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Purpose: Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted.Methods: This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data.Results: Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8-23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression.Conclusions: Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses. [ABSTRACT FROM AUTHOR]

Purpose: Hangeshashinto (TJ-14, a Kampo medicine), which reduces the level of prostaglandin E2 and affects the cyclooxygenase activity, alleviates chemotherapy-induced oral mucositis (COM). We conducted a double-blind, placebo-controlled, randomized comparative trial to investigate whether TJ-14 prevents and controls COM in patients with colorectal cancer. Methods: Ninety-three patients with colorectal cancer who developed moderate-to-severe COM (WHO grade ≧1) during any cycle of chemotherapy using FOLFOX, FOLFIRI, and/or XELOX treatment were randomly assigned to receive either TJ-14 ( n = 46) or placebo ( n = 47). Patients received the administration of placebo or TJ-14 for 2 weeks at the start of the next course of chemotherapy. Patients were assessed three times per week for safety and for COM incidence and its severity using the WHO grading. Results: Ninety eligible patients (TJ-14; 43, placebo; 47) per protocol set analysis were included in the analysis after the key-opening. Although the incidence of grade ≧2 oral mucositis was lower for patients treated with TJ-14 compared to those treated with placebo, there was no significant difference (48.8 vs. 57.4 %; p = 0.41). The median duration of grade ≧2 mucositis was 5.5 versus 10.5 days ( p = 0.018). No difference in other treatment toxicity was observed between the two groups, and patients exhibited high compliance in dosing administration. Conclusion: The present study results did not meet the primary endpoint. However, TJ-14 demonstrated a significant effect in the treatment of grade ≧2 mucositis in patients with colorectal cancer compared to the placebo. [ABSTRACT FROM AUTHOR]

Objective: Dihydropyrimidine dehydrogenase (DPYD) genotype is closely associated with fluoropyrimidine (FP)‐induced toxicities in Caucasian population and European Medicines Agency now recommends DPYD genotype‐based FP dosing strategy. Patients and Methods: The current study aimed to investigate their impact on FP‐related toxicities in an Asian population using genome‐wide association study (GWAS) data set from 1364 patients with colon cancer. Results: Among 82 variants registered in the Clinical Pharmacogenetics Implementation Consortium, 74 DPYD variants were directly genotyped in GWAS cohort; however, only 7 nonsynonymous DPYD variants (CPIC variants) were identified and none of the four recurrent DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G, c.1236G>A) were included. Seven CPIC variants were investigated for their association with the incidence of FP‐related toxicities; however, none of these variants revealed a significant correlation with FP‐related toxicities. Conclusion: These data suggested that the DPYD genotype registered in CPIC plays a minor role in FP‐related toxicities in an Asian population. [ABSTRACT FROM AUTHOR]

An optimal treatment strategy using oxaliplatin and bevacizumab for metastatic colorectal cancer has not been defined. We investigated whether the sequential treatment using fluoropyrimidines with bevacizumab followed by the addition of oxaliplatin at first progression was better than a combination treatment using fluoropyrimidines and oxaliplatin with bevacizumab. In the sequential treatment, the escalation from fluoropyrimidines plus bevacizumab to fluoropyrimidines plus oxaliplatin with bevacizumab was recommended in case of progressive disease. Time to failure of strategy was the primary end-point, whereas the secondary end-points were overall survival, progression-free survival, overall response rate and safety. Three hundred patients with previously untreated metastatic colorectal cancer were randomised to receive either the sequential treatment (n = 151) or the combination treatment (n = 149). The sequential treatment was superior to the combination treatment about time to failure of strategy (15.2 months; 95% CI, 12.5–17.2 months vs. 7.8 months: 95% CI, 6.3–9.5 months; P < 0.001). However, the median overall survival was 27.5 (95% CI, 24.4 to 32.7) months in the sequential treatment and 27.0 (95% CI, 22.8 to 36.0) months in the combination treatment (hazard ratio, 0.92; 95% CI, 0.66 to 1.28; P = 0.61). The overall response rate was 33.1% in the sequential treatment arm and 51.7% in the combination treatment. The findings support the extension of the sequential treatment starting from fluoropyrimidine plus bevacizumab to selected patients who do not need an objective response to the threatening disease. • The sequential arm showed superiority in the primary end-point, time to failure of strategy. • Overall survival was no difference between the sequential and combination arms. • Overall response was 20% more in the combination arm. • The sequential approach could cover selected patients with no need for shrinkage. [ABSTRACT FROM AUTHOR]

Background: The characterisation of desmoplastic reaction (DR) has emerged as a new, independent prognostic determinant in colorectal cancer. Herein, we report the validation of its prognostic value in a randomised controlled study (SACURA trial).Methods: The study included 991 stage II colon cancer patients. DR was classified by the central review as Mature, Intermediate or Immature based on the presence of hyalinised collagen bundles and myxoid stroma at the desmoplastic front. All clinical and pathological data, including DR characterisations, were prospectively recorded and analysed 5 years after the completion of the registration.Results: The five-year relapse-free survival (RFS) rate was the highest in the Mature group (N = 638), followed by the Intermediate (N = 294) and Immature groups (N = 59). Multivariate analysis revealed that DR classification was an independent prognostic factor, and based on Harrell's C-index, the Cox model for predicting RFS was significantly improved by including DR. In the conditional inference tree analysis, DR categorisation was the first split factor for predicting RFS, followed by T-stage, microsatellite instability status and budding.Conclusions: Histological categorisation of DR provides important prognostic information that could contribute to the efficient selection of stage II colon cancer patients who would benefit from postoperative adjuvant therapy. [ABSTRACT FROM AUTHOR]

Background: Cancer cachexia is characterized by weight loss and is associated with increased morbidity and mortality in patients with cancer. Anamorelin (ONO‐7643; ANAM) is a novel and selective ghrelin receptor agonist that improves appetite, lean body mass (LBM), body weight, and anorexia. Methods: This multicenter, open‐label, single‐arm study investigated the efficacy and safety of 100 mg anamorelin in 50 Japanese patients with advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer. ANAM was administered once daily over 12 weeks. The primary endpoint was the proportion of patients that maintained or gained LBM over the course of the study. Secondary endpoints included changes in LBM, body weight, quality of life (QoL), and nutritional status biomarkers. Results: The proportion of patients who responded to treatment was 63.3% (95% CI, 48.3%‐76.6%), with a least square mean ± SE change in LBM and body weight from baseline of 1.89 ± 0.36 kg and 1.41 ± 0.61 kg, respectively. Appetite‐related questions on the QoL questionnaire showed that ANAM improved appetite. Adverse events occurred in 79.6% of patients, and the most common treatment‐related adverse events were increased γ‐glutamyl transpeptidase (8.2%), diabetes mellitus (6.1%), hyperglycemia (6.1%), and prolonged QRS complex (6.1%). Conclusions: ANAM improved anorexia and patients' nutritional status, resulting in rapid increases in LBM and body weight in patients with advanced gastrointestinal cancer who had cancer cachexia. ANAM treatment was well tolerated over 12 weeks. ANAM is a potential clinically beneficial pharmacotherapeutic option for patients with advanced gastrointestinal cancer who have cancer cachexia. The receipt of 100 mg anamorelin increases lean body mass and improves symptoms of anorexia and nutritional status in patients with advanced gastrointestinal cancer who have cancer cachexia. Anamorelin is well tolerated in these patients. [ABSTRACT FROM AUTHOR]

Purpose: Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer.Methods: Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated.Results: Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2).Conclusions: Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up. [ABSTRACT FROM AUTHOR]

Background: The reintroduction of oxaliplatin as a third-or-later-line regimen has been a promising option for patients with metastatic colorectal cancer (mCRC) who previously received chemotherapy including oxaliplatin. In this single-arm phase II study, we evaluated the efficacy of biweekly SOX, which is the combination of oxaliplatin reintroduction and S-1, as a third-or-later-line treatment. Methods: Patients with mCRC who had previously received prior chemotherapy including oxaliplatin and irinotecan and were planned to receive the reintroduction of oxaliplatin were enrolled. Oxaliplatin (85 mg/m2) with/without bevacizumab (5 mg/kg) was given intravenously on day 1. Oral S-1 was administered on day 2–8 at a dose of 40–60 mg (calculated according to the body surface area) twice a day. Cycles were repeated every 2 weeks. The primary endpoint was the progression-free survival (PFS); our hypothesis was that the median PFS would be 3.5 months with a minimum threshold above 2.0 months. The secondary endpoints included the adverse events (AEs), response rate and overall survival (OS). Results: A total of 41 patients from 12 institutes were enrolled. The median PFS and OS survival were 3.3 months (95% confidence interval [CI] 2.7–4.2) and 10.1 months (8.3–14.6), and response rate and disease control rate were 10.0% and 65.0%, respectively. Grade 3 AEs included thrombocytopenia (5.0%), anorexia (5.0%), pneumonia (5.0%) and fatigue (5.0%). There were no cases of grade 4 AEs or treatment-related death. Conclusion: Biweekly SOX regimen with reintroduction of oxaliplatin could be exploitable as the third- and/or later-line treatments for patients with mCRC. [ABSTRACT FROM AUTHOR]

Purpose: The procedure for prolapse and hemorrhoids (PPH) has the advantage of less postoperative pain. However, serious postoperative complications have been reported after PPH, and the postoperative recurrence rate is high in comparison with conventional Milligan-Morgan hemorrhoidectomy (MMH). The purpose of this study was to evaluate PPH with low rectal anastomosis (PPH-LA) in comparison with the original PPH and MMH. Methods: Among a total of 1315 patients with hemorrhoids, MMH was conducted in 322, original PPH using a PPH 01 stapler (PPH01) in 63, PPH-LA using 01 (PPH-LA01) in 236, 03 (PPH-LA03) in 649, and sclerotherapy (SCL) in 45. Results: Length of hospital stay and number of working days lost were significantly greater for MMH than for any form of PPH. The rate of massive postoperative bleeding was significantly lower after PPH-LA03 than after PPH01 or PPH-LA01. No serious postoperative complications occurred after any form of PPH. A significantly higher proportion of patients complained of continued prolapse after PPH01 than after MMH, PPH-LA01, or -LA03. The 5- and 16-year postoperative cumulative recurrence rates after PPH-LA03 were significantly lower than after PPH01. Conclusions: The postoperative cumulative recurrence rate after PPH-LA03 is as low as that after MMH for up to 16 years, and compared with the original PPH01, the effectiveness is higher and the postoperative cumulative recurrence rate for up to 16 years is significantly lower. We conclude that PPH-LA03 is a superior procedure for hemorrhoids, having less postoperative pain and a low rate of recurrence. [ABSTRACT FROM AUTHOR]

Purpose: Hospital factors along with various patient and surgeon factors are considered to affect the prognosis of colorectal cancer. Hospital volume is well known, but little is known regarding other hospital factors. Methods: We reviewed data on 853 patients with stage IV colorectal cancer who underwent elective palliative primary tumor resection between January 2006 and December 2007. To detect the hospital factors that could influence the prognosis of incurable colorectal cancer, the relationships between patient/hospital factors and overall survival were analyzed. Among hospital factors, hospital type (Group A: university hospital or cancer center; Group B: community hospital), hospital volume, and number of colorectal surgeons were examined. Results: In univariate analysis, Group A hospitals showed significantly better prognosis than Group B hospitals ( p = 0.034), while hospital volume and number of colorectal surgeons were not associated with overall survival. After adjustment for patient factors in multivariate analysis, hospital type was significantly associated with overall survival (hazard ratio: 1.31; 95 % confidence interval: 1.05-1.63; p = 0.016). However, there was no significant difference in short-term outcomes between hospital types. Conclusions: Hospital type was identified as a hospital factor that possibly affects the prognosis of stage IV colorectal cancer patients. [ABSTRACT FROM AUTHOR]

A 75‐year‐old woman underwent laparoscopic abdominoperineal resection. Four months after abdominoperineal resection, the patient complained of a perineal bulge and urination disorder. Abdominal CT showed protrusion of the small intestine and bladder to the perineum. The patient underwent laparoscopic hernia repair with mesh. The size of the hernial orifice was 7.0 × 9.0 cm, and it had no solid rim. The mesh was tacked ventrally to the pectineal ligament and dorsally to the sacrum, and then sutured on the lateral side. The hernia has not recurred 10 months after the operation. Laparoscopic repair is a good treatment choice for secondary perineal hernia and fixing the mesh to the pectineal ligament, and the sacrum prevents the mesh from sagging. [ABSTRACT FROM AUTHOR]

Background: The aim of this multicenter, open-label, randomized phase II trial was to evaluate the efficacy of a dose-dense capecitabine and oxaliplatin (XELOX) regimen in patients with metastatic colorectal cancer (mCRC) for whom reintroduction of oxaliplatin had been planned as a third- or later-line regimen. Methods: The patients with mCRC who had received prior chemotherapy including oxaliplatin and were scheduled for reintroduction of oxaliplatin were randomized to capecitabine (1,000 mg/m) twice daily on days 1-14 and oxaliplatin (130 mg/m) on day 1 every 21 days (Q3W group) or capecitabine (2,000 mg/m) twice daily on days 1-7 and oxaliplatin (85 mg/m) on day 1 every 14 days (Q2W group). The primary endpoint was the time-to-treatment failure (TTF). Other endpoints included overall survival (OS), progression-free survival (PFS) and other adverse events (AEs). Results: A total of 46 patients were enrolled in the trial-22 patients were randomly assigned to the Q3W group and 23 to the Q2W group. The median TTF was 3.4 months in both groups (hazard ratio [HR] 1.053; p = 0.880). The median PFS and OS were 3.3 and 9.2 months in the Q2W group and 4.3 and 12.1 months in the Q3W group, respectively (HR 1.15; p = 0.153 and 0.672; p = 0.836). The most common grade 3−4 AEs in the Q3W and Q2W groups were fatigue (27.3 vs 21.7), neuropathy (9.1 vs 0 %) and diarrhea (9.1 vs 0 %), respectively. Conclusion: There was no significant inter-group difference in any of the efficacy and safety endpoints, including TTF, OS, RFS and AEs. The results of this clinical trial were convincingly negative. [ABSTRACT FROM AUTHOR]

Background: Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥ 75 years with mCRC.Methods: This prospective, open-label phase II trial recruited patients aged ≥ 75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m(2) of oxaliplatin on day 1 of each cycle combined with 2000 mg/m(2) of oral capecitabine per day on days 1-14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival.Results: Thirty-six patients (male 58%; median age 78 years; colon cancer 67%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3%) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2%) and neuropathy (13.9%). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1%). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7%, respectively. Median progression-free and overall survival times were 11.7 months (95% confidence interval, 8.0-13.4 months) and 22.9 months, respectively.Conclusion: XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥ 75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit. [ABSTRACT FROM AUTHOR]

Purpose: Oxaliplatin-induced peripheral neurotoxicity (OPN) is frequent and potentially severe, but successful treatment of this condition is still an unmet clinical need. We aimed to determine whether treatment with goshajinkigan (TJ-107), a traditional Japanese medicine, is better than placebo in preventing OPN in patients with advanced or recurrent colorectal cancer patients treated with standard FOLFOX regimens.Methods: In this phase 2, randomized, double-blind, placebo-controlled study, patients undergoing oxaliplatin-based chemotherapy were randomized to receive either oral TJ-107 (7.5 g) or matching placebo daily. The severity of OPN was assessed according to the Common Toxicity Criteria for Adverse Events at baseline, every 2 weeks until the 8th cycle, and every 4 weeks thereafter until the 26th week. The primary endpoint was the incidence of grade 2 or greater OPN until the 8th cycle of chemotherapy.Results: Analyses were done by intention to treat. Eighty-nine patients were randomly assigned to receive either TJ-107 (n = 44) or placebo (n = 45) between May 2009 and March 2010. The incidence of grade 2 or greater OPN until the 8th cycle was 39 and 51 % in the TJ-107 and placebo groups, respectively (relative risk (RR), 0.76; 95 % CI, 0.47–1.21). The incidence of grade 3 OPN was 7 % (TJ-107) vs. 13 % (placebo) (0.51, 0.14–1.92). No concerns regarding toxicity emerged with TJ-107 treatment.Conclusions: TJ-107 appears to have an acceptable safety margin and a promising effect in delaying the onset of grade 2 or greater OPN without impairing FOLFOX efficacy. [ABSTRACT FROM AUTHOR]

Purpose: Oxaliplatin-induced peripheral neurotoxicity (OPN) is frequent and potentially severe, but successful treatment of this condition is still an unmet clinical need. We aimed to determine whether treatment with goshajinkigan (TJ-107), a traditional Japanese medicine, is better than placebo in preventing OPN in patients with advanced or recurrent colorectal cancer patients treated with standard FOLFOX regimens. Methods: In this phase 2, randomized, double-blind, placebo-controlled study, patients undergoing oxaliplatin-based chemotherapy were randomized to receive either oral TJ-107 (7.5 g) or matching placebo daily. The severity of OPN was assessed according to the Common Toxicity Criteria for Adverse Events at baseline, every 2 weeks until the 8th cycle, and every 4 weeks thereafter until the 26th week. The primary endpoint was the incidence of grade 2 or greater OPN until the 8th cycle of chemotherapy. Results: Analyses were done by intention to treat. Eighty-nine patients were randomly assigned to receive either TJ-107 ( n = 44) or placebo ( n = 45) between May 2009 and March 2010. The incidence of grade 2 or greater OPN until the 8th cycle was 39 and 51 % in the TJ-107 and placebo groups, respectively (relative risk (RR), 0.76; 95 % CI, 0.47–1.21). The incidence of grade 3 OPN was 7 % (TJ-107) vs. 13 % (placebo) (0.51, 0.14–1.92). No concerns regarding toxicity emerged with TJ-107 treatment. Conclusions: TJ-107 appears to have an acceptable safety margin and a promising effect in delaying the onset of grade 2 or greater OPN without impairing FOLFOX efficacy. [ABSTRACT FROM AUTHOR]

A 62-year-old Japanese man presented with a 1-month history of inter-digestive epigastralgia. His family history included a sister with gastric cancer. Gastroendoscopy and gastrography demonstrated a type-2 tumor in the upper region of the stomach. CT scan and fluorodeoxyglucose–positron emission tomography (FDG–PET) scan demonstrated gastric cancer and its metastatic lymph nodes. The patient underwent total gastrectomy with splenectomy and extended lymph node dissection. Although postoperative adjuvant chemotherapy by S-1 was started, the deteriorating condition of the patient prevented drug administration and even eating meals. On the 19th postoperative day (POD), FDG–PET scan of the body demonstrated new uptake in the liver and lymph node around the aorta. Without any sign of infection, leukocytosis developed around the 30th POD. On the 49th POD, remarkable uptake in the whole upper abdomen was detected on FDG–PET scan. Finally, leukocyte count increased to 125,200 and granulocyte colony stimulating factor (G-CSF) was elevated to 28 pg/ml on the 54th POD. The patient died of multiple liver metastases and carcinomatous peritonitis only 56 days after surgery. G-CSF-producing tumor is a rare but aggressive disease, particularly as recurrent tumor. If leukocytosis is detected in relation to a non-lympho hematopoietic malignant tumor, G-CSF-producing tumor should be considered and FDG–PET scan is recommended for early detection. Chemotherapy for G-CSF-producing tumor must be conducted as soon as possible. [ABSTRACT FROM AUTHOR]

A phase I study of TCF therapy, which consists of paclitaxel (TXL: Taxol®) + cisplatin (CDDP) + 5-fluorouracil (5-FU), in advanced gastric cancer patients was performed to determine the recommended dose (RD) for a phase II study by checking the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of 5-FU above the fixed dose of TXL and CDDP. The doses of TXL and CDDP were fixed at 80 and 25 mg/m2, respectively, while that of 5-FU was increased by 100 mg/m2 in each cohort from 300 mg/m2 (level 1) to a maximum of 600 mg/m2 (level 4). One cycle consisted of administration of these agents once per week for 3 weeks, every 4 weeks. A total of twelve eligible patients were included in this study. At level 1, two of three cases showed grade 3 leukopenia. At level 2, one of three cases showed grade 4 neutropenia (recovered within 3 days), and another one case showed grade 3 neutropenia. At level 3, one of three cases showed grade 3 neutropenia, and at level 4, one of three cases showed grade 4 neutropenia (recovered within 3 days), with grade 3 neutropenia in the other two cases. Even at the highest dose administered, none of the patients showed DLT. Moreover, no non-hematological toxicity judged to be DLT was observed through all levels. Six of the twelve patients had measurable disease, and the overall response rate was 83%. Although the MTD level was not determined, based on the observed efficacy and the results of other clinical trials, the recommended doses of TXL, CDDP, and 5-FU for the TCF regimen were set as 80, 25, and 600 mg/m2, respectively, and a phase II study to investigate the clinical effectiveness and safety of this regimen has now begun. [ABSTRACT FROM AUTHOR]

Background: Cancer cachexia is characterized by weight loss and is associated with increased morbidity and mortality in patients with cancer. Anamorelin (ONO-7643; ANAM) is a novel and selective ghrelin receptor agonist that improves appetite, lean body mass (LBM), body weight, and anorexia.Methods: This multicenter, open-label, single-arm study investigated the efficacy and safety of 100 mg anamorelin in 50 Japanese patients with advanced and unresectable gastrointestinal (colorectal, gastric, or pancreatic) cancer. ANAM was administered once daily over 12 weeks. The primary endpoint was the proportion of patients that maintained or gained LBM over the course of the study. Secondary endpoints included changes in LBM, body weight, quality of life (QoL), and nutritional status biomarkers.Results: The proportion of patients who responded to treatment was 63.3% (95% CI, 48.3%-76.6%), with a least square mean ± SE change in LBM and body weight from baseline of 1.89 ± 0.36 kg and 1.41 ± 0.61 kg, respectively. Appetite-related questions on the QoL questionnaire showed that ANAM improved appetite. Adverse events occurred in 79.6% of patients, and the most common treatment-related adverse events were increased γ-glutamyl transpeptidase (8.2%), diabetes mellitus (6.1%), hyperglycemia (6.1%), and prolonged QRS complex (6.1%).Conclusions: ANAM improved anorexia and patients' nutritional status, resulting in rapid increases in LBM and body weight in patients with advanced gastrointestinal cancer who had cancer cachexia. ANAM treatment was well tolerated over 12 weeks. ANAM is a potential clinically beneficial pharmacotherapeutic option for patients with advanced gastrointestinal cancer who have cancer cachexia. [ABSTRACT FROM AUTHOR]