bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical costs associated with imatinib (IM) non-compliance in chronic myeloid leukemia (CML) patients (pts)
Authors: Wu E. Q. , Feng W. , Johnson S. , Beaulieu N. , Cremieux P. , Cortes J.
Published: March 2020

17514

Background: Not adhering to treatment (tx) may lead to suboptimal outcomes. This study examined associations between medical costs and IM compliance in CML pts. Methods: CML pts under age 65 were identified with ICD-9 diagnosis code (205.1X) using MarketScan Commercial Claims data between 1/1/02–12/31/05. Pts were required to be continuously enrolled in the 4 months prior to (baseline) and the 6 months following (study period) IM initiation. CML severity was categorized into 3 groups by diagnosis of CML and related comorbidities. Compliance was defined by medication possession ratio (MPR=total days of IM supply in the study period divided by 180), and stratified into 3 groups (low: <65%, medium: 65–95%, high: 95–100%). Tx interruption was defined as tx gap of 30 or more consecutive days in the study period. Costs for inpatient (IP), ER, outpatient (OP) services and OP drugs during the study period were adjusted to 2005 dollars. Costs, the number of IP admissions and hospital days were compared across different levels of tx compliance using Wilcoxon tests. A generalized linear model (GLM) was also used to compare costs controlling for age, sex, CML severity, Charlson comorbidity index, year of IM start, etc. Results: The study sample consisted of 404 pts. Compared to the high MPR group, pts in the low MPR group incurred 1.6 times the average total health care costs (p <.001), 5.9 times the IP costs (p<.001), 2.6 times the OP costs (p=.722), 2.1 times the non-IM drug costs (p<.001), and 0.39 times the IM drug costs (p<.001). Compared to the high MPR pts, low MPR pts had on average 3.8 times the IP admissions (p<.001), and 7.3 times the IP days (p<.001). Comparing costs of pts interrupting tx versus those who did not showed similar trends. GLM regression showed that 6-month total health care costs per patient in the low MPR group were 1.4 times (p<.01) those of the high MPR group. Pts who had tx interruption had 1.3 times the total health care costs (p<.01) compared to those who did not. Conclusions: This study shows that better IM compliance was associated with significantly lower health care costs in CML pts, especially for IP costs. Further analyses will be conducted to confirm whether lower compliance leads to more hospitalizations.

No significant financial relationships to disclose.
Immunotransplantation for multiple myeloma using allogeneic peripheral blood stem cell transplantation
Authors: Santos E. S. , Shah S. , Rink J. , Weiner R. S. , Miller A. M. , Safah H.
Published: March 2020

17516

Background: Despite the improvement seen in patients with multiple myeloma (MM) treated with autologous hematopoietic cell transplantation (auto-HCT), most of the patients relapse or die of their disease. The objective of the study was to decrease toxicity of allogeneic HCT for MM patients while allowing the benefit of graft-versus-myeloma effect by using a non-myeloablative HCT (NM- HCT) approach. Methods: Newly diagnosed or previously treated myeloma patients of any stage were enrolled. All patients but one received VAD regimen prior to conditioning regimen which consisted of Fludarabine at 30 mg/m2/day on days -5, -4, -3 and Melphalan at 80 mg/m2 x 2 on days -2 and -1. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine 3 mg/kg intravenously on day -2 and methotrexate at 10 mg/m2 intravenously on days 3, 6, and 11. Results: A total of 8 MM patients (4 IgG, 1 IgA, 1 light chain restriction, 2 non-secretory MM) with a median age of 46 years old (range, 35 to 57 years) have been enrolled. Only one patient received 3 regimens prior to NM-HCT. The initial responses to therapy prior to NM-HCT were: 2 CR, 1 nCR, and 5 PR. All patients received identical 6/6 HLA sibling donor stem cells. All patients but one attained CR (88%) after NM-HCT. The median time for ANC engraftment (≥ 500/mm3) was 12.5 days (range, 10–22 days). Four patients developed acute GVHD grade I-II (3 skin, 1 gastrointestinal); all of them responded well to methylprednisolone treatment. Four patients developed chronic GVHD (grade I-II). The 100-day mortality rate was 12% (1 patient died at day + 96 without evidence of MM). Post-transplant, all patients have reported a Karnofsky’s scale performance status between 80%-100%. Two patients relapsed after 31 months post-transplantation. After a median follow-up of 46 months, median survival has not been reached. Only 1 patient who relapsed has received treatment including auto-HCT. Conclusions: NM-HCT is a feasible treatment option in MM patients with a manageable toxicity profile and acceptable treatment-related mortality. Longer follow-up is needed to evaluate for graft-vs- myeloma effect using this approach.

No significant financial relationships to disclose.
Modulation of P-glycoprotein and proinflammatory cytokines with HMG-CoA reductase inhibitor simvastatin (SV) in chronic myelogenous leukemia (CML) patients with imatinib mesylate (IM) resistance
Authors: McPherson E. , Hazel E. , Tassy P. , Kleinfeld J.
Published: March 2020

17528

Background: Primarily monocyte-derived cytokines and soluble interleukin-2 receptor (sIL-2R) form a group of proinflammatory cytokines and mononuclear cell activaton respectively which are significantly elevated in patients with CML-chronic phase (CML-CP) or CML-blastic crisis (CML-BC).C-reactive protein (CRP) correlates with IL-6. IM is a tyrosine kinase inhibitor that specifically acts intracellularly by blocking the ATP-binding site of the kinase domain of Bcr/abl in CML. Acquired drug resistance in CML-CP patients treated with IM may occur by upregulation of P-glycoprotein (P-gp) drug efflux with P-gp+ leukemic cells and P-gp dependent decline of intracellular IM levels with retained phosphorylation Bcr/abl pattern and loss of IM effect on apoptosis and cellular proliferation. Modulation of P-gp with HMG-CoA reductase inhibitor (SV), a potent inhibitor of P-gp transport, readily overcame IM resistance. Methods: We present two cases of CML: CML-CP and CML-BC with evidence of IM resistance. After one year of IM therapy an 86 yo female with CML-CP stage II, developed reactivation of Bcr/abl signaling due to excretion of IM from the cell transmembrane transporters consistent with increased proinflammatory cytokines, sIL-2R, CRP, acute coronary syndrome but normal neopterin.Results: Modulation of proinflammatory cytokines with SV, IM dose adjustments, serial measurements of Bcr-abl/abl ratio didnot exceed 0.02% on three occasions or 0.05% on two occasions after changing from 0.001% to 0.003% and now after two years of IM plus SV, real-time Bcr-abl/abl ratio is 0.000 (a 5 log reduction).sIL-2R levels normalized from 31,709.55 pg/ml to 5,345.4 pg/ml (Normal 1770–9753 pg/ml). CRP decreased to 6.23 mg/dl from 16 mg/dl. Conclusions: IM an intracellular drug demonstrating high activity against Bcr/abl gene positive CML-CP or CML-BC patients may develop resistance and loss of cellular proliferation via upregulated P-gp-mediated drug efflux mechanism. Modulation of P-gp by HMG-CoA reductase (statins) inhibitor simvastatin, a potent inhibitor of P-gp, may allow intracellular levels of IM to restore its cytotoxicity and overcome resistance mechanism.

No significant financial relationships to disclose.
Autologous transplant of hematopoietic cells: Results from cryopreservation in Sanatorio Allende from Cordoba
Authors: Salvano M. L. , Molina Barrios G. , Bonini Colmano C. , Molnar S. , Arévalo M. , Dubersarsky C. , Minoldo D. , Rizzi M. L. , Lavarda M. , Jarchum G. D.
Published: March 2020

17530

Background: Preservation of hematopoietic cells (HC) is usually achieved by storing cells in liquid nitrogen at - 1960C (Cryopreservation) (CP). We aim to: observe how many leukapheresis (LK) were necessary in order to obtain the minimal number (n°) of HC (CD34+/kg) for a proper engraftment (EG); correlate the n° of cryopreservated and infused cells with the time of EG; determine if the time of CP at -800C influences the time of EG; determine if the pre-transplant (PT) condition (partial or complete remission) plays a role in the time of EG and/or the time of hospitalization of the patients (pts). Methods: This was a retrospective study. We included all pts that received autologous transplant which HC after CP in our institution between September 2004 and August 2006. Qualitative results were analyzed by Fischer exact test and relation between qualitative and quantitative results by Mann-Whitney/Wilcoxon two- sample test (Kruskal-Wallis test for two groups). Results: 27 pts were included (N=27); the average age was 48.3± 16.6 years with a range of 64 (4–68) years. Diagnosis included: Multiple Myeloma 40%, NHL 22%, Hodgkin disease 15%, AML 15%, Amyloidosis 4%, and Ependymoma 4%. In 66.7% of the pts only one round of LK was needed for recollection. The CP time at -800C had a range of 113 (8–122) days. The median time for EG was 11 days for neutrophils (nt) and 17 days for platelets (pl). There was not significant correlation between PT condition and: n° of nt before or after day 11 (p=0.515); n° of pl before or after day 17 (p=0.972); hospitalization time (p=0.55); time for EG of nt (p-0.553) and pl (p=0.936). There was a significant difference between receiving =5x106 CD34+/Kg and pl EG time before day 17 (p=0.01) but not for nt EG time (p=3.83). CP time had no significant difference in relation to the pl EG before or after day 17 (p=0.08) or nt EG before or after day 11 (p=0.49). Conclusions: The majority of pts had a proper CD34+/Kg count with one LK round. Doses =5x106 CD34+/Kg were associated with less time for pl EG. The storage of HC at -800C showed to be safe for periods between one week and 4 months. The time of storage at -800C did not seem to affect the time of EG but showed a trend towards slowing pl recovery. The PT condition did not correlate with the time for EG or the hospitalization time.

No significant financial relationships to disclose.
The expression and prognostic value of ZAP-70 and CD38 in chronic lymphocytic leukemia in a Chinese population
Authors: Wu Y. , Li J. , Zhang S.
Published: March 2020

17538

Background: Advances in the biology of CLL have led to the identification of new prognostic markers,which may improve the accuracy of classic parameters in predicting the clinical course.For this purpose,we evaluated the prognostic value of 70-kD zata-associated protein (ZAP-70) and CD38 in B-chronic lymphocytic leukaemia(B-CLL) combined with clinical state, β2-MG and LDH. Methods: Mult-parameter flow cytometry were used to detect the expression of ZAP-70 and CD38 in 71 B-CLL patients. Results: ZAP-70 and CD38 were concordantly expressed in 70.4% of B-CLL. (P<0.05) There was significant difference between ZAP-70+ and β2-MG(P<0.05).But no significant difference between ZAP-70 and LDH(P>0.05).In a subgroup of 15 consecutive patients analysis of CD38 and ZAP-70 expression were repeated in 2 years follow-up.The expression of CD38 was changed in 7 patients and ZAP-70 was not changed over time. Conclusions: Early prognostic parameters defected disease specificity. Using FCM to detect the expression of ZAP-70 and CD38 could be performed in clinical laboratory. The expression of ZAP-70 could be a novel prognostic indicators in B-CLL because it was not changed in whole course of disease. CD38 expression was an independent prognostic indicator and it could predict time to disease progression, as judged by treatment requirement.

No significant financial relationships to disclose.
A phase II trial of motexafin gadolinium (MGd) in advanced non-small cell lung cancer (NSCLC) patients who had failed platinum-based chemotherapy: Preliminary results of stage 1
Authors: Nicholas G. , Natale R. B. , Greco F. , Govindan R. , Chabot P. , Pandya K. , Eubank L. , Renschler M. F.
Published: March 2020

18001

Background: Motexafin gadolinium (MGd) is a tumor-selective antineoplastic agent that disrupts redox dependent pathways by targeting oxidative stress-related proteins such as thioredoxin reductase (TRX). TRX often is overexpressed in NSCLC and is associated with a poor prognosis. Inhibition of TRX reverses tumor phenotype in lung carcinoma cells in vitro and in vivo. This randomized 2-stage phase II trial investigated tumor response and survival with 2 regimens of single agent MGd for the 2nd line treatment of advanced NSCLC. Methods: Patients with locally advanced or metastatic NSCLC ± brain metastases, ECOG PS 0–1, who had received one prior platinum-based chemotherapy regimen ± kinase inhibitor were randomized to intravenous MGd (10 mg/kg/week - Group A) or MGd (15 mg/kg/q 3 weeks - Group B) given in 21 day cycles. The sample size was 30 per arm in stage 1, and 24 per arm in stage 2. Response was evaluated by RECIST every 6 weeks. Results: 51 evaluable patients, median age of 62 years (range 41–85), with locally advanced (14%) or metastatic (86%) adenocarcinoma (47%), squamous cell carcinoma (14%), large cell carcinoma (10%), bronchoalveolar carcinoma (2%) or other NSCLC (27%) were randomized to group A (N=22) or group B (N=29). 37% had not responded to first line chemotherapy. MGd treatment was well tolerated, with 1–12 cycles (median 2, mean 3) administered. The most common grade 3+ adverse events were hypophosphatemia (15.7%), fatigue (13.7%), dyspnea (9.8%), hypoxia (7.8%), and finger blisters (5.9%). 48 patients were evaluable for response, with a confirmed response rate of 4.2% (2 PR). Median time to progression was 7 weeks in each group, with 26% and 15% free from progression at 4 and 6 months, respectively. Median survival of 51 evaluable patients was 10.2 months (95% CI: 6.7 months - not reached), 9.2 months for group A and not reached at > 1 year for group B. Conclusions: MGd appears active as a single agent for second line treatment of NSCLC patients with advanced or metastatic NSCLC who have failed prior platinum-based chemotherapy, with a modest response rate and promising survival. The trial has met the criteria for continuation into stage 2 for each treatment group.

No significant financial relationships to disclose.
Phase II trial of carboplatin plus cetuximab for the treatment of stage IIIB/IV non-small cell lung cancer (NSCLC)
Authors: Bradford D. S. , Socinski M. A. , LaRocca R. V. , Hensing T. A. , Bordoni R. E.
Published: March 2020

18005

Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. At the time of study design, triplet therapy had not demonstrated activity greater than doublets. This ongoing phase II open-label trial evaluates the doublet of cetuximab in combination with carboplatin (Cb) in patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts receive cetuximab 400 mg/m2 IV on day 1. Starting on day 8, pts receive cetuximab 250 mg/m2 IV weekly plus Cb AUC=6 IV q3w for 4 cycles (12 weeks). Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objective is to evaluate the response rate. Secondary objectives are to determine median progression-free survival (PFS) at 6 months and median overall survival (OS) at 1 year. Results: The study has completed accrual, enrolling and treating 57 pts, all evaluable for response. None had received prior adjuvant chemotherapy for NSCLC. All pts received cetuximab; 49 received Cb. Of the 57 pts, 55 have discontinued: 30 (52.6%) for disease progression or relapse. Drug-related adverse events occurred in 53 pts (93%). Conclusions: These preliminary data of cetuximab in combination with Cb demonstrated modest response rates with an acceptable toxicity profile in pts with advanced NSCLC. Final PFS and OS data are pending.

[Table: see text]

No significant financial relationships to disclose.
Safety of erlotinib in TRUST, a phase IV trial in patients with advanced non-small cell lung cancer (NSCLC): Initial results from the East/South East (E/SE) Asian subgroup
Authors: Wu Y. , Zhang L. , Siu-Kie Au J. , Cheng A. , Park K. , Kim H. , Srimuninnimit V. , Sriuranpong V. , Lin M. , Kuo H.
Published: March 2020

18018

Background: Erlotinib significantly improved survival versus placebo and was well tolerated in patients (pts) with previously treated advanced NSCLC in the phase III BR.21 study (Shepherd et al. N Engl J Med 2005;353;123–32). TRUST, an open-label, multicenter study was initiated to provide erlotinib access to pts with advanced NSCLC. Here we report data for E/SE Asian pts. Methods: Eligible pts had failed 1–2 prior standard chemotherapy (CT) regimens, or were unsuitable for CT. Erlotinib 150 mg/day p.o. was given until disease progression/unacceptable toxicity. NCI CTC v3.0 was used to grade toxicities. Results: At data cut-off of 20/11/06, 885 pts were included in the analysis: n= Taiwan 297, mainland China 248, Hong Kong 160, South Korea 146, Thailand 30, Indonesia 2, Malaysia 2. Median age was 61yrs (range 22–95). Pt characteristics (%): male/female 55/45, ECOG PS 0/1/2/3 15/67/14/4, stage IIIb/IV 20/79, adenocarcinoma/other 68/32, erlotinib as 1st/2nd/3rd/other line therapy 11/55/33/<1, never/ever smoker 52/47 (no data <1). 83% pts experienced rash, of which 9% was grade (gr)3/4. Safety data forms were available for 598 pts; 54% had at least one adverse event (AE).104 pts (17%) had a treatment (tx)-related unexpected adverse event (AE) but no single AE occurred in >3% pts and only 3% were ≥gr3. Serious tx-related AEs were experienced by 19 pts (3%); 17 were gr3/4, most commonly gastrointestinal (n=6). One pt had suspected tx-related interstitial lung disease (gr2); the patient continued tx. 18 pts (3%) withdrew due to a tx-related event; 11 were gr3/4, most commonly gastrointestinal (n=4) and respiratory (idiopathic pulmonary fibrosis n=1, pneumonitis n=2). 76 pts (13%) required dose reduction due to a tx-related event (13%), mainly due to rash (n=57). 83% pts received erlotinib for >4 weeks. Efficacy will be presented. Conclusions: The results reported here for E/SE Asian pts in the TRUST study confirm in a community setting the good tolerability observed with erlotinib in clinical trials. Importantly, erlotinib was generally well tolerated and so could be administered at full tx dose to most pts.

[Table: see text]
Prognostic factors for response and survival of second-line chemotherapy in patients with relapsed small cell lung cancer (SCLC)
Authors: Kim Y. , Goto K. , Yoh K. , Niho S. , Ohmatsu H. , Kubota K. , Saijo N. , Nishiwaki Y.
Published: March 2020

18023

Background: Despite high response rates to initial chemotherapy, the majority of patients with SCLC experience tumor progression. Previous studies showed that both the response to initial chemotherapy and the response duration are important for predicting the efficacy of second-line chemotherapy. Therefore, relapsed SCLC is commonly classified into two groups: sensitive relapse (respond to initial chemotherapy and relapse more than 3 months after the completion of initial chemotherapy) and refractory relapse (not respond to initial chemotherapy or respond but relapse within 3 months). However, prognostic factors of the second-line chemotherapy have not been fully understood. Methods: From July 1992 to December 2003, four hundred and seventy-four patients with SCLC received chemotherapy as initial treatment, subsequently 229 patients received second-line chemotherapy (144 sensitive relapse and 85 refractory relapse) in our hospital. We analyzed the association of patients’ clinical factors with response and survival of second-line chemotherapy in sensitive relapsed patients and refractory relapsed patients, separately. For sensitive relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (CR/PR), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). For refractory relapsed patients, analyzed clinical factors were as follows: age (<70/=70), gender (M/F), response to initial chemotherapy (responder/non-responder), PS at relapse (<2/=2) and the extent of disease at relapse (LD/ED). Results: Response to second-line chemotherapy was significantly correlated with PS in sensitive relapsed patients, however, no significant factor was detected in refractory relapsed patients. For survival, PS was the only significant prognostic factor in both sensitive and refractory relapsed patients. The median survival time was 328 days (PS<2) and 128 days (PS=2) in sensitive relapsed patients (p<0.0001), while 195 days (PS<2) and 113 days (PS=2) in refractory relapsed patients (p=0.0001), respectively. Conclusions: PS was the only significant prognostic factor for survival both in sensitive and refractory relapsed SCLC.

No significant financial relationships to disclose.
Beneficial effects of elective brain irradiation (BI) in limited disease inoperable non-small cell lung cancer patients treated with combined chemo-radiotherapy (CCRT)
Authors: Umsawasdi T.
Published: March 2020

18033

Background: BI significantly decrease brain metastases (BM) and prolonged CNS relapse free (CRF) duration (J Neurooncol 2: 253, 1984). Studies of 5 CCRT protocols using chest irradiation with randomization to BI after 2–3 courses of chemotherapy showed that patients who had complete response (CR), partial response (PR), minor response (MR), or no change (NC) of the diseases with CCRT benefited from BI with significantly reduced BM, prolonged response (R) duration and time to progression (TTP). (Proc. ASCO 5: Abstract 728, 1986). The value of BI remains unclear. Methods: Re-evaluation of previously mentioned 5 CCRT protocols was done to determine the effects on S, duration of R, TTP, and CRF with evaluations at 75th percentiles. Results: Of 138 patients (59 BI+), there was no significant difference between BI+ and BI- in terms of characteristics and response to CCRT. The effects of BI on S, duration of R, TTP, and CRF are as above. Conclusions: 1) BI significantly improved the duration of R,TTP, and CRF; 2) Although no S benefit was found in standard evaluation, BI patients had 37 weeks S advantage at 75th percentiles; 3) Patients who had CR, PR, or MR had benefited from BI and the benefits were more when evaluated at 75th percentiles; 4) The standard study of duration curves should be modified to look at a higher percentiles if the proposed treatment had low responses; 5) Awaiting for the results of RTOG 0214, our information could possibly favor BI in these patients.

[Table: see text]

No significant financial relationships to disclose.
Serum cathepsin B (CB) levels are prognostic in chemotherapy-naive patients (pts) with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2
Authors: Singer J. W. , Oldham F. B. , Bandstra B. , Sandalic L. , Bianco J. , Bonomi P. , Ross H.
Published: March 2020

18036

Background: CB is an estrogen-influenced lysosomal cysteine protease produced by tumor cells and tumor-associated macrophages; tumor tissue CB protein levels and proteolytic activity are prognostic in NSCLC (Anticancer Res. 2004; 24:4147–61). The prognostic value of serum CB has not previously been evaluated in NSCLC. Here we evaluate the impact of pretreatment CB levels on survival in pts from 2 phase III trials in advanced NSCLC, STELLAR 3 and 4. These trials compared paclitaxel poliglumex (PPX) against commonly used regimens. As the intratumoral metabolic pathway of PPX is characterized by the CB-mediated release of paclitaxel (P) from a polymeric backbone (Ca Chemother Pharm. 2006. Epub ahead of print), correlation of CB levels with PPX efficacy was assessed as well. Methods: Pretreatment serum samples from 450 chemo-naive pts with advanced NSCLC and PS 2 enrolled in STELLAR 3 (P + carboplatin (C) v. PPX + C) (N=315) and STELLAR 4 (vinorelbine or gemcitabine v. PPX) (N=135) were assayed for CB by ELISA (ICON Labs). Values were assessed by quartiles and there was a clear breakpoint at the median. Pts were categorized as high or low CB based on values above or below the median (64 ng/ml). The effect of CB levels on survival was evaluated by log rank for pooled pts from the studies. Results: As detailed in the table , median survival for non-PPX-treated pts was worse if CB was high; in contrast, median survival for PPX-treated pts did not differ by CB level. Pts with high CB receiving PPX showed a trend towards better survival compared to those receiving control regimens. Conclusions: The data suggest that serum CB may be prognostic biomarker for NSCLC. Retrospective analysis suggests a trend towards improved survival in patients with high CB receiving PPX; prospective studies are required to confirm this observation.

[Table: see text]

No significant financial relationships to disclose.
Phase II study of weekly docetaxel and gemcitabine in relapsed patients (pts) with advanced, platinum-exposed non-small cell lung cancer (NSCLC)
Authors: Langer C. J. , Huang C. , Ruth K. , Shafer D. , Borghaei H. , Millenson M. , Mintzer D. , Staddon A. , Seldomridge J. , Tuttle H. , Treat J.
Published: March 2020

18039

Background: Docetaxel (D) has, clear-cut therapeutic superiority compared to best supportive care, or ifosfamide/vinorelbine in relapsed NSCLC and, as a result, is the standard of comparison in the second line setting. In the pre-pemetrexed era, gemcitabine (G) in phase II studies also demonstrated activity in the salvage setting with favorable survival rates. We therefore mounted a phase II trial pairing these two agents in pts with progressive disease (PD) after prior platinum-based therapy. Methods: Pts with advanced NSCLC and ECOG PS 0–1 progressing either during or after prior platin-based therapy received D 40 mg/m2 days 1 and 8, in combination with G 800 mg/m2 days 1 and 8 every 3 wks. In the absence of dose limiting myelosuppression or other gr=3 toxicities, the dose of G was escalated on an intra-patient basis to 1 g/m2 days 1 and 8. Pts continued treatment until disease progression or unacceptable toxicity. Results: 35 pts were enrolled: 20 pts (57%) were male; 69% were ECOG PS 1; 57% had received prior XRT. Median age was 61 (range 30–79); median time from initial diagnosis to enrollment was 12.4 months. 170 cycles total were administered (median 4, range 1–16). Overall response rate was 23% (95% CI 12–39%). Median event free survival (EFS) was 5.7 months; median overall survival 12.5 mos; with 1 year survival rate of 51%, and 2 year survival rate 20%. Those enrolled within 12 months of initial diagnosis had poorer EFS compared to those beyond 12 months (log rank p=0.04). There were no treatment-related deaths. Typical grade = 3 toxicities included neutropenia (43%), neutropenic fever (9%) diarrhea (6%), pneumonitis (9%), LFT elevations (9%) and dermatitis (9%), including nail changes. Conclusions: Combination docetaxel and gemcitabine administered days 1 and 8 every 3 weeks in good performance NSCLC pts with PD after/during platinum-based therapy appears encouraging, and presents a viable option in this population. Proof of benefit vs. docetaxel alone requires phase III testing.

No significant financial relationships to disclose.
Quality-of-life (QOL) evaluation for advanced non-small cell lung cancer (NSCLC): Comparison between vinorelbine and gemcitabine followed by docetaxel (VGD), and paclitaxel and carboplatin (PC) regimen on protocol JMTO LC00–03 (BRI LC03- 01)
Authors: Tada H. , Tokoro A. , Ishiwata R. , Teramukai S. , Fukushima M. , Kubota K. , Kawahara M. , Furuse K.
Published: March 2020

18043

Background: JMTO LC00–03, a randomized trial of VGD versus PC in patients with advanced NSCLC, showed differences between the two treatment groups in response rate (25 vs 37.1%) and regimens’ specific toxicities including taxane-related toxicities such as numbness (0 vs 16.2%) and neuropathy (0.5 vs 9.6%), but not in overall survival (MST, 13.6 vs 14.1 mos) and progression-free survival (MST, 5.5 vs 5.8 mos). (Kawahara et al, # 7013, ASCO, 2006). Methods: Patients with advanced NSCLC were randomly assigned to VGD or PC. The patients were assessed with Functional Assessment of Cancer Therapy- FACT-L and FACT-Taxane score in baseline, and at 6-, 12-, 18-weeks after the treatment. The longitudinal analysis was used to compare mean changes of the QOL score over the two treatment groups. Results: Sixty-eight patients from the trial (VGD: 34, PC: 34) who submitted both baseline questionnaire and at least one questionnaire over the course of the treatment were subjects of the study. The table presents the estimated changes in mean scores in treatment arms over the time period. The longitudinal analysis showed significant difference in FACT-Taxane (p<0.001) in the treatment over time, but no significant difference in the FACT-L score (p=0.261). The analysis assuming non-random missing mechanism resulted in slightly larger differences in the mean change. Conclusions: There was no statistically significant difference in FACT-L between the two groups, but VGD group was numerically better than PC group at any point from baseline. The significant difference in FACT-Taxane score favoring VGD would be due to the difference in frequency of neuropathy with docetaxel than with paclitaxel.

[Table: see text] [Table: see text]
Smoking and prognostic factors in advanced non-small cell lung cancer (NSCLC)
Authors: Altug S. , Li C. , Marek M. , Guclu S. , Kim Y. , Meshref M. , Qin S. , Krejcy K. , Reece W.
Published: March 2020

18048

Background: The aim of this prospective, multi-country, observational study (B9E-AA-B004) is to estimate the effect of prognostic factors, including continued smoking during therapy, on treatment outcomes in patients (pts) with advanced NSCLC receiving first- line chemotherapy with a gemcitabine (gem)-platinum combination as part of their routine care. Methods: Major eligibility criteria included: tissue diagnosis of advanced stage IIIB/IV NSCLC not amenable to curative surgery/radiotherapy; no prior chemotherapy; ECOG performance status (PS) 0 or 1; and written informed consent. A predictive model was constructed and validated by splitting the data at random by centre into two datasets in a ratio of 3:1 Construction:Validation. The primary and secondary endpoints are the effect of prognostic factors on survival and selected adverse events (AEs), respectively. The association of smoking with outcomes was tested in the Construction dataset. Results: This interim analysis to assess the effect of prognostic factors on AEs occurred when all pts had completed treatment. 1214 pts were enrolled: 75.1% male; mean age 60.5 yr, range 23–86 yr; 57.1% Stage IV; 66.2% PS 1; 69.4% received gem-cis, 30.5% gem-carb; 25.7% had never smoked, 70.8% had ever smoked and 11.2% continued smoking during therapy. 22.0% of pts had =1 AE. After variable selection in the Construction database (891 pts) the following factors were associated with an AE possibly related to therapy: disease stage (IV vs III, odds ratio (OR) =1.48, p=0.034), weight loss >10% (OR=0.60, p=0.017), age (<70 vs =70, OR=0.66, p=0.046), treatment (gem- carb vs gem-cis, OR=1.5, p=0.04), pain at baseline (present vs absent, OR=1.5, p=0.03), country (OR vs Taiwan ranged from 0.32 (Israel) to 4.2 (Egypt), p<0.0001). Sex (F vs M, OR=0.86) was then added to the model because of its clinical importance. There was a trend towards a higher probability of an AE with continued smoking during therapy (OR=1.4), but this was not statistically significant (p=0.28). Conclusions: This model can be used to improve the prediction of whether patients are likely to experience treatment-related AEs. While the trend was for a greater AE rate in pts who continued to smoke during therapy, this was not proven.

[Table: see text]
A phase II study of weekly docetaxel/cisplatin and concurrent radiotherapy followed by surgery in patients with stage III non-small cell lung cancer (NSCLC)
Authors: Maas K. W. , Phernambucq E. C. , Sharouni S. Y. , Stigt J. A. , Groen H. J. , van den Borne B. E. , Senan S. , Smit E. F. , Paul R. A. , Schramel F. M.
Published: March 2020

18050

Background: Concurrent chemoradiotherapy treatment is standard of care for patients with stage III NSCLC in good performance. Optimal chemotherapy have yet to be defined and the role of surgery is still unclear. This prospective phase II study analysed the feasibility and efficacy of weekly docetaxel/cisplatin (DC) and concurrent involved-field thoracic radiotherapy (CRT) followed by surgery in good performance status patients with stage IIIA/B NSCLC. Primary endpoint is radiological response of DC and CRT. Secondary endpoints included toxicity, efficacy of surgery, postoperative morbidity and mortality, time to progression and overall survival. Methods: DC consisted of IV docetaxel 20 mg/m2 and cisplatin 20mg/m2 at days 1,8,15,22,29 and 36. CRT was given in once-daily fractions of 1.8 Gy, 5 fractions a week to a total dose of 45 Gy during days 8 to 36. CT-based planning was used to minimise radiation to the contralateral lung. Invasive and non-invasive investigations were performed after induction treatment in order to restage the mediastinum. when mediastinal downstaging was achieved, surgery was performed in order to achieve radical resection. Results: Between January 2005 until August 2006, 45 patients were included, of whom 43 patients were evaluable. Stage IIIB disease was present in 18 patients (cT4N2=9, cT4N0/N1=5 and cN3=4) and 25 had stage IIIA-N2 disease. Radiologic response was seen in 20 patients (47%) and 8 (19%) showed progressive disease. Toxicity was mild. Explorative thoracotomy was performed in 24 (56%) patients. Of these, 14 were initially staged as IIIA and ten as stage IIIB (4 of whom had N3 metastases). Twenty patients (47%) underwent a radical resection without residual mediastinal malignant disease, and ten pneumonectomies (8 left sided) were performed. Three patients showed complete pathological response. The 30 days mortality after operation was 4% (one patient) due to ARDS. Conclusions: Weekly DC and CRT is possible in stage III NSCLC, with limited toxicity and nearly half of the treated patients (47%) could undergo a radical surgical resection (R0) without residual mediastinal malignant disease. This promising tri-modality regimen should be tested in future phase II or III trials.

No significant financial relationships to disclose.
Phase I trial of extrapleural pneumonectomy [EPP], and intracavitary intraoperative hyperthermic [IOHC] cisplatin with amifostine cytoprotection for malignant pleural mesothelioma. [MPM]
Authors: Zellos L. , Richards W. G. , Capalbo L. , Jaklitsch M. , Bueno R. , Johnson B. , Sugarbaker D. J.
Published: March 2020

18059

Background: Despite aggressive multimodality treatment, MPM remains a disease with poor survival. Innovative strategies that improve cytoreduction are needed. We sought to determine the maximum tolerated dose (MTD) and quantify the toxicity of cisplatin IOHC with amifostine cytoprotection in the setting of EPP for MPM. Methods: 42 MPM patients (pts) were enrolled in an IRB approved protocol. Those who underwent EPP with cytoreduction to < 1 cm3 received 910 mg/m2 of amifostine followed by 1-hour perfusion of the chest and abdomen with cisplatin dose escalation (75–200 mg/m2). Pts were monitored prospectively. Results: 13 pts were unresectable (9 with chest wall invasion, 3 with chest wall and mediastinal invasion and 1 with cardiac invasion). The 29 resected pts had median age 57 years; median stay 15 days, and mortality rate 6.8% (2/29 pts.). Complications were: atrial fibrillation 65.5% (19 pts.), deep vein thrombosis 31% (9 pts.), and grade 3 renal toxicity 31% (9 pts.). Renal toxicity was unrelated to cisplatin dose and no MTD was determined. Median follow-up was 17 months. Median survival (MS) for 42 enrolled pts was 17 months. The 13 unresected pts experienced a 10-month MS. The 29 resected pts had a 20-month MS while 24 epithelial pts experienced a 29-month MS and 5 non-epithelial pts 13 month MS (p=0.006). The 15 pts receiving higher cisplatin doses (175–200 mg/m2) had a 26-month MS while the 14 pts receiving lower doses (75–150 mg/m2) had 16-month median survival. (p=NS) The 10 pts with negative margins has a MS of 25.8 months while 19 pts with positive margins had a 13.4 month MS (p=NS). MS for 20 pts with N2 (-) nodes was 30 months and for 9 pts with N2 (+) 13 months (p= 0.0115). MS for 18 pts with BWH/DFCI stage 1–2 was 32 months and for the 11 stage 3 pts 14 months (p=0.0022). Conclusions: 1) IOHC was technically feasible with acceptable morbidity and mortality 2) Single dose amifostine was inadequate against cisplatin renal toxicity and MTD was not determined. 3) Stage 1–2, epithelial type or N2 (-) pts demonstrated survival greater that expected historic controls.

No significant financial relationships to disclose.
Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer (NSCLC)
Authors: Yoshino I. , Takenaka T. , Koso H. , Ohba T. , Yohena T. , Osoegawa A. , Shoji F. , Maehara Y.
Published: March 2020

18085

Background: DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti-cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair proteins and chemosensitivity in patients with NSCLC. Rad51 and ERCC1 play important roles in repair of double and single strand breaks of DNA, respectively, and may protect cells from cytotoxic effect of platinum agents. Methods: NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to an immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. Results: A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both two enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA), but not when either or neither of them was positive. Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5-FU, or irinotecan. Conclusions: Combined expression of Rad51 and ERCC1 is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum-based chemotherapies.

No significant financial relationships to disclose.
A population-based study of incidence, diagnostic approaches and therapy of thymic epithelial tumors
Authors: Schaapveld M. , De Jong W. K. , Timens W. , Klinkenberg T. J. , Blaauwgeers J. L. , Groen H. J.
Published: March 2020

18086

Background: Diagnostic and therapeutic approaches to thymic epithelial tumors are not standardized. Also, opinions differ on the biological behavior of thymomas. The purpose of this population-based study was to assess the incidence of the whole spectrum of thymomas and thymic carcinomas and to assess the diagnostic approaches, therapy, and survival of these tumors. Methods: The Dutch National Pathological Archives (PALGA) were used to evaluate the incidence of thymomas and other thymus neoplasms between 1994- 2003. Clinical and pathological characteristics were obtained from PALGA and the Netherlands Cancer Registry. Results: We identified 537 thymic epithelial tumors, male/female 262/275, median age 59 years (range 1–94). WHO classification was type A 12%, AB 21%, B1 16%, B2 18%, B3 12%, C 11%, unknown 10%. Clinical disease stage according to Masaoka was I in 26%, II 23%, III 13%, IV 12%, unknown 26%. Incidence of all thymic epithelial tumors in the Netherlands is 3.2/1,000,000 and of thymomas (WHO classes A-B2) is 2.2/1,000,000. Primary resection as first procedure for obtaining a diagnosis was performed in 56% of patients, and was associated with smaller tumors (p<0.001), younger age (p=0.006), and the presence of myasthenia gravis (p<0.001). Survival data were available for 232 patients. Five- year overall observed survival was 69%. Not only thymic carcinomas but also thymomas showed tumor-related mortality. The majority of patients (78%) was treated with resection, and had a better survival than non-operated patients (median survival more than 10 years versus 1.1 years, p<0.001). Among the surgically treated patients (n=180), the completeness of resection was not prognostic (p=0.17). Conclusions: Thymic epithelial tumors are rare and the majority shows tumor-related mortality. Primary resection is the most frequently used procedure to obtain a definite diagnosis and is also advisable in cases with questionable resectability.

No significant financial relationships to disclose.
The efficacy of second line chemotherapy (CHT) in platinum-sensitive advanced/metastatic small cell lung cancer (SCLC) patients: Results of an ongoing Italian multicenter survey
Authors: Martelli O. , Cinquini M. , Mancuso A. , Borgonovo K. , Petrelli F. , Sergi C. , Paleari D. , Fatigoni S. , Sdrobolini A. , Aglione S.
Published: March 2020

18090

Background: Despite CHT and radiotherapy for SCLC, most patients (pts) die within 2 years. Response rates for second-line CHT are low, with a median survival of 5 months in platinum-refractory pts. Re-challenge with platinum salts or salvage regimens is a standard option for pts with platinum-sensitive disease with a median overall survival (OS) of 6.5–8 months (Chua et al., Cancer Treat Rev. 2004). The purpose of this study was to explore the benefits of different second line regimens in this platiunum sensitive population. Methods: Clinical records of 73 platinum sensitive SCLC pts (first line relapse free survival > 6 months) were reviewed from 13 medical oncology departments in Italy from January 1993 to December 2006. Pt. characteristics: 59 males, 14 females, median age 64 years (range 27–93), median ECOG performance status (PS): 1, limited/extended disease: 33/40 pts. Pts received salvage chemotherapy which consisted of monotherapy in 37% and platinum-containing doublets in 55%. Doublets without platinum salts were administered in the remaining 8%. Results: Of 67 evaluable pt, second line CHT produced partial responses (PR) in 58 (79%) and stable disease (SD) in 9 pts (12%) by RECIST criteria. Overall tumor growth control (PR+SD) was 91%. Despite these encouraging results, the median TTP was 3 months and OS for all evaluable pts was 6.5 months. Survival at 1 year was 11%. Multivariate analysis revealed that the most important prognostic factor for response was age ( p<0.04) and there was no statistically significant difference between platinum-based regimens and monotherapy. Multivariate analysis showed no impact on survival by prior response to first line treatment, female sex or smoking status. Conclusions: Within the limits of a retrospective study, despite the high rate of responses obtainable in this setting, TTP and OS do not appear significantly improved by salvage regimens. Second line CHT has marginal activity and should be considered only in younger pts with a good PS. On the basis of these results, re-treatment with platinum salts could be avoided in these pts.

No significant financial relationships to disclose.
A phase II trial of combination chemotherapy with irinotecan and amrubicin in pretreated patients with non-small cell lung cancer
Authors: Segawa Y. , Nogami N. , Shinkai T. , Kiura K. , Tabata M. , Takigawa N. , Hotta K. , Shibayama T. , Ueoka H. , Tanimoto M.
Published: March 2020

18111

Background: Amrubicin, a totally synthetic anthracycline, is a topoisomerase II inhibitor and highly effective for non-small cell lung cancer (NSCLC) as a single agent with response rates of 25% to 28%. We previously conducted a phase I trial of combination chemotherapy with irinotecan and amrubicin for NSCLC and found acceptable toxicity profiles with a favorable efficacy in patients with pretreated NSCLC. The aim of this phase II trial was to further evaluate its efficacy and toxicity in this population. Methods: Primary endpoint was objective response. Patients with NSCLC previously treated with one or two chemotherapy regimens were enrolled in this trial. Irinotecan and amrubicin were both administered on days 1 and 8, every 3 weeks at doses of 100 and 40 mg/m2, respectively. Response and toxicity were assessed according to the RECIST guideline and NCI Common Terminology Criteria for Adverse Events v3.0. Results: Thirty-one pretreated NSCLC patients were enrolled between 2004 and 2006. A median number of courses administered was 3 (range: 1 to 6). All patients and courses were assessable for efficacy and safety. Demographics of the patients were as follows: M/F: 21/10, Ad/others: 21/10, ECOG-PS 0/1: 12/19, and smoker/non-smoker: 21/10. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in 9 of the 31 patients with a response rate of 29.0% (95%CI: 12.1–46.0%). Grade 4 leukopenia and neutropenia were observed in 6 (19%) and 14 (45%) patients, respectively, whereas thrombocytopenia were generally mild. Grade 3 febrile neutropenia was observed in 7 patients (23%), of whom two patients further developed Grade 4 and 5 septic shock each. Other grade 3 or greater non-hematological toxicities included diarrhea, vomiting, pneumonitis, liver dysfunction in 4, 1, 1 and 2 patients, respectively. At the time of this analysis with a median follow-up time in the surviving patients of 7.5 months, median survival time and median progression-free survival time were 11.9 and 4.0 months, respectively. Conclusion: This combination seemed highly effective for pretreated NSCLC despite the moderate toxicity profiles. Development of efficient patient selection is needed to avoid the serious toxicities.

No significant financial relationships to disclose.