median overall FU of 36 m., 11 patients (85%; 95%CI: 54–98%) from the no donor group had disease progression despite salvage therapy, and only 6 of them are still alive, of whom 5 (80%) in progressive disease at last FU. In contrast, only 5 pts (28%;P=0.001) from the donor group progressed after RIC allo-SCT. In the RIC allo-SCT group, 10 pts (56%;95%CI;33–79%) are still alive, with 4 pts being in CR, and 5 in PR or VGPR. Only one patient is currently experiencing disease progression and receiving salvage therapy. Interestingly, 11 pts (61%;95%CI,39–83%) from the RIC allo-SCT group showed objective disease response, usually concurrent to chronic GVHD. In all, 6 pts died from TRM for an overall incidence of TRM of 33% (95%CI,11–55%) in this population of heavily pretreated and relapsed or refractory MM population. In an intention-to- treat analysis, the KM estimate of progression-free survival was significantly higher in the donor group as compared to the no donor group (P=0.01; 46% vs. 8% at 3 y.). Conclusions: RIC allo-SCT from an HLA-identical sibling is a feasible and potential therapy that should be proposed for refractory or relapsed MM, since a potent graft-vs. -MM effect can be induced despite heavy pretreatments, allowing for significantly longer PFS. Also, the latter results are expected to be further improved with the systematic and early use of maintenance therapies after RIC allo-SCT.

No significant financial relationships to disclose.
A feasibility study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma
Authors: Kahl B. S. , Peterson C. , Blank J. , McFarland T. , Huie M. , Eickhoff J. , Werndli J. , Callander N. , Myers T.
Published: March 2020

8062

Introduction: Novel treatment strategies are needed for Mantle Cell Lymphoma (MCL). We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64%. Given the promising activity of bortezomib (VELCADER) in relapsed MCL, we hypothesized that the incorporation of VELCADE (Vc) into the induction regimen would improve the CR rate. Methods: Eligible patients have histologically confirmed MCL, PS 0–2, and adequate end organ function. VcR-CVAD regimen: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 CI over days 1–2, vincristine 2 mg IV day 3, dexamethasone 40 mg po days 1–4. The first 7 patients received a Vc dose of 1.5mg/m2 on days 1 and 4 but this was modified to 1.3 mg/m2 due to excessive peripheral neuropathy (PN). Cycles are repeated every 21 days for 6 cycles and all patients receive G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy. Results: Currently 15 patients are enrolled with 13 having completed the VcR-CVAD induction and two in active treatment. Patient characteristics: 11M, 4F, median age 64 (49–73), and 13/15 stage IV. Of the 13 assessable patients, one experienced PD during induction therapy and expired. The remaining 12 patients have all achieved a complete response (CR rate 92%) and are currently receiving maintenance rituximab. The major toxicities of this treatment regimen are painful PN and expected hematological toxicity. Five/seven patients at 1.5 mg/m2 and 3/6 patients at 1.3 mg/m2 experienced grade 3–4 PN. All PN eventually resolved to grade 1- 2 and resolved faster in the patients receiving 1.3 mg/m2. Conclusion: The VcR-CVAD induction has produced high overall and complete response rates (92%) in a very representative MCL patient population. A Vc dose of 1.3 mg/m2 is better tolerated than a dose of 1.5 mg/m2. However, PN remains an issue and the final cohort in this feasibility study will receive a vincristine dose of 1 mg. The encouraging response rates noted in this pilot study provide the basis for ECOG protocol 1405, which will test this regimen in a cooperative group setting.

No significant financial relationships to disclose.
Rituximab maintenance therapy (RM) for relapsed/refractory follicular lymphoma (FL): Long-term economic impact in the French setting
Authors: Brice P. , Miadi-Fargier H. , Le Pen C. , Pacull A. , Coudray-Omnes C. , Deconinck E.
Published: March 2020

8076

Background: FL in advanced stages is a life-threatening chronic disease. As recently demonstrated in the pivotal trial EORTC20981, RM significantly prolongs both progression free survival (PFS) and overall survival (OS) in relapsed/refractory FL patients responding to an induction treatment. Beyond these clinical benefits, the study objective was to assess, from the French Sickness Funds perspective, long-term costs and cost-effectiveness of RM after induction therapy versus current standard practice (observation). Methods: A lifetime transition model (30-years time horizon) with 3 health states (progression free, progressive disease and death) was developed comparing RM and observation (Obs). PFS and OS in the health states transition model were derived from the EORTC20981 trial with a median follow-up of 28 months. PFS and the OS benefits of RM therapy were conservatively assumed to last only 5 years. Standard French costs (2006 national tariffs) were applied to resources estimated from a prescription observational study, expert opinion and bibliography (in case of maintenance: acquisition and administration of RM, grade 3–4 adverse events, follow-up and in case of relapse: pre-treatment check- up, chemotherapy, radiotherapy, stem cell transplantation, adverse events, follow-up and supportive care). Costs were discounted at 3% and sensitivity analyses were performed. Results: RM is effective in the management of relapsed/resistant FL with more than one year of benefit in terms of survival. Patients receiving RM had a longer life expectancy than those with Obs (6.60 versus 5.41 years). Overall lifetime average costs were €71,314 and €62,251 respectively for RM and Obs. Incremental cost-effectiveness ratio (ICER) was €7,612 per life year gained, varying from €7,154 to €8,847 in one-way sensitivity analysis. This study did not include palliative care and productivity costs. As the relapse rate is lower in the RM group, those limitations are conservative. Conclusions: The economic assessment shows that RM is a cost-effective strategy in the management of relapsed/refractory FL in France with an ICER largely below the threshold commonly cited in such analysis.

No significant financial relationships to disclose.
Clinical significance of diffusion-weighted whole body magnetic resonance imaging with background body signal suppression (DWIBS) as a staging procedure for lymphoma patients in comparison with FDG-PET
Authors: Itoyama T. , Shibuya T. , Koga T. , Kitagawa M. , Yoshida T. , Kobayashi H. , Utsunomiya A. , Ochiai R.
Published: March 2020

8084

Background: FDG-PET is thought to be an important staging tool in lymphomas. However, high cost and exposure to radioactive agents are of disadvantage. Diffusion weighted whole body magnetic resonance imaging with background body signal suppression (DWIBS) is recently reported to be a new way of magnetic resonance imaging which can make FDG-PET-like imaging possible to detect tumors (Takahara et al; Radiation Medicine 22: 275–282, 2004). This study is aimed to compare accuracy and clinical significance of DWIBS to FDG - PET. Methods: We examined 19 lymphoma (Ly) patients (pts) by using both DWIBS and FDG -PET at the time of diagnosis before therapy. There were follicular Ly in 3 pts, nodal marginal zone Ly in 1, diffuse large B-cell Ly in 9 including primary stomach Ly in 2, peripheral T -cell Ly in 4, and MALT Ly of stomach (GI-MALT) in 2. DWIBS was performed with a 1.5 -Tesla system as previously reported (Ochiai et al; Nichidoku -Iho 50: 86–98, 2005). Clinical staging was made according to the Ann Arbor classification. Results: Both DWIBS and FDG -PET had positive findings in 18 of 19 pts except for a case of GI -MALT. In nodal lesions, DWIBS was positive in 16 pts at 66 sites compared to 16 pts at 68 sites with FDG -PET. DWIBS was negative in 3 pts at 5 sites in spleen, hilar and mediastinal lymphnodes where positive in FDG -PET. DWIBS was positive in 2 pts at 4 sites in iliac and inguinal lymphnodes that are negative in FDG -PET. In extranodal lesions, DWIBS was positive in 12 pts at 17 sites as compared to 12 pts at 18 sites with FDG -PET. Involvement of bone and stomach were equally identified at 8 sites. DWIBS was negative in 2 pts at 2 sites in liver and pleura with FDG -PET positive. Small skin lesions were clearly identified on DWIBS. Discordance of clinical staging was not observed between DWIBS and FDG -PET. Conclusions: Although some discrepancy was seen between DWIBS and FDG -PET, there was no disadvantage of DWIBS compared to FDG -PET. Furthermore, DWIBS has no risk of radiation exposure and is even advantageous to detect lesions with FDG -PET negative. We conclude DWIBS is a new useful tool to assess tumor spread in lymphomas.

No significant financial relationships to disclose.
Near absence of IL-15R-alpha T-cells in EBV-associated Hodgkin lymphoma patients
Authors: Baiocchi O. C. , Lin L. , Yang J. , Lemas M. V. , Post L. , Mueller N. , Ambinder R. F.
Published: March 2020

8087

Background: Epstein-Barr virus (EBV) (+) Hodgkin's lymphoma (HL) has been linked to acute infectious mononucleosis (AIM). EBV-associated AIM was recently reported (Sauce et al, Blood 2006, 108: 11) to be associated with a long lasting immunologic scar (near complete absence of IL-15 receptor alpha (IL-15Ra expression on T cells in peripheral blood mononuclear cells (PBMC)). We sought to confirm the scar observation and to determine whether such a scar might also be characteristic of EBV (+) HL patients. Methods: PBMCs from 5 donors with history of AIM (3 months to 4 years before), 10 EBV-seropositive donors without history of AIM, 10 EBV-seronegative donors, 22 HL patients with EBV (+) tumors and 29 HL patients with EBV (-) tumors were assayed to determine IL-15Ra expression on CD3/CD8+ cells using a FACScalibur flow cytometer. Results: IL-15Ra expression in healthy donors with history of AIM [mean: 2.9% (1.5–6.5%)] was much lower than in those without history of AIM [mean: 83% (65–98%)] (p = 0.001). Expression did not differ between healthy EBV-seropositive donors without history of AIM [mean: 82% (65–95%)] and healthy EBV-seronegative donors [mean: 89% (82–98%)] (p = 0.32). Expression was markedly different between EBV (-) HL [mean: 82% (72–99%)] and EBV (+) HL patients [mean: 3.2% (1.1–7.1%)] [p = 0.001, 95% CI(10.3–32.1)]. No difference was found when age, time blood was drawn (pre or post-treatment), disease stage and histological subtype were compared. This IL- 15Ra deficit was seen in patients before and more than one year after standard therapy. Conclusions: This study confirms the virtual absence of IL-15Ra expression in lymphocytes from patients with history of AIM. That observation is now extended to include patients with EBV (+) HL at presentation and in remission. Whether this deficit contributes to the pathogenesis of EBV (+) associated HL remains to be determined.

No significant financial relationships to disclose.
Cost-effectiveness of rituximab maintenance therapy for patients with follicular lymphoma: The Spanish perspective
Authors: Gómez Codina J. , Provencio M. , Rueda A. , Capote F. , Carbonell F. , Conde E. , Fernandez Rañada J. , Giraldo P. , Rios E. , Varela C.
Published: March 2020

8092

Background: In patients with relapsed or refractory follicular lymphoma (FL) who attain a response with either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone or Rituximab + CHOP, maintenance treatment with Rituximab has shown to significantly improve overall survival (OS) (85% at 3 years vs. 77%, p=0.011) and progression free survival (PFS) (51,5 vs. 14.9 months, p<0.001) as compared to observation alone (OA). We analyzed the cost-effectiveness, from a Spanish perspective, of Rituximab maintenance therapy (375mg/m2 every 3 months until progression or for 2 years) versus OA according to the population and data described for the European Organization for Research Treatment of Cancer (EORTC) 20981 study (van Oers MHJ Blood 2006). Methods: Incremental cost-effectiveness was assessed through a deterministic, three health states model (disease-free, progression and death) transition model. Base case model: PFS and OS were extrapolated from EORTC 20981 data using a Weibull distribution, Rituximab maintenance benefit was assumed to last 5 years, 10 years time horizon, 3.5% discount rate on costs and benefits, and Spanish National Health Service perspective (direct costs only). Resource use was estimated from a Spanish expert panel and EORTC 20981 study. Unit costs were obtained from local databases (May 2006 €). Health states utility values were derived from an ad hoc study. Sensitivity analyses were performed for all mentioned variables. Results: For the base case, more quality-adjusted life years (QALY), life-years (LY) and progression-free survival years per patient on maintenance therapy were obtained versus OA (incremental values of 0.85, 0.94 and 1.46, respectively). Total cost per patient was higher with Rituximab than with OA (+8,026€). Incremental cost per QALY gained was 9,358€, with a cost per LY gained of 8.493€ and a cost per PFS year gained of 5,485€. In the sensitivity analysis, values ranged between 7.263€ and 22.160€ per QALY gained. Conclusions: This study confirms that in patients with relapsed /refractory FL who attain a response with further therapy, maintenance treatment with Rituximab compared to observation alone is cost-effective.

No significant financial relationships to disclose.