A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies.
Sharma Manish R,Joshi Smita S,Karrison Theodore G,Allen Kenisha,Suh Grace,Marsh Robert,Kozloff Mark F,Polite Blase N,Catenacci Daniel V T,Kindler Hedy L
Cancer
BACKGROUND:FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. METHOD:5-FU (2400 mg/m over 46 hours), leucovorin (400 mg/m ), oxaliplatin (85 mg/m ), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2-sided 80% confidence interval for DLT rate was ≤33%. RESULTS:In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. CONCLUSION:On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.
10.1002/cncr.31938
Impact of Polymorphisms on Febrile Neutropenia in Pancreatic Cancer Patients Receiving FOLFIRINOX: A Single-Center Cohort Study.
Keum Jiyoung,Lee Hee Seung,Jo Jung Hyun,Chung Moon Jae,Park Jeong Youp,Park Seung Woo,Song Si Young,Bang Seungmin
Cancers
FOLFIRINOX (oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil) is a first-line chemotherapy for metastatic pancreatic cancer (PC). Chemotherapy-induced neutropenia is one of the most serious adverse events associated with advanced PC. Although polymorphisms are associated with the metabolism of irinotecan, their role as surrogate markers for FOLFIRINOX-induced neutropenia has not been confirmed. We investigated risk factors for FN-in particular, polymorphisms-in PC patients receiving FOLFIRINOX, using a single-center cohort registry. To investigate the association between polymorphisms and FN, we divided patients into three groups based on the predicted phenotype: extensive metabolizer (EM) vs. intermediate metabolizer (IM) vs. poor metabolizer (PM). A total of 154 patients (FN group ( = 31) vs. non-FN group ( = 123)) receiving first-line FOLFIRINOX were identified between December 2017 and July 2020. The Cox regression analysis showed that female sex (HR: 2.20; = 0.031), Eastern Cooperative Oncology Group performance status = 1 (HR: 2.83; = 0.008), IM (HR: 4.30; = 0.004), and PM (HR: 4.03; = 0.028) were statistically significant risk factors for FN. We propose that is the strongest predictive factor for FN and that this gene should be screened prior to the administration of chemotherapy.
10.3390/cancers14051244
The influence of UGT1A1 polymorphisms on modified FOLFIRINOX dose in double-variant-type patients with advanced pancreatic cancer.
International journal of clinical oncology
BACKGROUND:UGT1A1 polymorphisms should be considered when using irinotecan-containing regimens, especially in patients with a double-variant-type (DV), including homozygous for UGT1A1*28 and UGT1A1*6 and heterozygous for both UGT1A1*28 and UGT1A1*6. We investigated the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) (irinotecan 80 mg/m) in patients having DV. METHODS:Patients with advanced pancreatic cancer who had received FOLFIRINOX between January 2015 and December 2019 were included in this study. Non-DV patients received the standard mFOLFIRINOX (irinotecan 150 mg/m) as first-line (non-DV1) or second-line therapy (non-DV2); however, DV patients received mFOLFIRINOX (irinotecan 80 mg/m) as the second-line therapy (DV2). We retrospectively evaluated the safety and efficacy of the lowered irinotecan dose in the DV2 group relative to the non-DV1 (safety) or non-DV2 (safety and efficacy) groups. RESULTS:A total of 235 patients were eligible for this study with 118 patients in the non-DV1, 106 in the non-DV2, and 11 in the DV2 groups. Major grade 3-4 adverse events were neutropenia (33.9, 31.1, and 18.2%) and febrile neutropenia (6.8, 3.8, and 9.1%) in the non-DV1, non-DV2, and DV2 groups, respectively. The median progression-free survival was 3.4 months in the non-DV2 group, and 4.4 months in the DV2 group. The overall survival from the date of starting second-line chemotherapy was 8.8 months in the non-DV2 group and 11.5 months in the DV2 group. CONCLUSIONS:Based on our findings, the safety and efficacy of mFOLFIRINOX (irinotecan 80 mg/m) in DV patients were comparable with the standard mFOLFIRINOX (irinotecan 150 mg/m) in non-DV patients.
10.1007/s10147-022-02186-w
Network-guided modeling allows tumor-type independent prediction of sensitivity to all-trans-retinoic acid.
Bolis M,Garattini E,Paroni G,Zanetti A,Kurosaki M,Castrignanò T,Garattini S K,Biancardi F,Barzago M M,Gianni' M,Terao M,Pattini L,Fratelli M
Annals of oncology : official journal of the European Society for Medical Oncology
Background:All-trans-retinoic acid (ATRA) is a differentiating agent used in the treatment of acute-promyelocytic-leukemia (APL) and it is under-exploited in other malignancies despite its low systemic toxicity. A rational/personalized use of ATRA requires the development of predictive tools allowing identification of sensitive cancer types and responsive individuals. Materials and methods:RNA-sequencing data for 10 080 patients and 33 different tumor types were derived from the TCGA and Leucegene datasets and completely re-processed. The study was carried out using machine learning methods and network analysis. Results:We profiled a large panel of breast-cancer cell-lines for in vitro sensitivity to ATRA and exploited the associated basal gene-expression data to initially generate a model predicting ATRA-sensitivity in this disease. Starting from these results and using a network-guided approach, we developed a generalized model (ATRA-21) whose validity extends to tumor types other than breast cancer. ATRA-21 predictions correlate with experimentally determined sensitivity in a large panel of cell-lines representative of numerous tumor types. In patients, ATRA-21 correctly identifies APL as the most sensitive acute-myelogenous-leukemia subtype and indicates that uveal-melanoma and low-grade glioma are top-ranking diseases as for average predicted responsiveness to ATRA. There is a consistent number of tumor types for which higher ATRA-21 predictions are associated with better outcomes. Conclusions:In summary, we generated a tumor-type independent ATRA-sensitivity predictor which consists of a restricted number of genes and has the potential to be applied in the clinics. Identification of the tumor types that are likely to be generally sensitive to the action of ATRA paves the way to the design of clinical studies in the context of these diseases. In addition, ATRA-21 may represent an important diagnostic tool for the selection of individual patients who may benefit from ATRA-based therapeutic strategies also in tumors characterized by lower average sensitivity.
10.1093/annonc/mdw660
Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer.
Hurria Arti,Mohile Supriya,Gajra Ajeet,Klepin Heidi,Muss Hyman,Chapman Andrew,Feng Tao,Smith David,Sun Can-Lan,De Glas Nienke,Cohen Harvey Jay,Katheria Vani,Doan Caroline,Zavala Laura,Levi Abrahm,Akiba Chie,Tew William P
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Older adults are at increased risk for chemotherapy toxicity, and standard oncology assessment measures cannot identify those at risk. A predictive model for chemotherapy toxicity was developed (N = 500) that consisted of geriatric assessment questions and other clinical variables. This study aims to externally validate this model in an independent cohort (N = 250). PATIENTS AND METHODS:Patients age ≥ 65 years with a solid tumor, fluent in English, and who were scheduled to receive a new chemotherapy regimen were recruited from eight institutions. Risk of chemotherapy toxicity was calculated (low, medium, or high risk) on the basis of the prediction model before the start of chemotherapy. Chemotherapy-related toxicity was captured (grade 3 [hospitalization indicated], grade 4 [life threatening], and grade 5 [treatment-related death]). Validation of the prediction model was performed by calculating the area under the receiver-operating characteristic curve. RESULTS:The study sample (N = 250) had a mean age of 73 years (range, 65 to 94 [standard deviation, 5.8]). More than one half of patients (58%) experienced grade ≥ 3 toxicity. Risk of toxicity increased with increasing risk score (36.7% low, 62.4% medium, 70.2% high risk; P < .001). The area under the curve of the receiver-operating characteristic curve was 0.65 (95% CI, 0.58 to 0.71), which was not statistically different from the development cohort (0.72; 95% CI, 0.68 to 0.77; P = .09). There was no association between Karnofsky Performance Status and chemotherapy toxicity (P = .25). CONCLUSION:This study externally validated a chemotherapy toxicity predictive model for older adults with cancer. This predictive model should be considered when discussing the risks and benefits of chemotherapy with older adults.
10.1200/JCO.2015.65.4327
Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma.
Fukudo Masahide,Ito Takuma,Mizuno Tomoyuki,Shinsako Keiko,Hatano Etsuro,Uemoto Shinji,Kamba Tomomi,Yamasaki Toshinari,Ogawa Osamu,Seno Hiroshi,Chiba Tsutomu,Matsubara Kazuo
Clinical pharmacokinetics
BACKGROUND AND OBJECTIVES:Sorafenib has various adverse events that can cause treatment discontinuation or dose reduction. The aim of this study was to compare the safety profile between renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) patients receiving sorafenib under real-life practice conditions. Furthermore, we investigated the relationship between sorafenib exposure and clinical outcomes. METHODS:A total of 91 Japanese cancer patients (RCC, n = 21; HCC, n = 70) treated with sorafenib were enrolled. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 4.0. Single blood samples were collected at each clinic visit and serum sorafenib concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The incidence of adverse events was analyzed according to cancer type and sorafenib concentration. RESULTS:Hand-foot skin reaction (HFSR) was the most common adverse event among RCC (76 %) and HCC (66 %) patients. Elevations in hepatic transaminases and pancreatic amylase developed more frequently in patients with RCC than in those with HCC (p < 0.05), while hyperbilirubinemia and thrombocytopenia were observed more often in HCC patients than in RCC patients (p < 0.05). Pharmacokinetic data were available from 52 patients (RCC, n = 16; HCC, n = 36). HCC patients showed significantly higher dose-normalized concentrations than RCC patients (p = 0.0184). Sorafenib concentrations were significantly greater in patients with grade ≥2 HFSR and hypertension than in those not experiencing the adverse events (p = 0.0045 and 0.0453, respectively). Furthermore, receiver operating characteristic curves revealed optimal cutoff concentrations of sorafenib to predict grade ≥2 HFSR (5.78 μg/mL) and hypertension (4.78 μg/mL). In addition, a trend of prolonged overall survival was observed in HCC patients who achieved a maximal sorafenib concentration of ≥4.78 μg/mL during treatment compared with those who did not achieve the threshold concentration (12.0 vs. 6.5 months; log-rank p = 0.0824). CONCLUSIONS:The results of this study suggest that the safety and pharmacokinetic profiles of sorafenib differ between Japanese cancer patients with RCC and HCC. Furthermore, the serum sorafenib concentration could be used as a guide to avoiding the development of severe HFSR while allowing prediction of the incidence of grade ≥2 hypertension in patients with RCC and HCC, and may potentially be related to the clinical efficacy of sorafenib for HCC.
10.1007/s40262-013-0108-z
Predicting mortality and adverse events in patients with advanced pancreatic cancer treated with palliative gemcitabine-based chemotherapy in a multicentre phase III randomized clinical trial: the APC-SAKK risk scores.
Gargiulo Piera,Dietrich Daniel,Herrmann Richard,Bodoky György,Ruhstaller Thomas,Scheithauer Werner,Glimelius Bengt,Berardi Simona,Pignata Sandro,Brauchli Peter
Therapeutic advances in medical oncology
BACKGROUND:The prognosis of advanced pancreatic cancer (APC) is poor and differs considerably among patients. Therefore, it is clinically relevant to identify patients with APC who are more likely to benefit from palliative chemotherapy with reduced risk of toxicity. To date, there is no prognostic score universally recommended to help clinicians in planning the therapeutic management. METHODS:Using individual patient data from 319 cases of APC treated with gemcitabine-based chemotherapy and enrolled in the SAKK 44/00-CECOG/PAN.1.3.001 randomized trial, several baseline variables, including inflammatory markers, were analysed as predictors of mortality and/or grade 3 or 4 chemotherapy-related toxicity and separate risk scores were developed. RESULTS:Median survival of the study patients was 7.9 months (interquartile range 3.7-13.3 months). Independent predictors of mortality included increased Aspartate transaminase (ASAT), low performance status, increased derived neutrophil to lymphocyte ratio, increased Carbohydrate Antigen 19-9 (CA 19-9), low haemoglobin, presence of pain, presence of metastasis and increased alkaline phosphatase (ALP). During the study, 117 patients experienced at least one grade 3 or 4 adverse event. Independent predictors of toxicity included white blood cells, ALP, renal function and bilirubin levels at baseline. Both models displayed moderate levels of discrimination (C-statistic 0.68 and 0.64 for mortality and toxicity, respectively) and adequate calibration. CONCLUSIONS:We developed simple-to-use prognostic scores for mortality and severe toxicity for patients with APC. These scores can be useful in daily practice to identify patients with increased risk of death or toxicity and to plan the most appropriate therapeutic strategy to improve survival and quality of life. Further prospective studies to validate such scores are needed.
10.1177/1758835918818351
A model-based patient selection tool to identify who may be at risk of exceeding dose tolerances during pancreatic SBRT.
Magallon-Baro Alba,Granton Patrick V,Milder Maaike T W,Loi Mauro,Zolnay Andras G,Nuyttens Joost J,Hoogeman Mischa S
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
PURPOSE:Locally advanced pancreatic cancer (LAPC) patients are prone to experience daily anatomical variations, which can lead to additional doses in organs-at-risk (OAR) during SBRT. A patient selection tool was developed to identify who may be at risk of exceeding dose tolerances, by quantifying the dosimetric impact of daily variations using an OAR motion model. MATERIALS AND METHODS:The study included 133 CT scans from 35 LAPC patients. By following a leave-one-out approach, an OAR motion model trained with the remaining 34 subjects variations was used to simulate organ deformations on the left-out patient planning CT anatomy. Dose-volume histograms obtained from planned doses sampled on simulated organs resulted in the probability of exceeding OAR dose-constraints due to anatomical variations. Simulated probabilities were clustered with a threshold per organ according to clinical observations. If the prediction of at least one OAR was above the established thresholds, the patient was classified as being at risk. RESULTS:Clinically, in 20/35 patients at least one OAR exceeded dose-constraints in the daily CTs. The model-based prediction had an accuracy of 89%, 71%, 91% in estimating the risk of exceeding dose tolerances for the duodenum, stomach and bowel, respectively. By combining the three predictions, our approach resulted in a correct patient classification for 29/35 patients (83%) when compared with clinical observations. CONCLUSIONS:Our model-based patient selection tool is able to predict who might be at risk of exceeding dose-constraints during SBRT. It is a promising tool to tailor LAPC treatments, e.g. by employing online adaptive SBRT; and hence, to minimize toxicity of patients being at risk.
10.1016/j.radonc.2019.09.016
Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer.
Clinical oncology (Royal College of Radiologists (Great Britain))
AIMS:Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS:Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS:CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm). Using a threshold of 30 cm, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS:In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents.
10.1016/j.clon.2018.02.067
Novel models for prediction of benefit and toxicity with FOLFIRINOX treatment of pancreatic cancer using clinically available parameters.
Schlick Konstantin,Magnes Teresa,Ratzinger Lukas,Jaud Bernhard,Weiss Lukas,Melchardt Thomas,Greil Richard,Egle Alexander
PloS one
BACKGROUND:Despite modern chemotherapy regimens, survival of pancreatic cancer patients remains dismal. Toxicity is a major concern and it is a challenge to upfront identify patients with the highest benefit from aggressive polychemotherapy. We aimed to evaluate ORR and side effects of the FOLFIRINOX regimen, highlighting dose modification and to explore possible prognostic response factors as a clinical tool. METHODS:This retrospective study includes 123 patients with metastatic PC that were treated with FOLFIRINOX between the years 2007 to 2016 in a single academic institution. Survival rates were analysed using the Kaplan-Meier method. Prognostic models including laboratory and clinical parameters were calculated using Cox proportional models in univariate and multivariate analyses. RESULTS:Median age at diagnosis was 64 years (47-78 years), 71 (57, 7%) were male and the majority had an ECOG performance status of 0 or 1 (63 patients; 83.7%). After a median follow up of 17.8 months, median progression free survival (PFS) and overall survival (OS) were 5.7 (4.55-6.84; 95%CI) and 11.8 months (9.35-14.24; 95%CI) respectively. Overall response rate with FOLFIRINOX was 34.9% and stable disease rate was 21.9%. Regarding Grade 3/4 side effects, 62 events, were reported in 37 patients. Looking at risk factors e.g. patient characteristics, tumor marker, inflammatory markers and body composition multivariate analyses proved CEA >4 elevation and BMI > 25 at the time point before palliative chemotherapy to be independent negative prognostic factors for OS. Grouping patients with no risk factor, one or two of these risk factors we analyzed a median OS of 17.4 moths, 9.6 months and 6.7 months (p<0.001) respectively. In addition we identified thrombocytosis and low BMI as predictors of early toxicity. CONCLUSION:This study identifies two easily available factors influencing overall survival with FOLFIRINOX therapy. By combining these two factors to create a score for OS, we propose a prognostic tool for physicians to identify patients, who are unlikely to benefit more from FOLFIRINOX or likely to experience toxicity.
10.1371/journal.pone.0206688
Clinical risk score for invasive fungal diseases in patients with hematological malignancies undergoing chemotherapy: China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.
Wang Ling,Wang Ying,Hu Jiong,Sun Yuqian,Huang He,Chen Jing,Li Jianyong,Ma Jun,Li Juan,Liang Yingmin,Wang Jianmin,Li Yan,Yu Kang,Hu Jianda,Jin Jie,Wang Chun,Wu Depei,Xiao Yang,Huang Xiaojun
Frontiers of medicine
Invasive fungal disease (IFD) is a major infectious complication in patients with hematological malignancies. In this study, we examined 4889 courses of chemotherapy in patients with hematological diseases to establish a training dataset (n = 3500) by simple random sampling to develop a weighted risk score for proven or probable IFD through multivariate regression, which included the following variables: male patients, induction chemotherapy for newly diagnosed or relapsed disease, neutropenia, neutropenia longer than 10 days, hypoalbuminemia, central-venous catheter, and history of IFD. The patients were classified into three groups, which had low (0-10, ~1.2%), intermediate (11-15, 6.4%), and high risk ( > 15, 17.5%) of IFD. In the validation set (n = 1389), the IFD incidences of the groups were ~1.4%, 5.0%, and 21.4%. In addition, we demonstrated that antifungal prophylaxis offered no benefits in low-risk patients, whereas benefits were documented in intermediate (2.1% vs. 6.6%, P = 0.007) and high-risk patients (8.4% vs. 23.3%, P = 0.007). To make the risk score applicable for clinical settings, a pre-chemo risk score that deleted all unpredictable factors before chemotherapy was established, and it confirmed that anti-fungal prophylaxis was beneficial in patients with intermediate and high risk of IFD. In conclusion, an objective, weighted risk score for IFD was developed, and it may be useful in guiding antifungal prophylaxis.
10.1007/s11684-018-0641-0
Sensitivity of dose-estimations for acute acetaminophen overdose in predicting hepatotoxicity risk using the Rumack-Matthew Nomogram.
Chomchai Summon,Mekavuthikul Pattaraporn,Phuditshinnapatra Jariya,Chomchai Chulathida
Pharmacology research & perspectives
Timely assessment of acetaminophen concentration in overdose situations is not always available in resource-poor settings. The 150 mg/kg dose-estimate for acetaminophen is widely considered as criterion for acetaminophen overdose. Its sensitivity and specificity when compared to the 150 mg/L treatment line on the Rumack-Matthew Nomogram (150-treatment line) has rarely been evaluated. This is a retrospective chart review of acute acetaminophen overdose patients. We evaluated the sensitivity and specificity of the 150, 200 mg/kg and 8- and 10-g dose-estimates by plotting the serum acetaminophen levels and using 150-treatment line on the Nomogram as the treatment cut-off. A comparison of medical care costs was performed. We enrolled 784 cases for analysis. Median (IQR) age was 23 (20-28) years (81.9% female). There were 545 cases (69.5%) where the estimated ingested acetaminophen dose were ≥150 mg/kg and 406 cases (51.8%) with concentrations ≥150-treatment line. Hepatotoxicity and acute liver injury (ALI) occurred in 7.3% and 23.9%, respectively. The sensitivity and specificity of 150 mg/kg dose-estimate for the 150-treatment line were 92.6% (95% CI 89.6, 94.8) and 55.3% (95% CI 50.3, 60.2). Among patients with dose-estimate below150 mg/kg, none developed hepatotoxicity and 17 (7.1%) develop ALI. The administration of activated charcoal significantly decreased the risk of being above the 150-treatment line by half. In resource-poor setings, the use of 150 mg/kg dose-estimate as a stand-alone criteria for initiation of N-acetylcysteine therapy is satisfactory, especially when combined with decontamination with activated charcoal and follow up of aminotransferase at 24 h.
10.1002/prp2.920
Pre-treatment serum total bilirubin level as an indicator of optimal CPT-11 dosage.
Makihara Katsuya,Azuma Sayaka,Kawato Nobuyuki,Ueno Hiroyuki,Nakata Izumi
Cancer chemotherapy and pharmacology
BACKGROUND:Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. METHODS:Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. RESULTS:Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB ≥0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule. CONCLUSIONS:PTB can be used as a predictive marker of CPT-11-induced severe neutropenia and FN. In patients with PTB ≥0.8 mg/dL, the CPT-11 dose should be reduced to less than 80 mg/m(2) with weekly dosing.
10.1007/s00280-014-2633-3
The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.
Ramchandani Roshni P,Wang Yaning,Booth Brian P,Ibrahim Amna,Johnson John R,Rahman Atiqur,Mehta Mehul,Innocenti Federico,Ratain Mark J,Gobburu Jogarao V S
Journal of clinical pharmacology
Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.
10.1177/0091270006295060
Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients.
Karas Spinel,Etheridge Amy S,Tsakalozou Eleftheria,Ramírez Jacqueline,Cecchin Erika,van Schaik Ron H N,Toffoli Giuseppe,Ratain Mark J,Mathijssen Ron H J,Forrest Alan,Bies Robert R,Innocenti Federico
The AAPS journal
Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.
10.1208/s12248-020-0429-4
An internally and externally validated nomogram for predicting the risk of irinotecan-induced severe neutropenia in advanced colorectal cancer patients.
Ichikawa W,Uehara K,Minamimura K,Tanaka C,Takii Y,Miyauchi H,Sadahiro S,Fujita K,Moriwaki T,Nakamura M,Takahashi T,Tsuji A,Shinozaki K,Morita S,Ando Y,Okutani Y,Sugihara M,Sugiyama T,Ohashi Y,Sakata Y
British journal of cancer
BACKGROUND:In Asians, the risk of irinotecan-induced severe toxicities is related in part to UGT1A1*6 (UGT, UDP glucuronosyltransferase) and UGT1A1*28, variant alleles that reduce the elimination of SN-38, the active metabolite of irinotecan. We prospectively studied the relation between the UGT1A1 genotype and the safety of irinotecan-based regimens in Japanese patients with advanced colorectal cancer, and then constructed a nomogram for predicting the risk of severe neutropenia in the first treatment cycle. METHODS:Safety data were obtained from 1312 patients monitored during the first 3 cycles of irinotecan-based regimen in a prospective observational study. In development of the nomogram, multivariable logistic regression analysis was used to test the associations of candidate factors to severe neutropenia in the first cycle. The final nomogram based on the results of multivariable analysis was constructed and validated internally using a bootstrapping technique and externally in an independent data set (n=350). RESULTS:The UGT1A1 genotype was confirmed to be associated with increased risks of irinotecan-induced grade 3 or 4 neutropenia and diarrhoea. The final nomogram included type of regimen, administered dose of irinotecan, gender, age, UGT1A1 genotype, Eastern Cooperative Oncology Group performance status, pre-treatment absolute neutrophil count, and total bilirubin level. The model was validated both internally (bootstrap-adjusted concordance index, 0.69) and externally (concordance index, 0.70). CONCLUSIONS:Our nomogram can be used before treatment to accurately predict the probability of irinotecan-induced severe neutropenia in the first cycle of therapy. Additional studies should evaluate the effect of nomogram-guided dosing on efficacy in patients receiving irinotecan.
10.1038/bjc.2015.122
Pharmacogenetic impact of UGT1A1 polymorphisms on pulmonary neuroendocrine tumours treated with metronomic irinotecan-based chemotherapy in Chinese populations.
Ma Xu,Han Sen,Liu Ying,Liu Jing-Tao,Fang Jian,Zhang Yan-Hua
The Journal of pharmacy and pharmacology
OBJECTIVES:To evaluate the effects of UGT1A1*6 and UGT1A1*28 polymorphisms on the safety and efficacy of metronomic irinotecan-based chemotherapy (IBC) in Chinese patients with pulmonary neuroendocrine tumours (PNTs). METHODS:Sixty-eight PNT patients who received metronomic IBC were observed. The quantitative fluorescent polymerase chain reaction was used to detect UGT1A1*6 and UGT1A1*28 polymorphisms. The follow-up data were collected to investigate the relationship between different genotypes and adverse drug reactions. The clinical outcomes of metronomic IBC were also evaluated. KEY FINDINGS:In the genotype-toxicity association analysis, patients with homozygous UGT1A1*6 had the highest incidence of grade 3-4 diarrhoea (P = 0.010). Compared to other groups, patients with the haplotype of UGT1A1*28 showed a trend towards an increased incidence of grade 4 neutropaenia (P = 0.047). A higher incidence of grade 3-4 leucopaenia was found in groups with UGT1A1*1/*28 (P = 0.023) and UGT1A1*28/*28 (P = 0.022). Grade 1 total bilirubin elevation was associated with the homozygous UGT1A1*6 mutation (P = 0.027) or any UGT1A1*6 variants (P = 0.047). However, neither UGTA1A*28 nor UGT1A1*6 showed any significant association with tumour response or clinical outcomes. CONCLUSIONS:The impact of UGT1A1 polymorphisms varies in different irinotecan-based chemotherapies. UGT1A1*6 and UGTA1A*28 were useful for the prediction of irinotecan-related severe toxicity in Chinese PNT patients treated with metronomic IBC.
10.1111/jphp.13333
Integration of DNA sequencing with population pharmacokinetics to improve the prediction of irinotecan exposure in cancer patients.
British journal of cancer
BACKGROUND:Irinotecan (CPT-11) is an anticancer agent widely used to treat adult solid tumours. Large interindividual variability in the clearance of irinotecan and SN-38, its active and toxic metabolite, results in highly unpredictable toxicity. METHODS:In 217 cancer patients treated with intravenous irinotecan single agent or in combination, germline DNA was used to interrogate the variation in 84 genes by next-generation sequencing. A stepwise analytical framework including a population pharmacokinetic model with SNP- and gene-based testing was used to identify demographic/clinical/genetic factors that influence the clearance of irinotecan and SN-38. RESULTS:Irinotecan clearance was influenced by rs4149057 in SLCO1B1, body surface area, and co-administration of 5-fluorouracil/leucovorin/bevacizumab. SN-38 clearance was influenced by rs887829 in UGT1A1, pre-treatment total bilirubin, and EGFR rare variant burden. Within each UGT1A1 genotype group, elevated pre-treatment total bilirubin and/or presence of at least one rare variant in EGFR resulted in significantly lower SN-38 clearance. The model reduced the interindividual variability in irinotecan clearance from 38 to 34% and SN-38 clearance from 49 to 32%. CONCLUSIONS:This new model significantly reduced the interindividual variability in the clearance of irinotecan and SN-38. New genetic factors of variability in clearance have been identified.
10.1038/s41416-021-01589-2
Predictive effects of bilirubin on response of colorectal cancer to irinotecan-based chemotherapy.
Yu Qian-Qian,Qiu Hong,Zhang Ming-Sheng,Hu Guang-Yuan,Liu Bo,Huang Liu,Liao Xin,Li Qian-Xia,Li Zhi-Huan,Yuan Xiang-Lin
World journal of gastroenterology
AIM:To examine the predictive effects of baseline serum bilirubin levels and UDP-glucuronosyltransferase (UGT) 1A1*28 polymorphism on response of colorectal cancer to irinotecan-based chemotherapy. METHODS:The present study was based on a prospective multicenter longitudinal trial of Chinese metastatic colorectal cancer (mCRC) patients treated with irinotecan-based chemotherapy (NCT01282658). Baseline serum bilirubin levels, including total bilirubin (TBil) and unconjugated bilirubin (UBil), were measured, and genotyping of UGT1A1*28 polymorphism was performed. Receiver operating characteristic curve (ROC) analysis was used to determine cutoff values of TBil and UBil. The TBil values were categorized into > 13.0 or ≤ 13.0 groups; the UBil values were categorized into > 4.1 or ≤ 4.1 groups. Combining the cutoff values of TBil and UBil, which was recorded as CoBil, patients were classified into three groups. The classifier's performance of UGT1A1*28 and CoBil for predicting treatment response was evaluated by ROC analysis. Associations between response and CoBil or UGT1A1*28 polymorphism were estimated using simple and multiple logistic regression models. RESULTS:Among the 120 mCRC patients, the serum bilirubin level was significantly different between the UGT1A1*28 wild-type and mutant genotypes. Patients with the mutant genotype had an increased likelihood of a higher TBil (P = 0.018) and a higher UBil (P = 0.014) level compared with the wild-type genotype. Patients were stratified into three groups based on CoBil. Group 1 was patients with TBil > 13.0 and UBil > 4.1; Group 2 was patients with TBil ≤ 13.0 and UBil > 4.1; and Group 3 was patients with TBil ≤ 13.0 and UBil ≤ 4.1. Patients in Group 3 had more than a 10-fold higher likelihood of having a response in the simple (OR = 11.250; 95%CI: 2.286-55.367; P = 0.003) and multiple (OR = 16.001; 95%CI: 2.802 -91.371; P = 0.002) analyses compared with the Group 1 individuals. Patients carrying the UGT1A1*28 (TA)7 allele were 4-fold less likely to present with a response compared with the individuals harboring a homozygous (TA)6 genotype in the simple (OR = 0.267; 95%CI: 0.100-0.709; P = 0.008) and multiple (OR = 0.244; 95%CI: 0.088-0.678; P = 0.007) analyses. Classifier's performance of CoBil and UGT1A1*28 were comparable. CONCLUSION:CoBil and UGT1A1*28 are both independent biomarkers for predicting the treatment response of mCRC patients to irinotecan-based chemotherapy. After validation, CoBil, an easily determinable index in the clinic, might be helpful in facilitating stratification of mCRC patients for individualized treatment options.
10.3748/wjg.v22.i16.4250
The role of albumin-bilirubin grade and inflammation-based index in patients with hepatocellular carcinoma treated with stereotactic body radiotherapy.
Gkika Eleni,Bettinger Dominik,Krafft Leo,Schultheiss Michael,Neeff Hannes Philipp,Maruschke Lars,Schulenburg Michaela,Adebahr Sonja,Kirste Simon,Nestle Ursula,Thimme Robert,Grosu Anca-Ligia,Brunner Thomas Baptist
Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]
PURPOSE:We evaluated the prognostic accuracy of the albumin-bilirubin (ALBI) grade and the inflammation-based index (IBI) in estimating overall survival (OS) and toxicity in patients with hepatocellular carcinoma (HCC) treated with stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS:Forty patients with 47 HCC lesions with a Barcelona Clinic Liver Cancer (BCLC) classification stage B or C were treated with SBRT in 3-12 fractions. The ALBI grade and the IBI were calculated at different time points (baseline, during, at the end of treatment and at follow-up) and compared with the Child-Pugh (CP) score as well as other patient- and treatment-related parameters, concerning OS and toxicity. RESULTS:The median follow-up was 14.3 months for patients alive. The median OS from SBRT was 10 (95% confidence interval 8.3-11.6) months. The local control at 1 year was 79%. A lower IBI during treatment was associated with better OS (p = 0.034) but not CP and ALBI. Higher C‑reactive protein levels as well as higher alpha-fetoprotein concentrations correlated with worse survival (p = 0.001). Both higher ALBI (p = 0.02) and CTP (p = 0.001) at baseline correlated with a higher incidence of acute and late toxicities (CTC ≥2). Neither the mean radiation dose to the liver nor the dose to 700 cc of the liver correlated with the occurrence of toxicities. CONCLUSIONS:In this analysis, a higher ALBI grade as well as a higher CP were predictors of higher incidence of toxicity, whereas a lower IBI during treatment correlated with a better OS. These results should be further evaluated in prospective studies.
10.1007/s00066-017-1256-0
Pretreatment Systemic Inflammation Response Index in Patients with Breast Cancer Treated with Neoadjuvant Chemotherapy as a Useful Prognostic Indicator.
Cancer management and research
BACKGROUND AND OBJECTIVE:Systemic inflammation response index (SIRI=N×M/L), based on neutrophil (N), monocyte (M), and lymphocyte (L) counts, is used to predict the survival of patients with malignant tumors and can fully evaluate the balance between host immune and inflammatory condition. The present study is aimed to evaluate the potential prognostic significance of SIRI in patients with breast cancer undergoing neoadjuvant chemotherapy. SUBJECTS AND METHODS:A total of 262 breast cancer patients treated with neoadjuvant chemotherapy were enrolled in this retrospective study. The optimal cutoff value of SIRI by receiver operating characteristic curve stratified patients into low SIRI (<0.85×10/L) group and high SIRI (≥0.85×10/L) group. The associations between breast cancer and clinicopathological variables by SIRI were determined by chi-square test or Fisher's exact test. Kaplan-Meier plots and log-rank test were used to evaluate the clinical outcomes of disease-free survival (DFS) and overall survival (OS). Univariate and multivariate Cox proportional hazards regression models were used to analyze the prognostic value of SIRI. The toxicity of neoadjuvant chemotherapy was evaluated by the National Cancer Institute Common Toxicity Criteria (NCICTC). RESULTS:The results were shown that SIRI had prognostic significance by optimal cutoff value of 0.85×10/L on DFS and OS in univariate and multivariate Cox regression survival analyses. Compared with patients who had high SIRI, patients with low SIRI had longer DFS and OS (41.27 vs 30.45 months, HR: 1.694, 95% CI: 1.128-2.543, P=0.011; 52.86 vs 45.75 months, HR: 1.288, 95% CI: 0.781-3.124, P=0.002, respectively). The patients with low SIRI had better 3-, 5-, and 10-year rates of DFS and OS than those with high SIRI. The common toxicities after neoadjuvant chemotherapy were hematologic and gastrointestinal reaction, and the SIRI had no significance on toxicities of all enrolled patients, excepted diarrhea. In patients without neural invasion, those with low SIRI had better prognosis and lower recurrence rates than those with high SIRI. CONCLUSION:Pretreatment SIRI with the advantage of repeatable, convenient, and non-invasive is a useful prognostic indicator for breast cancer patients who received neoadjuvant chemotherapy and is a promising biomarker for breast cancer on treatment strategy decisions.
10.2147/CMAR.S235519
Prognostic Nutritional Index Predicts Toxicity in Head and Neck Cancer Patients Treated with Definitive Radiotherapy in Association with Chemotherapy.
Fanetti Giuseppe,Polesel Jerry,Fratta Elisabetta,Muraro Elena,Lupato Valentina,Alfieri Salvatore,Gobitti Carlo,Minatel Emilio,Matrone Fabio,Caroli Angela,Revelant Alberto,Lionello Marco,Zammattio Polentin Viviana,Ferretti Andrea,Guerrieri Roberto,Chiovati Paola,Bertolin Andy,Giacomarra Vittorio,Paoli Antonino De,Vaccher Emanuela,Sartor Giovanna,Steffan Agostino,Franchin Giovanni
Nutrients
BACKGROUND:The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy. METHODS:A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model; hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model. RESULTS:median PNI was 50.0 (interquartile range: 45.5-53.5). Low PNI was associated with higher risk of weight loss > 10% during treatment (OR = 4.84, 95% CI: 1.73-13.53 for PNI < 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84; 95% CI:1.09-3.12). PNI predicts acute weight loss >10% and late mucositis. CONCLUSIONS:PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.
10.3390/nu13041277
Comparison of the predictive value among inflammation-based scoring systems for bleomycin pulmonary toxicity in patients with germ cell tumors.
Maruyama Yuki,Sadahira Takuya,Araki Motoo,Mitsui Yosuke,Wada Koichiro,Edamura Kohei,Kobayashi Yasuyuki,Watanabe Masami,Watanabe Toyohiko,Nasu Yasutomo
International journal of urology : official journal of the Japanese Urological Association
OBJECTIVE:To compare the predictive value of pretreatment inflammation-based scoring systems in patients with germ cell tumors receiving first-line bleomycin-based chemotherapy. METHODS:Retrospectively, we evaluated 57 patients with germ cell tumors. Bleomycin pulmonary toxicity was defined as the presence of asymptomatic decline in pulmonary function tests, pulmonary symptoms or interstitial pneumonia on computed tomography in the absence of infection. The neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, albumin-to-globulin ratio, Prognostic Nutritional Index, Glasgow Prognostic Score and C-reactive protein were measured in all patients. To assess the predictive ability of each scoring system, the area under the receiver operating characteristic curve was calculated, and multivariate analysis was carried out to identify the predictive scores associated with bleomycin pulmonary toxicity. RESULTS:Of the 57 patients, 15 patients developed bleomycin pulmonary toxicity. The neutrophil-to-lymphocyte ratio had the highest area under the curve value (0.763) of all inflammation-based scoring systems, followed by the Prognostic Nutritional Index (0.749). In multivariate analysis, the neutrophil-to-lymphocyte ratio (odds ratio 11.5; P = 0.009) and Prognostic Nutritional Index (odds ratio 9.07; P = 0.013) were independently associated with development of bleomycin pulmonary toxicity. As these two independent markers were combined, the area under the curve achieved the highest value (0.822). CONCLUSIONS:The present study shows that the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index are independent risk factors for development of bleomycin pulmonary toxicity. The combination of the neutrophil-to-lymphocyte ratio and Prognostic Nutritional Index seems to have superior predictive value compared with other inflammation-based scoring systems.
10.1111/iju.14017
Pre-treatment systemic immune-inflammation index is a useful prognostic indicator in patients with breast cancer undergoing neoadjuvant chemotherapy.
Chen Li,Kong Xiangyi,Wang Zhongzhao,Wang Xiangyu,Fang Yi,Wang Jing
Journal of cellular and molecular medicine
The systemic immune-inflammation index (SII = N × P/L) based on neutrophil (N), platelet (P) and lymphocyte (L) counts is used to predict the survival of patients with malignant tumours and can fully reflect the balance between host inflammatory and immune status. This study is conducted to explore the potential prognostic significance of SII in patients with breast cancer undergoing neoadjuvant chemotherapy (NACT). A total of 262 patients with breast cancer received NACT were enrolled in this study. According to the receiver operating characteristic curve, the optimal cut-off value of SII was divided into two groups: low SII group (<602 × 10 /L) and high SII group (≥602 × 10 /L). The associations between breast cancer and clinicopathological variables by SII were determined by chi-squared test or Fisher's exact test. The Kaplan-Meier plots and log-rank test were used to determine clinical outcomes of disease-free survival (DFS) and overall survival (OS). The prognostic value of SII was analysed by univariate and multivariate Cox proportional hazards regression models. The toxicity of NACT was accessed by National Cancer Institute Common Toxicity Criteria (NCICTC). According to univariate and multivariate Cox regression survival analyses, the results showed that the value of SII had prognostic significance for DFS and OS. The patients with low SII value had longer DFS and OS than those with high SII value (31.11 vs 40.76 months, HR: 1.075, 95% CI: 0.718-1.610, P = .006; 44.47 vs 53.68 months, HR: 1.051, 95% CI: 0.707-1.564, P = .005, respectively). The incidence of DFS and OS in breast cancer patients with low SII value was higher than that in those patients with high SII value in 3-, 5- and 10-year rates. The common toxicities after NACT were haematological and gastrointestinal reaction, and there were no differences by SII for the assessment of side effects of neoadjuvant chemotherapy. Meanwhile, the results also proved that breast cancer patients with low SII value and high Miller and Payne grade (MPG) survived longer than those breast cancer with high SII value and low MPG grade. In patients without lymph vessel invasion, these breast cancer patients with low SII value had better prognosis and lower recurrence rates than those with high SII value. Pre-treatment SII with the advantage of reproducible, convenient and non-invasive was a useful prognostic indicator for breast cancer patients undergoing neoadjuvant chemotherapy and is a promising biomarker for breast cancer on treatment strategy decisions.
10.1111/jcmm.14934
Comparison of effects of UGT1A1*6 and UGT1A1*28 on irinotecan-induced adverse reactions in the Japanese population: analysis of the Biobank Japan Project.
Hikino Keiko,Ozeki Takeshi,Koido Masaru,Terao Chikashi,Kamatani Yoichiro,Murakami Yoshinori,Kubo Michiaki,Mushiroda Taisei
Journal of human genetics
It has been reported that there are differences in effects on irinotecan-induced adverse reactions between UGT1A1*6 and UGT1A1*28. In order to compare those differences in the Japanese population, we examined the associations between UGT1A1 and irinotecan-induced adverse reactions using the BioBank Japan Project database. We genotyped UTG1A1*6 and UGT1A1*28 and conducted case-control analyses. A total of 651 patients (102 cases and 549 tolerant controls) were included in this study. The results showed that UGT1A1*6/*6 is a predictor of adverse drug reactions (ADRs) (p-value 0.00070, odds ratio 6.59, 95% confidence interval 2.33-18.6), whereas UGT1A1*6/*28 and UGT1A1*28/*28 were not. The subanalysis comprising only patients with UGT1A1*6/*6, UGT1A1*6/*28, and UGT1A1*28/*28 revealed a trend towards an increased risk of ADRs in patients with UGT1A1*6 (p-value 0.0092, odds ratio 4.39, 95% confidence interval 1.57-14.9). Multiple logistic regression analyses showed that use of platinum-based antineoplastic drugs and presence of UGT1A1*6/*6 were independent variables, significantly associated with ADRs. The diagnostic performance of a predictive model had a sensitivity of 49.0%, specificity of 70.1%, and a number needed to screen of 5.8. We concluded that UGT1A1 testing could be useful to predict irinotecan-induced ADRs, and that UTG1A1*6 rather than UGT1A1*28 contributed to ADR occurrence.
10.1038/s10038-019-0677-2