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Challenges associated with systemic therapy for older patients with inoperable non-small cell lung cancer.
O'Leary, C, McSorley, L, Hennessy, B, Grogan, L, Breathnach, O, Morris, P
Expert opinion on pharmacotherapy. 2020;(17):2185-2194
Abstract
INTRODUCTION Lung cancer is the most common cancer diagnosed worldwide. Data from several studies fall short to make appropriate conclusions on the management for elderly patients. The discovery of targeted therapy and immunotherapy has allowed these patients access to a wider array of options. AREAS COVERED The authors review research for treating older patients with lung cancer focusing on research performed in this patient population. Data are presented relating to chemotherapy, immunotherapy, and targeted therapy in the advanced setting. EXPERT OPINION Elderly patients particularly benefit from advances in systemic therapy. Based on the tumor profile, treatment with targeted therapy or immunotherapy should be favored over chemotherapy where possible in the elderly population. Elderly patients benefit from EGFR, ALK, and ROS-1 inhibition in the setting of these tumor alterations. These agents should be utilized early in the treatment course. Across many studies, the benefit from immunotherapy is seen irrespective of age. Favorable outcomes and toxicity profiles from immunotherapy compared to chemotherapy are well described. Chemotherapy should be offered with caution after a detailed assessment. Options include combination or single-agent chemotherapy regimens. Best supportive care alone is a reasonable option in the frailer, highly co-morbid patient.
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Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis.
Hsu, CY, Chen, CY, Lin, YM, Tam, KW
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2020;(1):6-17
Abstract
AIM: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. METHOD The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. RESULTS Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. CONCLUSION Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.
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Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial.
Tolaney, SM, Barroso-Sousa, R, Keenan, T, Li, T, Trippa, L, Vaz-Luis, I, Wulf, G, Spring, L, Sinclair, NF, Andrews, C, et al
JAMA oncology. 2020;(10):1598-1605
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Abstract
IMPORTANCE Prior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies. OBJECTIVE To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC. DESIGN, SETTING, AND PARTICIPANTS Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy. INTERVENTIONS Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations. RESULTS Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03051659.
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Phase Ib study of FOLFOXIRI plus ramucirumab as first-line treatment for patients with metastatic colorectal cancer.
Kito, Y, Satake, H, Taniguchi, H, Yamada, T, Horie, Y, Esaki, T, Denda, T, Yasui, H, Izawa, N, Masuishi, T, et al
Cancer chemotherapy and pharmacology. 2020;(2):277-284
Abstract
PURPOSE Ramucirumab, an anti-vascular endothelial growth factor (VEGF) receptor2 monoclonal antibody, inhibits VEGF-A, VEGF-C, and VEGF-D binding and endothelial cell proliferation. We conducted a phase Ib study to determine the recommended phase II dose (RP2D) of fluorouracil, l-leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus ramucirumab. METHODS This phase Ib study investigated three dose levels of FOLFOXIRI plus ramucirumab (three dose levels of irinotecan and fluorouracil with fixed dose of oxaliplatin 85 mg/m2 and ramucirumab 8 mg/kg on day 1, repeated every 2 weeks) in chemotherapy-naïve patients with metastatic colorectal cancer (mCRC). Dose-limiting toxicity (DLT) was assessed during the first cycle. RESULTS A total of ten patients were enrolled. The first four patients received the treatment at dose level 0 (irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2), and subsequent six patients were treated at dose level 1 (irinotecan 165 mg/m2 and fluorouracil 3200 mg/m2). No DLT was observed in the nine DLT-evaluable patients, which indicated that the RP2D was dose level 1. Grade 3 or worse adverse events included neutropenia (70%), hypertension (20%), and febrile neutropenia (10%). No treatment-related death was observed in any cycle. The overall response rate was 70%. CONCLUSION The RP2D of FOLFOXIRI plus ramucirumab was determined to be 8 mg/kg of ramucirumab, 165 mg/m2 of irinotecan, 85 mg/m2 of oxaliplatin, 200 mg/m2 of l-leucovorin, and 3200 mg/m2 of fluorouracil. TRIAL REGISTRATION NUMBER UMIN000023277.
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Nivolumab in Combination with Irinotecan and 5-Fluorouracil (FOLFIRI) for Refractory Advanced Gastroesophageal Cancer.
Rogers, JE, Xiao, L, Trail, A, Blum Murphy, M, Palmer, M, Ajani, JA
Oncology. 2020;(5):289-294
Abstract
INTRODUCTION Advanced unresectable gastroesophageal cancers continue to confer a dismal patient prognosis. Limited options remain once the cancer is refractory to cytotoxics/biologics (like irinotecan, taxane, and ramucirumab). Recently, anti-programmed death-1 (anti-PD-1) inhibitors have been used with limited efficacy in select patients with adenocarcinoma. Similarly, irinotecan-based therapy has marginal efficacy. We combined irinotecan plus a fluoropyrimidine with an anti-PD-1 antibody, nivolumab, with hopes of having a higher advantage for patients. OBJECTIVES Primary objective was to assess safety judged by toxicities, dose delays, or dose reductions. Secondary endpoints included the assessment of response, overall survival (OS), and progression-free survival (PFS). METHODS We treated 15 patients with this combination during July 2017 to April 2019. Patients were included if they had follow-up at our institution. RESULTS Median doses given were nivolumab 240 mg + irinotecan 120 mg/m2 + 5-FU 2,000 mg/m2 over 46-48 h (or capecitabine 1,250 mg/m2/day; 7 days on, 7 days off) given every 2 weeks. Median age of the patients was 55 years, and all patients had an ECOG performance status of 0-1. The patients had a median of 1 prior therapy. Slightly over half of the patients had PD-L1 expression. The median number of cycles was 7. Five patients (33%) had a dose delay or dose adjustment. The most common reason for dose delay or adjustment was grade 2 fatigue. Disease control (response or stability) on first scan was 73.3% (n = 11). Median PFS and OS for the entire group was 7 and 13.3 months, respectively. CONCLUSION In this small cohort of patients, we conclude that this combination is quite feasible and resulted in prolonged stability in some patients. Further development of this regimen is warranted.
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Neoadjuvant FOLFIRINOX followed by Chemoradiotherapy for Middle and Lower Rectal Cancer.
Sakr, A, Elsherbiny, M, Abdel Moneim, R, Shaaban, S, Aldaly, M
Asian Pacific journal of cancer prevention : APJCP. 2020;(6):1717-1723
Abstract
OBJECTIVE Neoadjuvant concomitant chemoradiotherapy followed by surgical resection is the standard of care in the treatment of rectal cancer. We are investigating the value of adding combination chemotherapy oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX) before neoadjuvant chemoradiotherapy. METHODS Forty-one patients with middle and lower rectal cancer were included. FOLFORINOX were given every 2 weeks over 2 months (4 cycles) followed by concomitant chemoradiotherapy (CRT). Surgery was done 6-8 weeks after CRT and then adjuvant 4 months of FOLFOX or XELOX were given. The primary end point was sphincter preservation rate. RESULTS All patients received the four cycles of neoadjuvant chemotherapy FOLFORINOX, 38 patients completed CRT and only 29 patients underwent surgery. 32 patients were available for assessment (29 patients who underwent surgery and three patients who refuse surgery because of no evidence of disease by endoscopy, imaging and biopsy). Sphincter preservation was achieved in twenty-one patients (51.2%). Pathological complete response rate was 24.1%. After a median follow up of 24 months. Median PFS was 20 months and 2-years PFS was 62.3%. The median overall survival of all patients was not reached, while 2-years OS was 76.5%. CONCLUSION Neoadjuvant FOLFIRINOX followed by CRT for middle and lower rectal cancer is feasible, tolerable with satisfactory sphincter preservation rate.
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Chemotherapy-related cognitive impairment in patients with breast cancer based on MRS and DTI analysis.
Tong, T, Lu, H, Zong, J, Lv, Q, Chu, X
Breast cancer (Tokyo, Japan). 2020;(5):893-902
Abstract
The purpose of this study is to investigate chemotherapy-related cognitive impairment (CRCI) in breast cancer patients, analyze absolute concentration and structural changes of metabolites in different brain regions by multimodal neuroimaging technology, and explore correlation between them. Breast cancer patients with chemotherapy treatment group (Ctx+, N = 24) and control group without treatment (Ctx-, N = 20) underwent neuropsychological tests, multivoxel magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) before and after chemotherapy. Regions of interest (ROls) in magnetic resonance scan include bilateral posterior cingulate gyrus (PCG), bilateral dorsal thalamus (DT), bilateral lenticular nucleus (LN), bilateral posterior horn of the lateral ventricle paratrigonal white matter (PWM). In MRS, absolute concentrations of N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), total creatine (tCr), glutamine + glutamate (Glx) were quantified using LC Model and SAGE software. In DTI, we used fractional anisotropy (FA) and mean diffusivity (MD) to reflect white matter integrity. In Ctx+ patients, scores of functional assessment of cancer treatment cognition test (FACT-Cog), perceived cognitive impairments (PCI), impact of perceived impairments on quality of life (QOL), perceived cognitive abilities (PCA), auditory-verbal learning test (AVLT) recognition and clock drawing test (CDT) were lower than those before chemotherapy (p < 0.05). In MRS, Ctx+ patients had significantly lower NAA values in bilateral PCG, DT, respectively. The concentrations of tCr were observed to decline in bilateral PCG and right DT. Glx values decreased in right DT. Cho values decreased significantly in bilateral DT. In DTI, Ctx+ patients had lower FA values in bilateral PCG compared with patients before chemotherapy. Among imaging metrics and cognitive scores, positive correlations were observed between changes in AVLT recognition scores and changes in NAA values in bilateral PCG (left PCG: r = 0.470, p < 0.01; right PCG: r = 0.500, p < 0.01). Positive correlations were also found between changes in AVLT recognition and changes in FA values in bilateral PCG (left PCG: r = 0.513, p < 0.01; right PCG: r = 0.563, p < 0.01). Chemotherapy can lead to a decrease in memory function, accompanied by changes in brain metabolite concentration and white matter integrity in some parts of brain.
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Efficacy of Chinese herbal injections combined with fluoropyrimidine and oxaliplatin-based chemotherapy for advanced colorectal cancer: A protocol for systematic review and meta-analysis of randomized controlled trials.
Wang, S, Wang, X, Zhang, Y, Zhou, T, Hu, S, Tian, P, Li, Z, Li, Y, Gui, Y, Dong, J, et al
Medicine. 2020;(52):e23550
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Abstract
BACKGROUND Fluoropyrimidine combined with oxaliplatin-based chemotherapy have become the first-line treatment for advanced colorectal cancer (CRC). Chinese herbal injections (CHIs), as an important part of TCM, have been widely applied as adjunctive treatments to chemotherapy in patients with advanced CRC. However, the efficacy of this combination therapy has not been evaluated comprehensively. METHODS We will conduct this systematic review and meta-analysis in accordance with the Preferred Reported Items for Systematic Review and Meta-analysis (PRISMA) guidelines. 7 databases will be searched for related randomized controlled trials (RCTs) from their inception to August 31, 2020: PubMed, Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), SinoMED and Wanfang Database. Two researchers will perform study selection, data extraction, and assessment of risk of bias independently. The primary outcomes are the disease control rate (DCR) and the objective response rate (ORR), the secondary outcomes are progression-free survival (PFS), survival rate, quality of life (QoL) and adverse effects. Cochrane Review Manager (RevMan 5.3) software will be used to analyze the outcomes. RESULTS AND CONCLUSION This systematic review will evaluate the efficacy of CHIs and fluoropyrimidine and oxaliplatin-based chemotherapy for advanced CRC so as to provide valuable evidence to the application of CHIs in advanced CRC. SYSTEMATIC REVIEW REGISTRATION INPLASY registration number: INPLASY2020100050.
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Neoadjuvant Phase II Trial of Chemoradiotherapy in Patients With Resectable and Borderline Resectable Pancreatic Cancer.
Thanikachalam, K, Damarla, V, Seixas, T, Dobrosotskaya, I, Wollner, I, Kwon, D, Winters, K, Raoufi, M, Li, J, Siddiqui, F, et al
American journal of clinical oncology. 2020;(6):435-441
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma is a largely incurable cancer. Surgical resection remains the only potential option for cure. Even in surgically resectable patients, only about 10% to 20% are long-term survivors. Emerging data suggest a role for neoadjuvant therapy to target occult micrometastatic disease. AIM: To report our institutional experience with a novel neoadjuvant chemoradiation (CRT) regimen in resectable and borderline resectable pancreatic cancer. MATERIALS AND METHODS Patients were treated with 2 cycles of induction chemotherapy with FOLFOX and then received CRT with gemcitabine and intensity-modulated radiotherapy (IMRT). RESULTS From April 2014 to June 2017, 24 patients were enrolled. Eighteen patients were borderline resectable and 6 patients were resectable. All patients received induction chemotherapy with FOLFOX. Thirteen patients underwent pancreatectomy after CRT with a resection rate of 62%. R0 resection achieved in 11 patients (84.6%) and 2 patients had R1 resection (15.4%). For patients who underwent resection, the median progression-free survival (PFS) was 31 months, 1-year PFS rate was 69.2% (95% confidence interval [CI], 0.48-0.99), and 2-year PFS rate was 51.9% (95% CI, 0.3-0.89). Median overall survival (OS) was 34.8 months (95% CI, 1.045 to infinity), 1-year OS rate was 91.7% (95% CI, 0.77-1.0), and 2-year OS rate was 75% (95% CI, 0.54-1.0). Median CA 19-9 at screening for patients who underwent surgery was 659 (range, 18 to 2154), which decreased to 146.9 (range, 18 to 462) after CRT before resection. CONCLUSION Neoadjuvant therapy for borderline resectable and resectable pancreatic ductal adenocarcinoma with CRT facilitated R0 resection in 84% patients who underwent surgery.
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Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial.
Rezvani, H, Mortazavizadeh, SM, Allahyari, A, Nekuee, A, Najafi, SN, Vahidfar, M, Ghadyani, M, Khosravi, A, Qarib, S, Sadeghi, A, et al
Clinical therapeutics. 2020;(5):848-859
Abstract
PURPOSE The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.