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1.
PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients.
Lapucci, A, Perrone, G, Di Paolo, A, Napoli, C, Landini, I, Roviello, G, Calosi, L, Naccarato, AG, Falcone, A, Bani, D, et al
Oncology research. 2021;(6):631-644
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Abstract
The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages IIIII CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages IIIII CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages IIIII CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.
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Hypertriglyceridemia induced by S-1: A novel case report and review of the literature.
Saito, Y, Takekuma, Y, Komatsu, Y, Sugawara, M
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2021;(4):1020-1025
Abstract
INTRODUCTION S-1, a compounding agent of tegafur, gimeracil, and oteracil potassium, is one of the most effective chemotherapeutic agents for colorectal cancer. In this case, following S-1 administration, we observed predominant elevation of serum triglyceride. CASE REPORT A 49-year-old man with stage IV transverse colon adenocarcinoma received S-1 + irinotecan + bevacizumab. At the end of the S-1 administration period in every course, his serum triglyceride level was found to be elevated. Finally, it reached grade 4, without any symptoms of acute pancreatitis in the fifth course, and fenofibrate 80 mg once a day was administered.Management & outcome: Interestingly, the elevation spontaneously normalized without any pharmacotherapy 14 days after S-1 withdrawal, and this elevation did not occur when S-1 was not administered. Further, fenofibrate administration attenuated the hypertriglyceridemia to grades 1-3, with no complications. DISCUSSION S-1 administration induced hypertriglyceridemia owing to the elevated serum triglyceride; however, a contrasting result was observed in the S-1 withdrawal period and during the S-1-cessation cycle. Since dietary intake was poorer during the S-1 administration period, it is considered that S-1 might have disturbed lipid metabolism. Further, we know that capecitabine, which is a prodrug of fluorouracil, also induces hypertriglyceridemia. As the end product of these medicines is fluorouracil, the presence of fluorouracil or its metabolizing enzymes, the genetic background of the patient might have affected the results. We have to be aware of the risk of asymptomatic and temporal occurrence of hypertriglyceridemia by S-1 administration for the early detection with appropriate pre-emptive treatment.
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Advances in adjuvant therapy of biliary tract cancer: an overview of current clinical evidence based on phase II and III trials.
Belkouz, A, Wilmink, JW, Haj Mohammad, N, Hagendoorn, J, de Vos-Geelen, J, Dejong, CHC, Homs, MYV, Groot Koerkamp, B, van Gulik, TM, van Oijen, MGH, et al
Critical reviews in oncology/hematology. 2020;:102975
Abstract
Patients with biliary tract cancer (BTC) have a high recurrence rate after complete surgical resection. To reduce the risk of recurrence and to improve survival, several chemotherapeutic agents that have shown to be active in locally advanced and metastatic BTC have been investigated in the adjuvant setting in prospective clinical trials. Based on the results of the BILCAP phase III trial, capecitabine was adapted as the standard of care by the ASCO clinical practice guideline. Ongoing randomized controlled trials mainly compare capecitabine with gemcitabine-based chemotherapy or chemoradiotherapy. This review provides an update of adjuvant therapy in BTC based on published data of phase II and III trials and ongoing randomized controlled trials (RCTs).
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Dose-dense TPF induction chemotherapy for locally advanced head and neck cancer: a phase II study.
Hsieh, CY, Lein, MY, Yang, SN, Wang, YC, Lin, YJ, Lin, CY, Hua, CH, Tsai, MH, Lin, CC
BMC cancer. 2020;(1):832
Abstract
BACKGROUND Phase 3 studies suggest that induction chemotherapy (ICT) of cisplatin and 5-fluorouracil plus docetaxel (TPF) is effective but toxic for patients with squamous-cell carcinoma of the head and neck (SCCHN). Dose-dense chemotherapy may yield favorable outcomes compared with standard-dose chemotherapy, yet the optimal induction regimen remains undefined. We assessed the efficacy and tolerability of biweekly dose-dense TPF ICT in patients with SCCHN. METHODS In this prospective phase II study, We enrolled patients with stage III/IV (AJCC 7th edition) unresectable squamous cell carcinoma of head and neck cancer. Patients received dose-dense TPF (ddTPF) with cisplatin and docetaxel 50 mg/m2 on day 1, leucovorin 250 mg/m2 on day1, followed by 48-h continuous infusion of 2500 mg/m2 of 5-fluorouracil on day 1 and 2, every 2 weeks for 6 cycles followed by radiotherapy. The primary endpoint was the response rate (RR) after ICT. RESULTS Fifty-eight patients were enrolled from June 2014 to September 2015. Overall RR after ICT was 89.6% [complete response (CR), 31%; partial response (PR), 58.6%]. Grade 3/4 neutropenia, mucositis, and diarrhea incidences were 25.9, 1.7, and 1.7%, respectively. 94.8% of patients completed all treatment courses of ICT without dose reduction. The 3-year overall survival (OS) was 54.3% (95%CI: 39.7 to 66.8%) and progression-free survival (PFS) was 34.3% (95%CI: 22.0 to 46.9%). Multivariate analysis showed that CR after ICT is an independent prognostic factor for OS and PFS. CONCLUSIONS Six cycles of ddTPF is an active, well-tolerated induction regimen for patients with SCCHN. The presence of CR after ICT predicted long-term survival. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04397341 , May 21, 2020, retrospectively registered.
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Maintenance treatment with fluoropyrimidine plus bevacizumab versus fluoropyrimidine alone after induction chemotherapy for metastatic colorectal cancer: The BEVAMAINT - PRODIGE 71 - (FFCD 1710) phase III study.
Manfredi, S, Turpin, A, Malka, D, Barbier, E, Laurent-Puig, P, Zaanan, A, Dahan, L, Lièvre, A, Phelip, JM, Michel, P, et al
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2020;(10):1143-1147
Abstract
BACKGROUND Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. METHODS BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.
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How to rescue high-dose methotrexate induced nephrotoxicity and literature review about hemodiafiltration?
Yang, YY, Gao, L, Ding, N, Wang, XB, Zhang, LP, Gao, LH, Wang, Z
Pakistan journal of pharmaceutical sciences. 2020;(3):1163-1167
Abstract
Methotrexate (MTX) is a highly renal and liver toxicity drug used in hematological malignancy treatment in children and adults. High-dose methotrexate (HD-MTX) therapy may cause impairment of kidney and decrease the elimination of MTX, at the same time, the serum concentration of MTX increased. Today the treatment for preventing MTX toxicity after renal shutdown is Carboxypeptidase. We report a patient who experienced nephrotoxicity after the HD-MTX infusions during the treatment for non-Hodgkin lymphoma (NHL) and received hemodiafiltration (HDF) with large dose of leucovorin (LV) to treat MTX intoxication. LV is very potent in the prevention of neurotoxicity and administration of LV could protect the normal cells, but the dosage and duration of LV should be according to the MTX concentration. Although a large dose of LV was applied, the patient's condition did not improve. It was found that the HDF with large dose of LV to save the patient and steadily improved the patient's clinical condition.
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Potential thiamine deficiency and neurological symptoms in patients receiving chemotherapy for gastrointestinal cancer.
Iimura, Y, Kurokawa, T, Nojima, M, Kanemoto, Y, Yazawa, K, Tsurita, G, Kuroda, S
International journal of clinical pharmacology and therapeutics. 2020;(3):139-145
Abstract
OBJECTIVES The aim of this retrospective study was to search for risk factors for neurological adverse events in gastrointestinal cancer patients receiving chemotherapy and analyze the relationship between thiamine serum levels and neurological adverse events. MATERIALS AND METHODS This is a single-center retrospective observational study. We enrolled patients who were diagnosed with gastrointestinal cancer at our hospital, for whom we measured the thiamine serum levels. We then performed a multivariate analysis (logistic regression) to identify risk factors for the neurological symptoms in our cohort. We then divided the patients into two groups, with and without neurological symptoms, based on their electronic medical records. By using the Mann-Whitney U-test, we performed a comparative analysis of the thiamine serum levels between the two groups. We also used descriptive statistics to examine the presence/absence of neurological symptoms or other potentially related clinical features in patients with decreased thiamine serum levels. RESULTS The logistic regression analysis detected the decrease in thiamine serum levels as a statistically significant risk factor for neurological symptoms. The analysis of the relationship between the presence/absence of neurological symptoms and thiamine serum levels showed that the thiamine serum levels were significantly lower in the group presenting neurological symptoms. Descriptive statistics showed that all the patients with decreased thiamine serum levels had either cognitive decline, attention decline, or depression symptoms, and most of them were receiving the 5-fluorouracil anticancer drug and showing decreased serum albumin levels. We also observed a slight decrease in serum sodium, vitamin B12, and folate levels. CONCLUSION When neurological symptoms occur in patients receiving chemotherapy for gastrointestinal cancer, the measurement of thiamine serum levels may become a standard reference for treatment indication.
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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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Consumption of Lactose, Other FODMAPs and Diarrhoea during Adjuvant 5-Fluorouracil Chemotherapy for Colorectal Cancer.
Holma, R, Laatikainen, R, Orell, H, Joensuu, H, Peuhkuri, K, Poussa, T, Korpela, R, Österlund, P
Nutrients. 2020;(2)
Abstract
Chemotherapy-induced mucosal injury of the small intestine may interfere with the enzymes and transporters responsible for the hydrolysis and absorption of dietary carbohydrates causing diarrhoea, abdominal discomfort and pain. The aim of this study was to investigate the association between the consumption of foods rich in FODMAPs (fermentable oligo-, di- and monosaccharides and polyols) and gastrointestinal symptoms in patients receiving adjuvant therapy for colorectal cancer. The patients (n = 52) filled in a 4-day food diary at baseline and during therapy and kept a symptom diary. The intakes of FODMAP-rich foods were calculated as portions and the intakes were divided into two consumption categories. Patients with high consumption of FODMAP-rich foods had diarrhoea more frequently than those with low consumption (for lactose-rich foods the odds ratio (OR) was 2.63, P = 0.03; and for other FODMAP-rich foods 1.82, P = 0.20). Patients with high consumption of both lactose-rich and other FODMAP-rich foods had an over 4-fold risk of developing diarrhoea as compared to those with low consumption of both (OR, 4.18; P = 0.02). These results were confirmed in multivariate models. Conclusion: Consumption of lactose-rich foods results in an increased risk of diarrhoea during adjuvant therapy for colorectal cancer, especially when the consumption of other FODMAP-rich foods is also high.
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Efficacy of Oral Vitamin A in Reducing β-hCG Levels in Low-Risk Gestational Trophoblastic Neoplasia Patients.
Hidayat, YM, Darmadi A, E, Rachmayati, S, Kusumah, WP, Djuwantono, T, Pramatirta, AY, Suardi, D
Asian Pacific journal of cancer prevention : APJCP. 2020;(11):3325-3329
Abstract
OBJECTIVE Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy and methotrexate (MTX) as a first-line therapy. Vitamin A helps to increase trophoblast cell regression, as well as to decrease β-hCG levels. Vitamin A also increases the effectiveness of MTX by inducing more malignant cell death than MTX alone. Therefore, the aim of the current study was to analyze the changes in β-hCG levels in low-risk GTN patients following vitamin A administration. METHODS This study was a randomized clinical trial, which examined initial serum vitamin A and β-hCG levels in GTN patients before and after three cycles of MTX therapy. Patients were given vitamin A supplementation of 6,000 IU (1.8 mg RAEs) per day, and the changes in serum β-hCG were observed after three cycles. Patients were grouped by β-hCG levels (decreased or stagnant). RESULTS A total of 32 low-risks GTN patients were divided into the intervention group (16 patients who received vitamin A supplementation) and the control group (16 patients who did not receive vitamin A supplementation). In the intervention group, the average initial β-hCG level was 170,949.3 ± 354,452.1 mIU/mL, and the average β-hCG post-cycle level was 1,611.9 ± 3,652.5 mIU/mL. In the control group, the average initial β-hCG level was 178,834.1 ± 2913844.6 mIU/mL, and the average β-hCG post-cycle level was 25,388.5 ± 58,437.7 mIU/mL. CONCLUSION In patients with low-risk GTN who underwent MTX chemotherapy, the levels of β-hCG and the incidence of chemo resistance in the intervention group were lower than those in the control group. Older age may also influence the incidence of chemo resistance in GTN patients. Oral administration of 6,000 IU vitamin A could help to reduce β-hCG levels in low-risk GTN patients who receive MTX chemotherapy.
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