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Clinical factors associated with early progression and grade 3-4 toxicity in patients with advanced non-small-cell lung cancers treated with nivolumab.
Dumenil, C, Massiani, MA, Dumoulin, J, Giraud, V, Labrune, S, Chinet, T, Giroux Leprieur, E
PloS one. 2018;(4):e0195945
Abstract
INTRODUCTION The prognosis of advanced non-small-cell lung cancer (NSCLC) has been improved by development of immune checkpoint inhibitors (ICIs) such as nivolumab for second-line treatment. As phase III trials include only selected patients, we here investigated the clinical factors associated with efficacy and safety of nivolumab in 'real life' patients with advanced NSCLC. METHODS Clinical and histological characteristics, therapies and survival data of all consecutive patients with advanced NSCLC included prospectively and treated by nivolumab in two French academic hospitals between February 2015 and December 2016 were examined. RESULTS Sixty-seven patients were included, mostly male (69%), current or former smokers (87%) with PS <2 (73%). Median age was 68.5 years and 42% were aged ≥70 years. According to uni- and multi-variate analyses, only PS 2 (OR = 0.17, 95% CI 0.03-0.99, p = 0.049) and number of previous treatment lines (OR = 0.33, 95% CI 0.13-0.85, p = 0.022) were significantly negatively associated with tumor control. Worse progression-free survival (PFS) was significantly associated with PS 2 (HR = 5.17, 95% CI 1.99-13.43, p = 0.001) and use of steroids (HR = 3.27, 95% CI 1.39-7.69, p = 0.006). Worse overall survival was associated with symptomatic brain metastasis (HR = 3.15, 95% CI 1.23-8.85, p = 0.029). Treatment-related adverse events occurred in 47 patients (70%), symptomatic brain metastasis being significantly associated with Grade ≥3 toxicity (OR = 8.13, 95% CI 1.21-55.56, p = 0.031). Age and nutritional status were not associated with response, PFS, OS or toxicity. CONCLUSION Our results suggest that nivolumab is not beneficial or safe for patients with PS 2 and symptomatic brain metastases.
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A randomized, controlled trial evaluating the efficacy and safety of BTH1677 in combination with bevacizumab, carboplatin, and paclitaxel in first-line treatment of advanced non-small cell lung cancer.
Engel-Riedel, W, Lowe, J, Mattson, P, Richard Trout, J, Huhn, RD, Gargano, M, Patchen, ML, Walsh, R, Trinh, MM, Dupuis, M, et al
Journal for immunotherapy of cancer. 2018;(1):16
Abstract
BACKGROUND BTH1677, a beta-glucan pathogen-associated molecular pattern molecule, drives an anti-cancer immune response in combination with oncology antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with bevacizumab/carboplatin/paclitaxel in patients with untreated advanced non-small cell lung cancer (NSCLC). METHODS Patients were randomized to the BTH1677 arm (N = 61; intravenous [IV] BTH1677, 4 mg/kg, weekly; IV bevacizumab, 15 mg/kg, once each 3-week cycle [Q3W]; IV carboplatin, 6 mg/mL/min Calvert formula area-under-the-curve, Q3W; and IV paclitaxel, 200 mg/m2, Q3W) or Control arm (N = 31; bevacizumab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4-6 cycles and patients who responded or remained stable received maintenance therapy with BTH1677/bevacizumab (BTH1677 arm) or bevacizumab (Control arm). Efficacy assessments, based on blinded central radiology review, included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, and progression-free survival. Overall survival and adverse events (AEs) were also assessed. RESULTS ORR was higher in the BTH1677 vs Control arm but the difference between groups was not statistically significant (60.4% vs 43.5%; P = .2096). All other clinical endpoints also favored the BTH1677 arm but none statistically differed between arms. PK was consistent with previous studies. Although a higher incidence of Grade 3/4 AEs occurred in the BTH1677 vs Control arm (93.2% vs 66.7%), no unexpected AEs were observed. Serious AEs and discontinuations due to AEs were lower in the BTH1677 vs Control arm. CONCLUSIONS Improvements in tumor assessments and survival were observed with BTH1677/bevacizumab/carboplatin/paclitaxel compared with control treatment in patients with advanced NSCLC. TRIAL REGISTRATION ClinicalTrials.gov registration ID: NCT00874107 . Registered 2 April 2009. First participant was enrolled on 29 September 2009.
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Vitamin E and beta-carotene supplementation and hospital-treated pneumonia incidence in male smokers.
Hemilä, H, Virtamo, J, Albanes, D, Kaprio, J
Chest. 2004;(2):557-65
Abstract
BACKGROUND Vitamin E and beta-carotene affect various measures of immune function and accordingly might influence the predisposition of humans to infections. However, only few controlled trials have tested this hypothesis. STUDY OBJECTIVE To examine whether vitamin E or beta-carotene supplementation affects the risk of pneumonia in a controlled trial. DESIGN AND SETTING The Alpha-Tocopherol Beta-Carotene Cancer Prevention (ATBC) study, a randomized, double-blind, placebo-controlled trial that examined the effects of vitamin E, 50 mg/d, and beta-carotene, 20 mg/d, on lung cancer using a 2 x 2 factorial design. The trial was conducted in the general community in southwestern Finland in 1985 to 1993; the intervention lasted for 6.1 years (median). The hypothesis being tested in the present study was formulated after the trial was closed. PARTICIPANTS ATBC study cohort of 29,133 men aged 50 to 69 years, who smoked at least five cigarettes per day, at baseline. MAIN OUTCOME MEASURE The first occurrence of hospital-treated pneumonia was retrieved from the national hospital discharge register (898 cases). RESULTS Vitamin E supplementation had no overall effect on the incidence of pneumonia (relative risk [RR], 1.00; 95% confidence interval [CI], 0.88 to 1.14) nor had beta-carotene supplementation (RR, 0.98; 95% CI, 0.85 to 1.11). Nevertheless, the age of smoking initiation was a highly significant modifying factor. Among subjects who had initiated smoking at a later age (> or =21 years; n = 7,469 with 196 pneumonia cases), vitamin E supplementation decreased the risk of pneumonia (RR, 0.65; 95% CI, 0.49 to 0.86), whereas beta-carotene supplementation increased the risk (RR, 1.42; 95% CI, 1.07 to 1.89). CONCLUSIONS Data from this large controlled trial suggest that vitamin E and beta-carotene supplementation have no overall effect on the risk of hospital-treated pneumonia in older male smokers, but our subgroup finding that vitamin E seemed to benefit subjects who initiated smoking at a later age warrants further investigation.
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Phase I study of gemcitabine given weekly as a short infusion for non-small cell lung cancer: results and possible immune system-related mechanisms.
Levitt, ML, Kassem, B, Gooding, WE, Miketic, LM, Landreneau, RJ, Ferson, PF, Keenan, R, Yousem, SA, Lindberg, CA, Trenn, MR, et al
Lung cancer (Amsterdam, Netherlands). 2004;(3):335-44
Abstract
PURPOSE To define the maximum tolerated dose (MTD) and the nature of the toxicities associated with gemcitabine given as a short infusion to patients with non-small cell lung cancer (NSCLC). Secondary objectives were to monitor immunologic response, clinical response, and survival. PATIENTS AND METHODS Thirty-two patients diagnosed with advanced inoperable NSCLC and performance status of 0 or 1 participated in this study. Patients consisted of 22 males and 10 females whose median age was 62 years (range 32-79). Gemcitabine was administered as a 30 min infusion once weekly for 3 weeks followed by 1 week of rest. Patients were enrolled at six gemcitabine dose levels ranging from 1000 to 3500 mg/m2. Patients completed a median of four cycles (range 1-17). Responses were evaluated after every two cycles. RESULTS Toxicity was evaluated in all 32 patients. The MTD was not reached as gemcitabine was well tolerated at all dose levels. Grade 4 toxicity occurred in three (9%) patients: pulmonary and lymphocytopenia in one patient each, and both neurocortical and cardiac in one patient. Grade 3 toxicity was found in a total of 20 (63%) patients: pulmonary in 10 (31%) patients; pain in 6 (19%) patients; liver toxicity in 6 (19%) patients; leukopenia and lymphocytopenia in 5 (16%) patients each; anemia, nausea, and cardiac toxicity in 3 (9%) patients each; proteinuria and infection in 2 (6%) patients each; and hemorrhage in 1 (3%) patient. Of the 29 patients evaluable for response, seven objective responses were achieved: six at the 2200 mg/m2 dose level and one at the 2800 mg/m2 dose level. The distribution of responses differed significantly by dose (P = 0.0124 by the exact chi-square test for independence). The overall response rate was 24.1% (95% CI, 10.3-43.5%). At 6 h post-infusion, there was a significant increase in spontaneous tumor necrosis factor (TNF) release and stimulated interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte counts (CD3+, CD8+, and CD16+ lymphocytes) and resting and stimulated superoxide production by formyl-methionyl-leucyl-phenylalanine (fMLP), phorbol myristate acetate, and opsonized zymosan (OPS-Z). At 24 h post-infusion, there were significant decreases in total lymphocyte count, lymphocyte subsets (CD3+, CD4-, CD8+, CD56+, CD19+), and in resting and stimulated superoxide production by fMLP and OPS-Z. There also appeared to be an association between the levels of spontaneous TNF release and the severity of both gastrointestinal (GI) and pulmonary toxicities. CONCLUSION Gemcitabine given as a short infusion was well tolerated at the dose levels of 1000-3500 mg/m2. The MTD was not reached. Toxicities appeared to be cumulative with multiple cycles. Gemcitabine appears to have activity against NSCLC. Although there was a differential dose-response rate among dose levels, increasing the gemcitabine dose beyond 2200mg/m2 did not show increased clinical response. Gemcitabine appears to modulate the immune response, which may in turn mediate both response and toxicity, although no statistically significant correlation between immune and clinical response was detected.
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[Clinical observation of music therapy combined with anti-tumor drugs in treating 116 cases of tumor patients].
Cai, GR, Li, PW, Jiao, LP
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2001;(12):891-4
Abstract
OBJECTIVE To observe the clinical effect of music therapy in treating tumor patients. METHODS Music therapy combined with anti-tumor drugs, including chemotherapy and Chinese drugs, was given to 162 tumor patients according to syndrome differentiation to observe the change of self-rating depression scale (SDS), self-rating anxiety scale (SAS), minnesota multiphasic personality inventory (MMPI), Hamilton rating scale for depression (HAMD) and T lymphocyte subsets (immuno-histochemical assay), NK cell anti-tumor activity (NAG method), etc. while 46 caces didn't receive music therapy were taken as the control group. RESULTS The scale marks of SDS and SAS of the treated group after treatment were obviously lower than that of the control group significantly (P < 0.05, P < 0.01). After treatment, the average values of MMPI on falseness (F), hypochondriasis (HS), depression (D) and psychosthenia (Pt) in the treated group were all improved (P < 0.01 or P < 0.05); but in the control group, significant difference only showed in MMPI on HS (P < 0.05). HAMD in the treated group revealed some improvement in insomnia, early awakening, daily work and interest, systemic symptoms and hypochondriasis (P < 0.05), and significant improvement in depression, difficulty in falling asleep, psychiatric anxiety and somatic anxiety (P < 0.01); while in the control group, only work interest and HS had some improvement (P < 0.05). CD8 percent was reduced in both groups after treatment (P < 0.01), but in the treated group CD3, CD4 and CD4/CD8 ratio were not significantly changed after treatment (P > 0.05); while in the control group they lowered obviously (P < 0.05). As for NK cell anti-tumor activity in the treated group before and after treatment, it was not significantly lowered (P > 0.05); while in the control group the lowering after treatment was significant (P < 0.05). CONCLUSION Music therapy could regulate the emotion of tumor patient, optimize the emotional effect, improve the somatic symptoms, enhance the immune function, motivate the active principle and raise the self-regulating power in the body.
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[Clinical study on treatment of advanced non-small cell lung cancer with Chinese herbal medicine combined with synchronous radio- and chemotherapy].
Liu, X, Wang, B, Fu, X
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2000;(6):427-9
Abstract
OBJECTIVE To explore the effect of applying Chinese herbal medicine according to Syndrome Differentiation of TCM combined with synchronous radio- and chemotherapy (combination therapy) in treating advanced non-small cell lung cancer (NSCLC). METHODS The 56 patients in the group A were treated with combination therapy, and the 44 patients in the group B treated with synchronous radio- and chemotherapy, while the 34 patients in the group C treated with non-synchronous radio- and chemotherapy. The efficacy of treatment in the three groups were observed and compared. RESULTS The immediate effective rate in the A, B, C groups was 87.5%, 84.1% and 55.9% respectively, that in the group A and B was better than that in the group C (P < 0.01). The median survival time in the three groups was 16.4, 11.8 and 10.6 months respectively. The 2-year and 3-year survival rate in the group A were markedly higher than those in the group B (P < 0.05), moreover, the clinical symptoms, Karnovsky scoring and immune function were obviously improved in the group A (P < 0.05, P < 0.01). CONCLUSION Effect of the combination therapy is superior to that of synchronous radio- and chemotherapy alone in improving immune function, elevating quality of life and prolongating survival time of patients with NSCLC.