Chemotherapy For Solid Tumors Research Articles

Differential effects of an electronic symptom monitoring intervention based on the age of patients with advanced cancer

Symptom monitoring interventions enhance patient outcomes, including quality of life (QoL), health care utilization, and survival, but it remains unclear whether older and younger patients with cancer derive similar benefits. We explored whether age moderates the improved outcomes seen with an outpatient electronic symptom monitoring intervention. We carried out a secondary analysis of data from a randomized trial of 766 patients receiving chemotherapy for metastatic solid tumors. Patients received an electronic symptom monitoring intervention integrated with oncology care or usual oncology care alone. The intervention consisted of patients reporting their symptoms, which were provided to their physicians at clinic visits, and nurses receiving alerts for severe/worsening symptoms. We used regression models to determine whether age (older or younger than 70 years) moderated the effects of the intervention on QoL (EuroQol EQ-5D), emergency room (ER) visits, hospitalizations, and survival outcomes. Enrollment rates for younger (589/777= 75.8%) and older (177/230= 77.0%) patients did not differ. Older patients (median age= 75 years, range 70-91 years) were more likely to have an education level of high school or less (26.6% versus 20.9%, P= 0.029) and to be computer inexperienced (50.3% versus 23.4%, P < 0.001) compared with younger patients (median age= 58 years, range 26-69 years). Younger patients receiving the symptom monitoring intervention experienced lower risk of ER visits [hazard ratio (HR)= 0.74, P= 0.011] and improved survival (HR= 0.76, P= 0.011) compared with younger patients receiving usual care. However, older patients did not experience significantly lower risk of ER visits (HR= 0.90, P= 0.613) or improved survival (HR= 1.06, P=0.753) with the intervention. We found no moderation effects based on age for QoL and risk of hospitalizations. Among patients with advanced cancer, age moderated the effects of an electronic symptom monitoring intervention on the risk of ER visits and survival, but not QoL. Symptom monitoring interventions may need to be tailored to the unique needs of older adults with cancer.

Immunotherapy versus chemotherapy for solid tumours: lower risk of AEs

Immunotherapy versus chemotherapy for solid tumours: lower risk of AEs

Reversible Posterior Leukoencephalopathy Syndrome in Patients Undergoing Chemotherapy for Solid Tumors. A Case Report and Review of the Literature

Introduction: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical entity of subtle onset of headaches, seizures, impaired vision and usually acute hypertension associated with characteristic neuroimaging findings of subcortical oedema affecting the posterior cerebral circulation. In the last two decades the causative relationship of cytotoxic and targeted antineoplastic agents with RPLS is increasingly recognized among cancer patients.

Dual-responsive click-crosslinked micelles designed for enhanced chemotherapy for solid tumors.

The design of multiple stimuli-responsive, stable polymeric drug carriers is key for efficient drug release against solid tumors. Herein, core-crosslinked micelles were readily prepared from a pair of redox/pH-sensitive clickable copolymers. The two copolymers comprised the same poly(ethylene glycol) (PEG)-poly(ε-benzyloxycarbonyl-l-lysine) (PZLL) block but with either disulfide-linked azadibenzocyclooctyne (DBCO) or azide (AZ) group-tagged branched polyethylenimine (BPEI, 1.8 kDa). The data showed that an equivalent of the two copolymers could self-assemble into nanosized micelles with the crosslinked core via the DBCO-AZ click chemistry. The click-crosslinked micelles showed excellent size stability under multiple dilutions but destabilization in an acidic or reductive environment. Besides, they could load doxorubicin (DOX), an anticancer drug, and mediate slow drug release in a neutral environment but sufficient drug unloading under acidic plus reductive conditions. In vitro, DOX-loaded crosslinked micelles led to higher DOX accumulation in the cellular nucleus in comparison with non-crosslinked micelles from the PEG-PZLL-BPEI copolymer (PP), thus causing more marked cytotoxicity in SKOV-3 cells. In vivo, DOX-loaded crosslinked micelles caused significant growth inhibition of SKOV-3 tumors xenografted in BALB/c nude mice, and showed superior anticancer efficacy to non-crosslinked PP micelles. Chemotherapy with core-crosslinked micelles had no adverse side effects on the health (serum levels and body weight) of the mice. This study highlights the design of clickable block copolymers to easily construct core-crosslinked and multiple stimuli-responsive micelles for enhanced anticancer therapy.

Emerging role of glucocorticoid receptor in castration resistant prostate cancer: A potential therapeutic target.

Glucocorticoids are used as co-medication with chemotherapy for solid tumors to reduce inflammation as well as cytotoxic side effects and are effective in easing symptoms related to chemotherapy. However, emerging evidence suggests that glucocorticoids may contribute to failure of chemotherapy and tumor progression of castration resistant prostate cancer (CRPC). Thus, in recent years, glucocorticoid signaling pathway has become an important therapeutic target for CRPC. Understanding the exact mechanism of GR actions in CRPC is still work in progress. There are studies suggesting that GR expression can be upregulated following antiandrogen therapy and can contribute to resistance to hormone therapies. Therefore, attempts are being made to develop selective glucocorticoid receptor modulators that specifically antagonize GR activity in CRPC, and thereby provide clinical benefit by blocking the GR mechanism for tumor growth. However, more targeted approaches are needed to understand the role of the GR-mediated target gene expressions in the CRPC that could in near future lead to better therapeutic options for patients with CRPC. This review highlights current perspectives on the actions of glucocorticoids during tumor progression and metastasis of CRPC.

68P - A novel anti-EGFR antibody HLX07 for potential treatment of squamous cell carcinoma of the head and neck

BackgroundHLX07 is a fully-humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with re-engineered Fab rendering its less immunogenic and better binding affinity than cetuximab. In-vivo studies of HLX07 demonstrated either equal or superior efficacy to cetuximab at the same dose level. Here, we present the data from the phase 1 study of HLX07 in advanced solid tumours. MethodsWe conducted an open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), PK and clinical response of HLX07 in subjects with recurrent or metastatic solid tumours unamendable to standard therapy. Subjects received once weekly intravenous infusion of HLX07 at doses of 50, 100, 200, 400, 600 and 800 mg until disease progression, withdrawal of consent or development of toxicities. Dose-limiting toxicities (DLTs) were evaluated within 28 days after the first dose and CT/MRI scans were evaluated every 8 weeks after the first infusion for treatment response. Safety, immunogenicity, PK and clinical response evaluations were performed throughout the study period. ResultsHLX07 was first approved to initiate clinical trial by the Taiwan and US FDAs; subject recruitment began in late 2016. As of 13-June-2019, 19 subjects received HLX07 in the study with the longest follow-up period of over 224 days. Among the 16 subjects who had been evaluated for efficacy, 1 subject with advanced colon cancer in 600 mg cohort achieved partial response and 5 subjects in different cohorts achieved stable disease status. Particularly at the 400 mg dose level, 30% of patients were in stable disease status at week 16 evaluation. Possibly related to HLX07 AEs with grade >2 severity included skin rashes (10.6%), hypophosphatemia (5.3%), hypomagnesemia (5.3%) and hypocalcemia (5.3%). No novel safety signal was identified; no DLT was noted up to 800 mg cohort. The PK data up to 600 mg was described in the following table.Table68P PK parameter of HLX07 at 50, 100, 200, 400 and 600 mg dose levelsTableDose (mg)Cmax (×μg/mL)AUC0-t (×h*μg/mL)t1/2 (MEAN CV%)(h)-1st dose4th dose1st dose4th dose1st dose4th dose5015.01535131131.08 (14.12%)23.11(32.61%)10043.2412067311039.70 (37.61%)55.87 (11.98%)20076.1995793954174.61 (12.49%)154.56 (38.73%)400119216908523274106.60 (19.68%)131.28 (57.48%)6001583111427869567138.64 (10.49%)210.27 (26.59%) ConclusionsHLX07 is generally well tolerated without reaching the MTD up to 800 mg weekly cohort and exhibits antitumour activity with durable objective responses at various doses. These findings support the initiation of a phase 1b/2 study of HLX07 plus chemotherapy in advanced solid tumours with the longest follow-up time of over 275 days as of 20-June-2019. Additionally, HLX07 is currently under safety and efficacy investigation combined with anti-PD-1 antibody, HLX10, in squamous cell carcinoma of head and neck. Clinical trial identificationHLX07-001 Phase 1 study (NCT02648490); HLX07-002 Phase 1b/2 study (NCT03577704). Legal entity responsible for the studyShanghai Henlius Biotech, Inc.; Taiwan Henlix Biotech Co., Ltd. FundingShanghai Henlius Biotech, Inc. DisclosureM.M. Hou: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. C.L. Ho: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. H.Y. Lin: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. Y. Hong: Full / Part-time employment: Shanghai Henlius Biotech, Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S.F. Lin: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd. T.C. Hsieh: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd. E. Liu: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd.

Improved chemotherapeutic efficacy against resistant human breast cancer cells with co-delivery of Docetaxel and Thymoquinone by Chitosan grafted lipid nanocapsules: Formulation optimization, in vitro and in vivo studies

In recent years, multi-targeted chemotherapeutic combinations have received considerable attention in solid tumor chemotherapy. Here, we optimized low-molecular-weight chitosan (CS)-grafted lipid nanocapsules (LNCs, referred to as CLNCs) for the co-delivery of docetaxel (DTX) and thymoquinone (THQ) to treat drug-resistant breast cancer. We first screened size reduction techniques (homogenization vs ultrasonication), and then the 33-Box-Behnken design was employed to determine optimal conditions of the final LNCs with the desired quality attributes. Uncoated LNCs had a particle size of 141.7 ± 2.8 nm (Polydispersity index, PdI: 0.17 ± 0.02) with entrapment efficiency (%EE) of 66.1 ± 3.5 % and 85.3 ± 3.1 % for DTX and THQ, respectively. The CS functionalization of LNCs improved the uptake and endosomal escape effect, and led to a significantly higher cytotoxicity against MCF-7 and triple-negative (MDA-MB-231) breast cancer cells. Furthermore, an enhanced antiangiogenic effect was observed with DTX- and THQ-carrying CLNCs in the Chick embryo chorioallantoic membrane (CAM) assay.

Appropriateness of using granulocyte colony-stimulating factor (G-CSF) for primary prophylaxis of febrile neutropenia in solid tumors.

Febrile neutropenia (FN) is one of the dose-limiting adverse effects of chemotherapy. Granulocyte-Colony Stimulating Factors (G-CSFs) minimize the incidence of FN and reduce the risk of neutropenia complications. This study was conducted to address the prescription pattern of G-CSF for primary prophylaxis of FN during the first cycle of chemotherapy in solid tumors. This prospective observational study was done to investigate the G-CSF prescription pattern in patients receiving the first cycle of chemotherapy for solid tumors and compare it with the NCCN guideline recommendations. Based on the guideline, prophylactic G-CSF administration was indicated in 26 of the 96 patients (27.1%) and all of them received G-CSF. On the other hand, 70 patients (72.9%) did not meet the guideline criteria for prophylaxis, but 60 (62.5%) of them received G-CSF. Seven doses of pegfilgrastim and 165 doses of filgrastim were used inappropriately in the study population, which was associated with an economic burden of about 224.7 million IRR (5350 USD). Taken together, inconsistencies with the guideline were observed in this prospective evaluation, suggesting that submitting rationalized policies to decrease G-CSF prescription, especially in patients with a lower or intermediate FN risk, yields substantial cost savings.

472P - A phase I study of varlitinib (VAR; ASLAN001) an oral pan-HER tyrosine kinase inhibitor (TKI) combined with mFOLFIRI chemotherapy in advanced solid tumours

BackgroundVAR is a potent TKI against EGFR, HER2 and HER4. Efficacy of VAR combined with fluoropyrimidine and platinum chemo in colorectal cancer (CRC) and biliary tract cancer (BTC) has been reported (ESMO 2018 430P, GI ASCO 2019 #319). MethodsPatients (pts) ECOG PS 0-1 with advanced solid tumors and adequate organ function were eligible. Homozygous UGT1A1*6/*6 and *28/*28 pts were excluded. VAR was combined with mFOLFIRI up to 9 cycles followed by VAR monotherapy. Each cycle was 14 days with dose limiting toxicity (DLT) period of 28 days. VAR was evaluated at 3 dose levels (DL): DL1 200mg/BD D1-14; DL2 200mg/BD D4-11; DL3 300mg/BD D4-11. Dose escalation by 3+3 design. Primary endpoint was safety and maximum tolerated dose (MTD). Secondary endpoints were pharmacokinetics (PK) and response. Tumor NGS (Oncomine OCP v3) and IHC (HER2, cMET, PTEN) were performed. ResultsAs of 15-Feb-19, 16 pts were treated, 5 (31%) BTC, 5 (31%) CRC, 3 (19%) gastroesophageal, 2 (13%) pancreatic and 1 (6%) ovarian clear cell cancer (OCCC). Sex M/F 13/3, median (range) for age was 62yrs (45-79), ECOG 0 (0-1) and lines of prior therapy was 3 (0-6). 4/4 pts at DL1 had G3/4 neutropenia on cycle 2 D1 lasting <7 days, possibly by VAR inhibition of UGT1A1 mediated-clearance of SN-38. Intermittent dosing of VAR in DL2 (n=5) and DL3 (n=6) was tolerable with a DLT of G3 stomatitis (HSV co-infection) at DL3. PK study showed widely variable VAR levels but no VAR accumulation. VAR was not escalated as prior studies showed limited tolerability at 400mg/BD combined with chemo. G3/4 treatment related adverse events (TRAE) seen in≥10% of pts was neutropenia (44%; 4 DL1, 1 DL2, 2 DL3) with no events of neutropenic sepsis. Of the 16 pts, 2 (13%) had PR (BTC, 1 prior line; HER2 over-expressing OCCC, 6 prior lines) maintained at 7.5 and 6.1 mths respectively, 9 (56%) had disease control (DCR, PR+SD) of which in 4 (25%) DCR was >6 mths, and median PFS was 4.2 mths. HER2 alterations were seen in 4 pts (1 PR, 2 SD, 1 PD). ConclusionsVAR 300mg/BD D4-11 combined with mFOLFIRI is the MTD and well tolerated. Durable response in HER2 positive OCCC was seen and warrants further investigation. Clinical trial identificationNCT02435927. Legal entity responsible for the studyNational Cancer Centre Singapore. FundingNational Medical Research Council (NMRC) Singapore, ASLAN Pharmaceuticals. DisclosureA.C. Tan: Travel / Accommodation / Expenses: ASLAN Pharmaceuticals. M.C.H. Ng: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): ASLAN Pharmaceuticals. All other authors have declared no conflicts of interest.

ABCB1 polymorphism predicts the toxicity and clinical outcome of lung cancer patients with taxane-based chemotherapy.

BackgroundTaxane‐based chemotherapy is widely used in lung cancer. ABCB1 have a role in the prediction of treatment response and toxicity of chemotherapy in solid tumors. In this retrospective study, we investigated ABCB1 polymorphism on response and toxicity in taxane‐based chemotherapy in lung cancer patients.MethodsA total of 122 lung cancer patients who received taxane‐based chemotherapy were included in this study. Fluorescence in situ hybridization (FISH) was used for ABCB1 polymorphism detection. Turbidimetric inhibition immunoassay was used for pharmacokinetic analysis. Statistical analysis was performed using SPSS 20.0.ResultsThe frequency of the ABCB1 2677 site TT/TG/GG genotype was 32.8%, 43.4% and 23.8%, respectively and the frequency of the 3435 sites the TT/TC/CC genotype was 13.9%, 44.3% and 41.8%, respectively. The occurrence of neurotoxicity was higher in patients who had ABCB1 3435 site mutation (TT 88.2%, TC 22.2%, CC 21.6% P = 0.004). There was no significant difference between ABCB1 genotypes with regard to other chemotherapy‐induced toxicity. For non‐small cell lung cancer (NSCLC) patients, those harboring ABCB1 2677 and 3435 site wild‐type patients had longer median progression‐free survival (PFS) in the paclitaxel subgroup (3435 site: TT 3.87 vs. TC 9.50 vs. CC 14.13 months; P < 0.001; 2677 site: TT 4.37 vs. TG 9.73 vs. GG 12.1 months; P = 0.013). The area under the concentration‐time curve (AUC) of 20 patients treated with docetaxel increased for ABCB1 mutation subgroups.ConclusionABCB1 mutation is associated with higher neurotoxicity of taxane‐based chemotherapy. It also predicts shorter PFS for NSCLC in paclitaxel‐based treatment.

Immune Checkpoint Inhibitors as Switch or Continuation Maintenance Therapy in Solid Tumors: Rationale and Current State.

First-line chemotherapy for many solid tumors is limited by toxicity. There is a growing interest in maintenance therapy as a strategy for prolonging the benefits of first-line therapy while minimizing toxicity. Maintenance therapy can comprise either continuation of an agent given as part of the first-line regimen (continuation maintenance) or treatment with a new agent (switch maintenance). Maintenance therapy is already established in several solid tumors, including lung, breast, gastric, colorectal, and ovarian cancer. Immune checkpoint inhibitor treatment has been shown to prolong duration of response and overall survival, but efficacy is generally restricted to a limited proportion of patients with selected tumors. Thus, efforts are ongoing to determine whether the clinical benefits of immune checkpoint inhibitors can be extended using novel treatment schedules and settings, including maintenance therapy. Early- and late-phase clinical trials have investigated the efficacy and safety of immune checkpoint inhibitors as switch and continuation maintenance in different tumors, and a range of phase III trials are ongoing. Interpretation of results requires consideration of trial designs, eligibility criteria, and primary endpoints, in addition to biomarker exploration, andassessment of quality of life and cost effectiveness. Findings from ongoing trials will help further define the role of immune checkpoint inhibitors as maintenance therapy across a spectrum of solid tumors.

Activity and Trafficking of Copper-Transporting ATPases in Tumor Development and Defense against Platinum-Based Drugs.

Membrane trafficking pathways emanating from the Golgi regulate a wide range of cellular processes. One of these is the maintenance of copper (Cu) homeostasis operated by the Golgi-localized Cu-transporting ATPases ATP7A and ATP7B. At the Golgi, these proteins supply Cu to newly synthesized enzymes which use this metal as a cofactor to catalyze a number of vitally important biochemical reactions. However, in response to elevated Cu, the Golgi exports ATP7A/B to post-Golgi sites where they promote sequestration and efflux of excess Cu to limit its potential toxicity. Growing tumors actively consume Cu and employ ATP7A/B to regulate the availability of this metal for oncogenic enzymes such as LOX and LOX-like proteins, which confer higher invasiveness to malignant cells. Furthermore, ATP7A/B activity and trafficking allow tumor cells to detoxify platinum (Pt)-based drugs (like cisplatin), which are used for the chemotherapy of different solid tumors. Despite these noted activities of ATP7A/B that favor oncogenic processes, the mechanisms that regulate the expression and trafficking of Cu ATPases in malignant cells are far from being completely understood. This review summarizes current data on the role of ATP7A/B in the regulation of Cu and Pt metabolism in malignant cells and outlines questions and challenges that should be addressed to understand how ATP7A and ATP7B trafficking mechanisms might be targeted to counteract tumor development.

Clinical manifestations of BK virus infection in pediatric kidney transplant patients.

BackgroundPolyomavirus BK (BKV) infection is an important cause of graft loss in kidney transplant patients.PurposeThe purpose of this study was to evaluate clinical findings and risk factors for BKV in pediatric patients after kidney transplantation.MethodsThis retrospective single-center study included 31 pediatric kidney transplant recipients from January 2002 to December 2017. Two patients received 2 transplantations during the study period, and each transplant was analyzed independently. Total number of cases is 33 cases with 31 patients. BKV infection was confirmed from blood samples via periodic quantitative polymerase chain reaction.ResultsThe mean age at kidney transplantation was 11.0±4.7 years, and the male-to-female ratio was 2.7:1. Three patients had a past medical history of high-dose chemotherapy and autologous stem-cell transplantation for solid tumors. Nine patients (27.3%) developed BKV infection. The median period from kidney transplantation to BKV detection in blood was 5.6 months. There was no statistically significant difference in estimated glomerular filtration rate between patients with and those without BKV infection. Among 9 patients with BKV viremia, 7 were treated by reducing their immunosuppressant dose, and BKV was cleared in 6 of these 7 patients. In the other 2 BKV-positive patients, viremia improved without immunosuppressant reduction.ConclusionBKV infection is common in children with kidney transplantation and might not have affected short-term renal function in our patient sample due to early immunosuppressant reduction at the time of BKV detection.

Pneumocystis jiroveci pneumonia during first and second-line chemotherapy for solid tumours.

e18330 Background: Pneumocystis jiroveci pneumonia (PJP) is an opportunistic fungal infection, historically associated with individuals with advanced immunodeficiency, sustained temozolamide chemotherapy and in those who have undergone multiple lines of chemotherapy. PJP is now increasingly being recognised in patients undergoing first-line chemotherapy. This is a retrospective study of ten cases of PJP at our institution amongst patients undergoing first or second-line chemotherapy for solid tumours. Methods: An electronic database search was conducted, looking at cases of PJP diagnosed in our institution over a five year period. Ten patients with a history of PJP were identified. These patients’ pharmacy records, pathology, imaging and laboratory results were examined. Results: All identified patients developed PJP whilst undergoing first-line (70%) or second-line (30%) chemotherapy for solid tumours. These included metastatic cancers such as: pancreatic adenocarcinoma (50%), lung cancer (20%), prostate adenocarcinoma (10%), gastric adenocarcinoma (10%); and colon adenocarcinoma (10%). Eight of ten patients were lymphopenic, with lymphocytes counts of 0.1 - 0.5 (reference range 1.0 - 4.0 x 109/L). One patient had a recorded CD4 count of 114 (reference range 500-1500). On the basis of clinical context, ground-glass changes on CT and/or a positive sputum PCR for PJP, each patient was treated with intravenous high-dose trimethoprim/sulfamethoxazole until they were clinically stable. Patients were then switched on to a life-long prophylactic dose. Four patients required intensive care for management of respiratory failure. Nine out of ten patients recovered well without any long-term sequelae and one patient died. Conclusions: PJP is being diagnosed more frequently than previously thought in those receiving first and second-line chemotherapy. Limited research has been conducted into the potential benefit of prescribing trimethoprim/sulfamethoxazole prophylaxis to patients commencing chemotherapy. Monitoring of CD4 count prior to each chemotherapy cycle could provide guidance to oncologists regarding when to commence prophylactic treatment as a means to reducing patients diagnosed with PJP.

Prospective cohort study of the impact of hospital-wide dihydropyrimidine dehydrogenase (DPYD) genotype testing for fluoropyrimidine-based chemotherapy on adverse events and hospital costs.

3028 Background: Fluoropyrimidines remain integral components of modern chemotherapy for solid tumors, and their toxicities can be reduced by pretreatment DPYD genotyping. Our main objective was to demonstrate the feasibility of implementing a hospital-wide pretreatment DPYD testing service based on the CPIC 2013 guideline on fluoropyrimidines and DPYD. Methods: We enrolled participants prior to planned fluoropyrimidine treatment as well as those who had experienced adverse events (AEs) after initiation of therapy, from December 1, 2013 to November 30, 2018. The patients tested pretreatment were analyzed as a prospective cohort to assess AEs within 90 days of fluoropyrimidine initiation and associated hospital cost. The primary outcome was the rate of severe global fluoropyrimidine-related toxicity in the pretreatment cohort (grade≥3, CTCAE v.4.0.3). Results: Of 1362 patients genotyped for DPYD within the study period 1041 were enrolled pretreatment and included in the primary analysis. The median age was 65 years (19-90), 57% male, 51% 5-FU, and 49% capecitabine. Dose reductions were recommended for 21 DPYD variant carriers who were detected pretreatment. There was no significant difference in the primary outcome between DPYD variant (29%) and wild type (18%) patients (Fisher’s exact test p = 0.25). Costs associated with ER visits and hospitalizations at our tertiary care centre were $1,268 (89-8,562) (Median (IQR)) and $2,961 (341-13,567) for DPYD variant (n = 4) and wild-type (n = 99) patients respectively. Post-AE genotyping (n = 70) found five DPYD variant patients; all experienced grade≥3 toxicity, costs were $15,825 (10,962-25,310), and one poor metabolizer died due to complications. Targeted next generation exome sequencing of DPYD wild-type patients who experienced severe AEs identified five potentially deleterious genetic variants in ABC efflux transporters. Conclusions: Pretreatment DPYD genotype guided dosing of fluorouracil and capecitabine is feasible and benefits patients, health care providers, and hospitals. Our data supports adoption of pretreatment DPYD genotyping as a standard of care.

Comparative safety analysis of immunotherapy combined with chemotherapy versus monotherapy in solid tumors: a meta-analysis of randomized clinical trials.

Background: Combination treatment (chemotherapy plus immune checkpoint blockade [ICB]) has shown promising activity in terms of efficacy, but it has been suggested that its toxicity profile is less favorable compared to monotherapy.Methods: We conducted a meta-analysis of published randomized clinical trials comparing combination treatment to monotherapy (chemotherapy or ICB) in patients with metastatic solid tumors. Differences in rates of safety issues (all-grade adverse events, grade 3/4 adverse events, treatment-related deaths, treatment discontinuations) between groups were estimated. Subgroup analyses for the control group (chemotherapy or ICB as monotherapy) and immune checkpoint inhibitor (anti-CTLA-4 or anti-PD-1/PD-L1 antibodies) were performed.Results: A total of 4379 patients (ten studies) were included (monotherapy: 2026 patients; combination treatment: 2353 patients). Combination treatment presented more grade 3/4 adverse events (RR 1.32, 95% CI 1.12–1.55) and discontinuations (RR 2.31, 95% CI 1.28–4.16). There were no differences in the mortality rate between groups. Subgroup analyses showed a potentially more toxic profile with anti-CTLA-4 agents.Conclusions: Combination treatment is associated with an increase in grade 3/4 adverse events and treatment discontinuations compared to monotherapy, but not increased mortality. The toxicity profile of combination therapy should be considered with regard to the overlapping safety profiles.

Tunable Hollow Bimetallic MnFe Prussian Blue Analogue as the Targeted pH-Responsive Delivery System for Anticancer Drugs.

Owning to the improved ability of selectivity and penetration toward cancer cells, drug delivery systems (DDSs) play essential roles in chemotherapy for solid tumors. Herein, a series of bimetallic MnFe Prussian blue analogues (PBAs) with a tunable nanostructure was prepared by using sodium citrate (SC) as a structure regulator (represented by MnFe-PBA-SC). An advanced targeted drug delivery system was obtained by adding folic acid (FA) to the preparation system of MnFe-PBA-SC nanospheres (denoted as MnFe-PBA-SC-FA). The shape of pure MnFe PBA was changed from a typical nanocube to a hollow nanosphere when adding SC, leading to the formation of the core-shell nanospheres of the MnFe-PBA-SC-FA composite. The hollow nanostructures and intrinsic cavities in PBA can carry large amounts of doxorubicin (DOX), showing a high loading efficiency of MnFe-PBA-SC1.0-FA (91.8%), which was higher than that in MnFe-PBA-SC0.5 (63.2%). Additionally, the series of MnFe-PBAs showed pH-responsive drug release behaviors. A cell viability assay illustrated no remarkable cytotoxicity of MnFe-PBA-SC-FA against human breast cancer cells, Michigan Cancer Foundation-7 (MCF-7) cells, for 24 h. Confocal laser scanning showed that the MnFe-PBA-SC1.0-FA/DOX system significantly entered FA receptor-expressing MCF-7 cells in vitro and in vivo, while an increased DOX release was observed in the cytoplasm of the MCF-7 cells. In consequence, this novel anticancer delivery system based on bimetallic PBAs can be potentially applied to drug delivery.

Assessment of Chemotherapy-Induced Febrile Neutropenia in Cancer Patients

Abstract Purpose: Chemotherapy-induced febrile neutropenia (CIFN) is an adverse drug reaction which needs medical attention. The treatment options for the CIFN are mandatory to improve treatment outcomes and quality of life. Methods: A prospective observational study was conducted in the in-patients and out-patients of oncology department who received chemotherapy from October 2016 to March 2017. The information such as demographics (age, gender, and comorbidities), complaints on admission, hematological investigations (neutrophil counts, platelet counts, hemoglobin levels, erythrocyte sedimentation rate, and white blood cells), type of tumor, stage of cancer, prophylaxis, cycle of antineoplastic chemotherapy that cause febrile neutropenia, treatment history, and outcome data were obtained from the patient's clinical record. The Multinational Association for Supportive Care in Cancer score and Absolute Neutrophil Count grading was used to predict the patient's risk of developing CIFN. Results: Out of 200 patients, 19 patients developed 22 episodes of CIFN. The overall occurrence of CIFN during the study was 9.5%. The higher incidence of CIFN has been observed among male gender (57.89%), stage III patients (42.10%), solid tumor (73.68%), and double chemotherapy regimen (59.1%). The higher incidence of CIFN was developed in I cycle (36.36%) followed by II cycle (22.72%) and VI cycle (18.18%). Conclusions: The incidence of CIFN during the study was 9.5%. In the 19 chemotherapy-induced FN patients, there has no significant effect of prophylaxis to prevent the febrile neutropenia.

A novel gold nanorods coated by stimuli-responsive ABC triblock copolymer for chemotherapy of solid tumors

Gold nanoparticles have been used for centuries in medicine for clinical procedures. In this context, gold nanorods are considered as very promising in cancer therapy. For this purpose, gold nanorods (GNRs) coated by stimuli-responsive thiol-end capped ABC triblock copolymer [poly (metacrylic acid)-block-poly (N-isopropylacrylamide)-block-poly (N,N-dimethylaminoethyl methacrylate)-SH; P(MAAc-b-NiPAAM-b-DMAEMA)-SH] for intracellular delivery of doxorubicin (DOX). The chemical structures of triblock copolymer were explored by means of Fourier Transform Infrared (FTIR), 1HNMR spectroscopies and gel permeation chromatography (GPC). The success of coating gold nanorods with triblock copolymer was confirmed by means of ultraviolet–visible (UV–Vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray powder diffraction (XRD) and thermogravimetric analysis (TGA) measurement. Then, the doxorubicin (DOX)-loading capacity and dual sensitivity drug release ability of the nanocariers (GNRs@triblock copolymer-DOX) were also assessed. The biocompatibility of the prepared nanomaterials was confirmed through the evaluating survival rate of breast cancer cell line (MCF7) using MTT assay. Finally, cellular uptake study and DAPI staining analysis confirmed that nanocarrier successfully improved drugs anticancer activity and the potential of nanocarrier as a bioactive structure. As a result, it is expected that GNRs@tribloc copolymer-DOX may provide promising prospect in the field of nanomedicine mainly due to its biocompatibility and smart physicochemical properties.

β-Caryophyllene, a natural bicyclic sesquiterpene attenuates doxorubicin-induced chronic cardiotoxicity via activation of myocardial cannabinoid type-2 (CB2) receptors in rats

The cannabinoid type 2 receptor (CB2) has recently emerged as an important therapeutic target for cancer as well as cardiovascular diseases. The CB2 receptor downregulation has been reported in solid tumors and cardiovascular diseases, therefore the CB2 receptor activation has been considered as a viable strategy for chemotherapy as well as cardioprotection. Doxorubicin (DOX) is an important drug that continues to be the mainstay of chemotherapy in solid tumors, leukemia, and lymphoma. However, the use of DOX is often limited due to its lethal cardiotoxicity. Considering the role of CB2 receptors in cardiovascular diseases and cancer, the activation of CB2 receptors may protect against DOX-induced chronic cardiotoxicity in rats. In the present study, we investigated the cardioprotective effect of a selective CB2 receptor agonist; β-Caryophyllene (BCP), a natural bicyclic sesquiterpene, against DOX-induced chronic cardiotoxicity in rats. AM630, a CB2 receptor antagonist was administered as a pharmacological challenge prior to BCP treatment to demonstrate CB2 receptor mediated cardioprotective mechanism of BCP. DOX (2.5 mg/kg) was injected intraperitoneally once a week for five weeks to induce chronic cardiotoxicity in rats. BCP was also injected into rats six days a week for a total duration of five weeks. DOX induced a significant decline in cardiac function and oxidative stress evidenced by the depletion of antioxidant enzymes, glutathione, and increased lipid peroxidation. DOX also triggered activation of nuclear factor kappa B (NF-κB) and increased the levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and expression of the inflammatory mediators (iNOS and COX-2) in the heart. Furthermore, DOX also upregulated the expression of pro-apoptotic markers such as Bax, p53, cleaved PARP, active caspase-3 and downregulated anti-apoptotic marker Bcl-2 in the myocardium. BCP treatment exerted significant cardioprotective effect by salvaging the heart tissues, improving cardiac function, mitigating oxidative stress, inflammation, and apoptosis. The histological and ultrastructural studies also appear in line with our findings of biochemical and molecular parameters. The CB2 receptor-mediated cardioprotective mechanism was further confirmed by the abrogation of the beneficial effects of BCP with prior administration of the CB2 receptor antagonist; AM630. Our study revealed the novel mechanism of BCP in cardioprotection against DOX-induced chronic cardiotoxicity by the activation of CB2 receptors.