Evaluating the effects of duloxetine on prophylaxis of oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancer: A randomized double-blind placebo controlled clinical trial.

BACKGROUND: Oxaliplatin is a key drug in treatment of gastrointestinal (GI) cancer. Peripheral neuropathy (PN) is a troublesome and dose-dependent adverse effect of oxaliplatin. It can occur in two distinct forms: acute and chronic. Its incidence is estimated about 65-98%, of which 22% of cases need to stop chemotherapy. In some cases, PN has a long-lasting effect on patient's quality of life (QOL). Therefore, this study was done to evaluate efficacy of duloxetine on prevention of oxaliplatin- induced peripheral neuropathy (OIPN) in patients with GI cancer. METHODOLOGY: In this randomized and double -blind clinical trial study conducted in a tertiary teaching hospital, eligible patients were divided into two groups. Treatment group received duloxetine the day before initiation of chemotherapy regimen at a dose of 30 mg/day for one week and then, the dose was titrated up to 60 mg/day until 12 weeks. For placebo group, one placebo capsule was prescribed daily for one week followed by 2 capsules daily until 12 weeks. In each of chemotherapy courses, PN was assessed using national cancer institute-common terminology criteria for adverse effects (NCI-CTCAE v4.03). Also, chemotherapy -related QOL at the baseline and 12 weeks was assessed by functional assessment of cancer treatment gynecologic oncology group - neurotoxicity (FACT/GOG-NTX). RESULTS: Forty patients were randomly assigned to treatment and placebo groups which were similar to each other in terms of chemotherapy regimen, type, and stage of cancer. Analysis of results obtained from the NCI-CTCAE (v4.03) showed that duloxetine could prevent worsening of paresthesia more than placebo (P = 0.025) and patients in duloxetine group experienced less peripheral sensory neuropathy (P = 0.001) than placebo group. Analysis of results obtained from the FACT/GOG-NTX demonstrated a significant worsening of tingling and discomfort in hands (P = 0.002, 0.001, respectively) and feet (P = 0.017, 0.019, respectively) in placebo group compared to duloxetine group. Also, patients experienced more cold temperature -induced pain in extremities (P = 0.001) in placebo group compared to duloxetine group. On the other hand, duloxetine could not improve QOL (P = 0.06) and had not significant effects on trouble feeling the shape of small objects in hand (P = 0.420) or trouble buttoning buttons (P = 0.086). The P-value < 0.05 was considered to be statistically significant.

[GEM plus CDDP Combination Therapy for Unresectable Biliary Tract Cancer-A Single Institution Experience].

BACKGROUND: Since a randomized phase Ⅲ trial conducted in the UK in 2009 showed the superiority of gemcitabine (GEM)plus cisplatin(CDDP)combination therapy over GEM monotherapy, GEM plus CDDP combination therapy has been first-line chemotherapy for unresectable biliary tract cancer. METHODS: GEM plus CDDP combination therapy was administered to 29 patients with unresectable biliary tract cancer from 2016 to 2021. RESULTS: The mean age was 71.9 years, male/ female 19/10. The target of chemotherapy was below, local progression was 3 cases, first distant metastasis 7 cases, metastatic recurrence 19 cases. The type of cancer was below, intrahepatic bile duct carcinoma was 8 cases, hepatic hilar bile duct carcinoma 6 cases, gallbladder carcinoma 5 cases, cystic duct carcinoma 1 case, distal bile duct carcinoma 6 cases, and papilla Vater's cancer 3 cases. The dosing period was 23.1 weeks(range 2-52 weeks). The relative dose intensities of GEM and CDDP were 73.7% and 75.1%. The adverse events were below, the hematological toxicities of Grade 3 or higher were neutropenia(65.5%), leukopenia(3.4%), and thrombocytopenia(10.3%). Non-hematological toxicities of Grade 2 or higher were fatigue(13.7%)and skin rash(6.9%). There was no interstitial pneumonia. The disease control rate was 66.7 %(complete response, n=0; partial response, n=6; stable disease, n=10; progressive disease, n=8). CONCLUSION: GEM plus CDDP combination therapy was safe to perform and was an effective treatment for unresectable biliary tract cancer.

Impact of L-carnitine on imatinib-related muscle cramps in patients with gastrointestinal stromal tumor.

Introduction Muscle cramps constitute one of the leading adverse events of imatinib, the standard first-line treatment for advanced gastrointestinal stromal tumor (GIST). This study aims to assess the impact of L-carnitine on relieving cramps in patients with GIST taking imatinib. Materials and methods We reviewed our prospective database for patients with GIST who took L-carnitine (500-mg tablet, 2-3 times daily) for muscle cramps in Asan Medical Center. The assessment tool included severity by the numeric rating scale (NRS), frequency, duration of cramps, and questionnaire for the disturbance in basic activities of daily living (ADL), instrumental ADL (iADL), outdoor activity, or sleeping before and after L-carnitine treatment. Results We examined 42 patients [median age: 60 (range: 17-81) years; males, 52.4%] who received L-carnitine for cramps on NRS ≥ 4 intensity during 2016-2017. In 83.3% of patients (n = 35), the NRS score declined to <4 points, with 8 patients (19.0%) experiencing complete disappearance of symptoms [median response time: 10 (range: 2-30) days]. Moreover, the median duration of each episode and frequency decreased from 5 to 2 min and from 30 to 3 times per month (P < 0.001), respectively. We observed substantial improvement in all quality-of-life aspects after L-carnitine (ADL, 73.2%-14.6%; iADL, 73.2%-17.1%; sleeping, 78.0%-22.0%; outdoor activity, 68.3%-17.1%; P < 0.001). ConclusionL-carnitine could effectively relieve imatinib-related muscle cramps in patients with GIST. Accordingly, a randomized phase 3 study is currently ongoing (NCT03426722).

Neuroendocrine Cancer, Therapeutic Strategies in G3 Cancers.

BACKGROUND: According to the latest WHO classification, neuroendocrine neoplasm (NEN) G3 of the gastrointestinal tract is defined by a proliferation index Ki67 above 20%. Gastrointestinal neuroendocrine carcinoma (NEC) is a rare and highly aggressive malignancy and despite responsiveness to chemotherapy, overall survival is poor. In the last 3-4 years, the heterogeneity of the NEN G3 group has become evident. SUMMARY: In addition to the proliferative activity, the tumour differentiation seems to play a major role, further dividing the NEN G3 group into neuroendocrine tumour (NET) G3 and NEC. NET G3 often arise in the pancreas, and their median proliferation rate is lower and prognosis is better as compared to NEC. However, NET G3 show a limited response to platinum-based chemotherapy. Lack of specific data for NET G3 hampers clear therapeutic recommendations. Cisplatin combined with etoposide is the established standard regimen for advanced gastrointestinal NEC. Substituting carboplatin for cisplatin or irinotecan for etoposide is considered alternative first-line regimen. There is no standard second-line treatment; options are discussed within this review. KEY POINTS: (1) In NEN G3, the distinction between NET G3 and NEC G3 is clinically and prognostically meaningful. (2) Platinum-based chemotherapy remains the recommended first-line treatment in metastasized NEC patients. (3) There is no established standard for NET G3; treatments established for NET G2 such as temozolomide-based chemotherapy or peptide receptor radiotherapy may be considered. (4) Specific trials for NET G3 are necessary. (5) New therapies for NEC are urgently needed. Checkpoint inhibitors should be evaluated.

[Gastrointestinal stromal tumors: surgical treatment and targeted therapy]. / Gastrointestinal'nye stromal'nye opukholi: khirurgicheskoe lechenie i targetnaia terapiia.

AIM: To improve surgical and complex treatment of patients with gastrointestinal stromal tumors (GIST). MATERIAL AND METHODS: Our analysis included 97 GIST patients who were at Petrovsky Russian Research Center of Surgery and Moscow City Oncological Hospital #62 from January 2006 to September 2016. RESULTS: Advisability of surgery for GIST patients was confirmed. We have assessed surgical outcomes, defined the indications for adjuvant targeted therapy depending on GIST prognostic risk and additional factors for unfavorable course of disease. CONCLUSION: It was concluded that surgical treatment is preferred for patients with resectable GISTs. Adjuvant therapy is indicated in patients with high risk of progression if mutations indicating tumor sensitivity to the drugs are revealed. Adjuvant targeted therapy is not indicated in patients with low and very low risk of progression.

Efficacy of Sucralfate Mouth Wash in Prevention of 5-fluorouracil Induced Oral Mucositis: A Prospective, Randomized, Double-Blind, Controlled Trial.

Sucralfate has been used for the prevention and treatment of radiotherapy- and chemotherapy-induced stomatitis and mucositis in a number of studies, but the results are contradictory. To answer such discrepancies, the present study was designed to evaluate the efficacy of sucralfate mouthwash in prevention of 5-fluorouracil (5-FU)-induced oral mucositis in patients with gastrointestinal malignancies. Patients with gastrointestinal cancers receiving 5-FU-based chemotherapy regimens were included in this randomized, blinded, controlled trial and were randomly allocated to either sucralfate mouthwash (every 6 h) or placebo. The patients were visited at fifth and tenth day of trial; the presence and severity of oral mucositis and the intensity of pain were assessed. The patients receiving sucralfate experienced lower frequency and severity of mucositis (76% vs. 38.5%, P = 0.005 and 84 vs. 38.5%, P < 0.001, respectively) and less intense pain (2.5 ± 2.2 vs. 5.08 ± 3.82, P = 0.004 and 1.33 ± 0.86 vs. 4.12 ± 3.5, P = 0.001, respectively) compared with the placebo group both at day 5 and day 10. Within the sucralfate group, a decrease in frequency and severity of mucositis was observed throughout the trial period, while in the placebo group no such effect was observed. Sucralfate mouthwash reduced the frequency and severity of 5-FU-induced oral mucositis in patients with gastrointestinal malignancies compared with placebo, indicating its efficacy in the prevention of chemotherapy-induced mucositis.

Successful treatment with personalized dosage of imatinib in elderly patients with gastrointestinal stromal tumors.

Imatinib is the standard first-line therapy for metastatic gastrointestinal stromal tumors. It has markedly improved the prognosis and outcome of patients affected by gastrointestinal stromal tumors, especially in the case of exon 11 KIT mutations. Imatinib-associated adverse events are generally mild to moderate; however, in clinical practice, intolerance caused by chronic toxicities frequently leads to breaks in treatment. This is particularly true in elderly patients in whom age, decline in drug metabolism, and polypharmacy, with a possible drug-drug interaction, may influence the tolerability of imatinib. In the present article, we report our extensive experience with the management of imatinib therapy in a 'real' population, in particular in very elderly patients, discussing whether the use of personalized imatinib dosage could be a safe and advantageous option, enabling continuous administration, thus ensuring effective treatment. Only a few case reports in the literature provide data on outcome with low tailored dosage of imatinib and none of them has been carried out on a Western population. Here, we report four cases treated with low imatinib dosage as a safe and useful option enabling continued treatment with imatinib, improving tolerance, and maintaining good and lasting disease control.

Pharmacological Intervention through Dietary Nutraceuticals in Gastrointestinal Neoplasia.

Neoplastic conditions associated with gastrointestinal (GI) tract are common worldwide with colorectal cancer alone accounting for the third leading rate of cancer incidence. Other GI malignancies such as esophageal carcinoma have shown an increasing trend in the last few years. The poor survival statistics of these fatal cancer diseases highlight the need for multiple alternative treatment options along with effective prophylactic strategies. Worldwide geographical variation in cancer incidence indicates a correlation between dietary habits and cancer risk. Epidemiological studies have suggested that populations with high intake of certain dietary agents in their regular meals have lower cancer rates. Thus, an impressive embodiment of evidence supports the concept that dietary factors are key modulators of cancer including those of GI origin. Preclinical studies on animal models of carcinogenesis have reflected the pharmacological significance of certain dietary agents called as nutraceuticals in the chemoprevention of GI neoplasia. These include stilbenes (from red grapes and red wine), isoflavones (from soy), carotenoids (from tomatoes), curcuminoids (from spice turmeric), catechins (from green tea), and various other small plant metabolites (from fruits, vegetables, and cereals). Pleiotropic action mechanisms have been reported for these diet-derived chemopreventive agents to retard, block, or reverse carcinogenesis. This review presents a prophylactic approach to primary prevention of GI cancers by highlighting the translational potential of plant-derived nutraceuticals from epidemiological, laboratory, and clinical studies, for the better management of these cancers through consumption of nutraceutical rich diets and their intervention in cancer therapeutics.

Somatostatin analogues in functioning gastroenteropancreatic neuroendocrine tumours: literature review, clinical recommendations and schedules.

OBJECTIVE: Neuroendocrine tumours (NETs) represent a heterogeneous group of neoplasms, which include functioning and non-functioning forms. Somatostatin analogues (SSAs) play a key role in the management of these tumours. Herein, we aimed at reviewing the current evidence about the role of SSAs in the treatment of gastro-entero-pancreatic (GEP)-NETs. MATERIAL AND METHODS: An extensive bibliographical search was performed in PubMed using the following keywords: gastro-entero-pancreatic neuroendocrine tumours, somatostatin analogues, octreotide, lanreotide, in order to identify all the pertinent English-written articles published between 1990 and 2015. RESULTS: SSAs have shown to help the symptomatic and biochemical improvement of patients with NETs and to exhibit a good safety profile. Recent studies have also reported a role for SSAs in tumour growth control, although the results are less impressive and the underlying mechanisms are not fully understood. CONCLUSIONS: SSAs are well known as a symptomatic and, to lesser extent, anti-proliferative treatment in GEP-NETs. However, some issues, including optimal dosage, benefits and adverse events of combination with other molecules, and the role of new analogues, remain to be elucidated in further randomised studies.

Oral administration of the amino acids cystine and theanine attenuates the adverse events of S-1 adjuvant chemotherapy in gastrointestinal cancer patients.

BACKGROUND: Nutritional therapy is used to reduce the adverse events (AEs) of anticancer drugs. Here, we determined whether the amino acids cystine and theanine, which provide substrates for glutathione, attenuated the AEs of S-1 adjuvant chemotherapy. METHODS: Patients scheduled to receive S-1 adjuvant chemotherapy were randomized to the C/T or the control groups. The C/T group received 700 mg cystine and 280 mg theanine orally 1 week before the administration of S-1, which then continued for 5 weeks. Each group received S-1 for 4 weeks. Blood sampling was performed and AEs were evaluated (CTCAE ver. 4.0) before and after the administration of S-1. S-1 was discontinued when AEs ≥ grade 2 occurred. RESULTS: The incidences of AEs of any grade and those over grade 2 were lower in the C/T group than in the controls. The incidence of diarrhea (G ≥ 2) was significantly less (p < 0.05) in the C/T group (3.1 %) than in the controls (25.8 %). The duration and completion rate of the S-1 adjuvant chemotherapy were significantly longer (p < 0.01) and higher (p < 0.01), respectively, in the C/T group (complete ratio: 75.0 %, duration: 24.8 ± 5.8 days) than in the controls (complete ratio: 35.5 %, duration: 20.0 ± 7.7 days). CONCLUSIONS: The oral administration of cystine and theanine attenuated the AEs of S-1 adjuvant chemotherapy and increased the S-1 completion rate, suggesting that cystine and theanine is a useful supportive care for chemotherapy.

Intraoperative infusion of branched-chain amino acids in patients undergoing gastrointestinal tumor surgery.

BACKGROUND: The purpose of this study is to investigate the effects of intraoperative infusion of branched-chain amino acids (BCAA) in patients undergoing gastrointestinal tumor surgery. METHODS: Sixty-one patients with gastrointestinal tumors undergoing gastrointestinal surgery were enrolled and randomly assigned to receive an intraoperative infusion of 3-compound BCAA solution (N = 20), amino acids (AA) solution (N = 21), or normal saline (NS) (N = 20). Nasopharyngeal temperature, blood glucose (BG), plasma insulin, and blood free fatty acids (FFA) concentrations were measured at 30 min before and 10 min after induction (T 0,T 1), 30 min and 2 h after skin incision (T 2,T 3), and 1 h after tracheal extubation (T 4). Intensity of shivering and pain was accessed at 1 h after extubation. RESULTS: The temperature in the BCAA and AA group was significantly higher than that in the NS group at T 4 (P = 0.014 and 0.033). The incidence of shivering in the BCAA and AA group was significantly lower than in the NS group (P = 0.027 and 0.012). BG increased in AA group at T 3 and T 4 (P = 0.001 and 0.045). The plasma insulin concentration increased in the BCAA and AA group from T 1 to T 3. The plasma FFA concentrations in the BCAA group were lower than in the AA and NS group from T 2 to T 4. CONCLUSIONS: Intraoperative BCAA and AA infusion alleviated postoperative hypothermia and shivering. BCAA infusion also inhibited fat mobilization, without adversely affecting blood glucose. TRIAL REGISTRATION: ChiCTR-TRC-14004668.

Clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor.

Aiming at exploring clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor, this study divided 60 patients with gastrointestinal tumor into control and observation groups, each containing 30 patients. The observation group was treated with oxaliplatin combined with flurouracil, while the control was treated with FOLFOX4, i.e., intravenously dropping 85mg/m(2)Oxaliplatin (L-OHP), 200mg/m(2) calcium folinate (CF) and intravenously injecting 400mg/m(2) 5-fluorouracil (5-Fu), and 600mg/m(2) 5-Fu; then continuously performing intravenous drop infusion for 22h, every two weeks for a cycle. Hypodermic injection of granulocyte colony-stimulating factor (G-CSF) was conducted immediately when leukocytes occurred the III, IV degree of inhibition. The observation results of curative effect and negative reaction indicated higher effective rate with 83.33% in the observation and 50.00% in the control. Besides, in the observation, negative reactions possessed 10.00% that was much lower than 33.33% in the control. Thereby, the conclusion reached that the treatment of gastrointestinal tumor with oxaliplatin combined with flurouracil was worth promoting.

Pleural effusion in a patient with metastatic gastrointestinal stromal tumor treated with imatinib: case report.

Gastrointestinal stromal tumors are rare malignancies characterized by c-kit and PDGFR-α mutations targeted by imatinib. Pleural effusion is a very rare side effect of imatinib treatment. A 65-year-old female with metastatic gastrointestinal stromal tumor developed electrolyte imbalance, severe peripheral edema and progressively worsening dyspnea 2 months after starting imatinib. Having excluded cardiovascular and pulmonary disorders, imatinib was discontinued and prednisone 25 mg orally daily was begun. The patient's condition improved substantially over the next 48 h with a progressive decrease in dyspnea and a reduction in pleural effusion and peripheral edema. All side effects had resolved within 1 month. In view of the partial response obtained, the patient re-started imatinib after a 1-week interruption. Prednisone was maintained and there was no further toxicity.

Intraperitoneal chemotherapy: rationale, applications, and limitations.

Intraperitoneal chemotherapy, involving the administration of certain chemotherapeutic agents directly to the intraperitoneal cavity, was developed as a novel therapeutic strategy early in the 1950s. Intraperitoneal administration of chemotherapy results in higher intraperitoneal concentration of the cytotoxic medications and minimal systemic exposure than observed with intravenous administration, which in turn may increase the efficacy of these agents with substantial reduction in systemic toxicity. Intraperitoneal chemotherapy was used successfully in peritoneal surface malignancies, including malignant peritoneal mesothelioma, pseudomyxoma peritonei, malignant ascites, sarcomatosis, and peritoneal carcinomatosis from gastrointestinal and ovarian cancers. Pharmacists may play a major role in optimizing intraperitoneal chemotherapy through verification of chemotherapy order for proper doses, dilution, preparation, and administration. Moreover, pharmacists are medication experts who can provide other health care professionals with the necessary drug information. Despite the local application of chemotherapy, intraperitoneal chemotherapy is not free of systemic side effects and can be associated with serious complications. The benefits of intraperitoneal chemotherapy should be weighed against its potential harm to maximize efficacy and to minimize morbidity and mortality as much as possible. The aim of this article is to review the current available literature regarding the safety and efficacy of intraperitoneal chemotherapy in cancer treatment.

Sarcopenia affects the clinical efficacy of immune checkpoint inhibitors in patients with gastrointestinal cancers.

OBJECTIVE: The impact of sarcopenia on the efficacy of immune checkpoint inhibitors (ICI) in gastrointestinal cancer (GIC) patients remains uncertain in clinical practice. Hence, this study aims to investigate the potential correlation between sarcopenia and the clinical outcomes of GIC patients treated with ICIs. METHODS: To gather pertinent studies, a systematic literature search was implemented across multiple databases, including PubMed, Embase, the Cochrane Library, and Google Scholar. The primary outcomes of interest were overall survival (OS) and progression-free survival (PFS), measured with the hazard ratio (HR). And the secondary outcomes, including disease control rate (DCR), overall response rate (ORR), and adverse events (AE), were evaluated with the odd ratio (OR). RESULTS: A total of 13 articles involving 1294 patients were collected for this analysis. The pooled results revealed that GIC patients with sarcopenia had significantly poorer OS (HR = 1.697, 95% CI = 1.367-2.106, p < 0.001) and PFS (HR: 1.551, 95% CI: 1.312-1.833, p < 0.001), and lower ORR (OR = 0.594, 95% CI = 0.388-0.909, p = 0.016) and DCR (OR: 0.553, 95% CI: 0.360-0.850, p = 0.007) compared to those without sarcopenia. However, sarcopenia did not increase the incidence of treatment-related adverse events compared with non-sarcopenia (OR = 1.377, 95% CI = 0.693-2.737, p = 0.361). According to subgroup analysis, the association between sarcopenia and the therapeutic effect of ICI on patients with primary liver cancer or gastric cancer was consistent with the above findings. CONCLUSION: Sarcopenia is significantly correlated with poorer treatment response and worse long-term efficacy in GIC patients treated with ICIs. Moreover, sarcopenia does not increase the incidence of adverse events.

COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention.

Arachidonic acid metabolism through cyclooxygenase (COX) pathways leads to the generation of biologically active eicosanoids. Eicosanoid expression levels vary during development and progression of gastrointestinal (GI) malignancies. COX-2 is the major COX-isoform responsible for G.I. cancer development/progression. COX-2 expression increases during progression from a normal to cancerous state. Evidence from observational studies has demonstrated that chronic NSAID use reduces the risk of cancer development, while both incidence and risk of death due to G.I. cancers were significantly reduced by daily aspirin intake. A number of randomized controlled trials (APC trial, Prevention of Sporadic Adenomatous Polyps trial, APPROVe trial) have also shown a significant protective effect in patients receiving selective COX-2 inhibitors. However, chronic use of selective COX-2 inhibitors at high doses was associated with increased cardiovascular risk, while NSAIDs have also been associated with increased risk. More recently, downstream effectors of COX-signaling have been investigated in cancer development/progression. PGE(2), which binds to both EP and PPAR receptors, is the major prostanoid implicated in the carcinogenesis of G.I. cancers. The role of TXA(2) in G.I. cancers has also been examined, although further studies are required to uncover its role in carcinogenesis. Other prostanoids investigated include PGD(2) and its metabolite 15d-PGJ2, PGF(1α) and PGI(2). Targeting these prostanoids in G.I. cancers has the promise of avoiding cardiovascular toxicity associated with chronic selective COX-2 inhibition, while maintaining anti-tumor reactivity. A progressive sequence from normal to pre-malignant to a malignant state has been identified in G.I. cancers. In this review, we will discuss the role of the COX-derived prostanoids in G.I. cancer development and progression. Targeting these downstream prostanoids for chemoprevention and/or treatment of G.I. cancers will also be discussed. Finally, we will highlight the latest pre-clinical technologies as well as avenues for future investigation in this highly topical research field.

Update on the management of gastroenteropancreatic neuroendocrine tumors with emphasis on the role of imaging.

OBJECTIVE: The purposes of this article are to review the current management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) based on the 2012 National Comprehensive Cancer Network guidelines and to describe the role of imaging in a multidisciplinary approach. CONCLUSION: The management of GEP-NETs has become complex, requiring a multidisciplinary approach. The World Health Organization classification of GEP-NETs has been revised; the U.S. Food and Drug Administration has approved molecular targeted agents (sunitinib, everolimus) for the treatment of pancreatic NETs; and the National Comprehensive Cancer Network clinical practice guidelines have been updated.