[MSI-high ascending colon cancer treated with second-line ipilimumab plus nivolumab for conversion surgery:a case report].

A 68-year-old woman with ascending colon cancer was the patient (cT4bN2M1a [LYM] cStage IVA, BRAF V600E mutation-positive, and MSI-high). She was given modified FOLFOXIRI as first-line therapy but did not respond. The infiltration of the primary lesion in the abdominal wall was alleviated, allowing conversion surgery to be performed.

Second-line chemotherapy using taxane in patients with advanced gastric cancer who presented with severe peritoneal metastasis: a multicenter retrospective study.

BACKGROUND: Individuals with advanced gastric cancer (AGC) who present with severe peritoneal metastasis (SPM) have poor prognosis. This study aimed to evaluate efficacy and safety of second-line treatment for patients with such condition. METHODS: This retrospective study included patients receiving taxane-based second-line chemotherapy at three Japanese institutions between 2010 and 2016. Patients with AGC who present with SPM were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. RESULTS: In this study, 43 (40%) of 108 patients had an Eastern Cooperative Oncology Group Performance Status score ≥ 2, and the median serum albumin level of the patients was 3.3 g/dL. Ramucirumab was used in combination with paclitaxel in 21 patients. The median overall survival (OS) and progression-free survival (PFS) were 5.1 and 2.8 months, respectively. Inadequate oral intake was considered a negative prognostic factor of both OS and PFS in the multivariate analysis. Three treatment-related deaths were observed, which include those attributed to febrile neutropenia, gastrointestinal perforation, and pneumonitis. Common grade ≥ 3 adverse events were neutropenia (35%), leukopenia (30%), anemia (24%), and anorexia (16%). We observed febrile neutropenia in 8% and gastrointestinal perforation in 4% of patients, and such conditions were dominantly observed in patients with inadequate oral intake. CONCLUSION: Taxane-based second-line chemotherapy was effective and safe for patients with AGC who present with SPM. Attention must be provided when treating patients with inadequate oral intake as they are likely to have short prognosis and serious toxicities.

Multicenter Cohort Study to Assess the Association between Changes on Imaging and Outcome after Regorafenib Treatment (KSCC1603).

BACKGROUND: Molecular targeted drugs having angiogenesis-inhibiting properties allow the induction of necrosis inside tumors. We retrospectively investigated the relationship between changes on imaging associated with regorafenib (REGO) and treatment outcomes using real-world data. PATIENTS AND METHODS: The eligibility criteria included an ECOG PS of 0-1, a starting dose of 120 or 160 mg/day of REGO, and a duration of treatment of at least 35 days. Regarding changes on imaging, cavitation in lung lesions (CLL), morphologic response of liver lesions (MRL), and change of liver metastasis density (CLD) were evaluated. RESULTS: We finally screened 671 cases, and 226 cases were eligible. In total, 172 and 145 patients had lung and liver metastases, respectively. Among the patients with lung metastasis, CLL was found in 69 patients (40.0%). The median progression-free survival (PFS) of the patients with and those without CLL was 3.2 and 2.4 months, respectively (hazard ratio [HR] = 0.758; 95% confidence interval [CI]: 0.529-1.087), and the median overall survival (OS) of these groups was 10.5 and 8.9 months, respectively (HR = 0.862; 95% CI: 0.579-1.285). MRL and CLD of liver metastasis were analyzed in 145 and 90 patients, respectively. The median OS with and without MRL was 8.9 and 8.2 months, respectively, whereas the median OS with and without CLD was 11.6 and 7.7 months, respectively (HR = 0.523; 95% CI: 0.275-0.992). CONCLUSION: CLL may predict PFS but not OS among patients with lung metastasis. CLD was predictive of favorable outcomes for REGO in patients with liver metastasis.

Fluoropyrimidine with or without platinum as first-line chemotherapy in patients with advanced gastric cancer and severe peritoneal metastasis: a multicenter retrospective study.

BACKGROUND: There is no standard first-line chemotherapy for advanced gastric cancer with severe peritoneal metastasis. Although fluoropyrimidine is often used, its efficacy is limited, and it remains unclear whether combination therapy with platinum improves clinical outcomes. METHODS: This retrospective study involved patients at six Japanese academic hospitals between 2010 and 2016. Patients with advanced gastric cancer and severe peritoneal metastasis were included if they had massive ascites and/or inadequate oral intake requiring intravenous nutritional support. We then compared the efficacy and safety of fluoropyrimidine monotherapy with those of fluoropyrimidine/platinum combination therapy. RESULTS: Compared with the combination therapy group (n = 64), the monotherapy group (n = 65) had worse general health (more patients with elderly age, performance status > 2, and having both massive ascites and inadequate oral intake). Both overall survival (9.0 vs 5.0 months, p < 0.01) and progression-free survival (4.3 vs 2.3 months, p < 0.01) were significantly longer in the combination group, and the significance remained after adjusting for prognostic variables (hazard ratios of 0.47 and 0.41, respectively; p < 0.01). Improvements in ascites and oral intake were also greater in the combination group. Although neutropenia (grade ≥ 3) occurred more frequently with combination therapy, both treatments in this study were tolerable. CONCLUSIONS: Combination therapy with fluoropyrimidine and platinum might be more effective than monotherapy with fluoropyrimidine and was tolerable for patients with advanced gastric cancer and severe peritoneal metastasis.

Pharmacokinetics of S-1 monotherapy in plasma and in tears for gastric cancer patients.

BACKGROUND: S-1 is an oral anticancer drug composed of tegafur (FT), which is a prodrug of 5-FU, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate. Recently, some studies have been reported on watering eyes caused by S-1. However, the mechanism of watering eyes caused by S-1 is still unclear. The aim of this study was to investigate the correlation between tears and plasma concentrations of FT, 5-FU, and CDHP, which are components and active modulator of S-1. METHODS: We prospectively investigated the pharmacokinetics (PK) of FT, 5-FU, and CDHP in plasma and in tears of gastric cancer patients who were treated with S-1 monotherapy at the dose of 80 mg/m2/day. Plasma and tears from both eyes were obtained 1, 2, 4, and 8 h after S-1 administration on day 1 and 14 of the first cycle. RESULTS: Total of eight patients were enrolled. All the FT, 5-FU and CDHP were detected both in plasma and in tears, and their PK parameters were measured. There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears on day 1 and day 14 (correlation coefficients r, right eye/left eye: r = 0.882/0.878, 0.877/0.890, and 0.885/0.878, respectively). CONCLUSION: There was a positive correlation between the concentrations of FT, 5-FU and CDHP in the plasma and those in the tears. The result is expected to facilitate the further investigation into the causes of watering eyes and the establishment of the effective methods for the prevention and the treatment.

Role of hepatectomy in gastric cancer with multiple liver-limited metastases.

BACKGROUND: Several studies have demonstrated the benefit of hepatectomy for treating gastric cancer (GC) with liver-limited metastases (LLM). The survival benefit of hepatectomy compared with that of systemic chemotherapy is unknown, particularly in patients with multiple LLM. This study investigated the survival benefit of hepatectomy compared with that of systemic chemotherapy administered to patients with GC with multiple LLM. METHODS: We retrospectively reviewed the data of consecutive patients with GC with two or three LLM who underwent hepatectomy or received systemic chemotherapy as initial treatment at the Shizuoka Cancer Center between December 2004 and December 2015. RESULTS: Nine of 24 patients who met the inclusion criteria underwent hepatectomy, and 15 received chemotherapy. In the hepatectomy group, all patients achieved R0 resection and none died during hospitalization. Three patients received adjuvant chemotherapy. Disease recurred in eight patients (88.9%). In the chemotherapy group, three patients underwent hepatectomy following initial chemotherapy and did not experience recurrence or death during follow-up. Median follow-up was 47.9 months and median overall survival (OS) was 38.1 and 24.8 months in the chemotherapy and hepatectomy groups, respectively. Multivariate analysis of OS, including initial treatment, revealed that unilobar liver metastasis was the only independent favorable prognostic factor. CONCLUSIONS: Although hepatectomy for patients with GC with multiple LLM is not recommended as the initial therapy, it prolonged the survival of patients with tumors controlled using systemic chemotherapy.

Primary prophylactic granulocyte colony-stimulating factor according to ASCO guidelines has no preventive effect on febrile neutropenia in patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

BACKGROUND: The efficacy of primary prophylactic granulocyte colony-stimulating factor (G-CSF) in preventing febrile neutropenia (FN) in patients treated with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy remains controversial. We compared the incidence of FN in patients treated with and without primary prophylactic G-CSF. METHODS: We performed a retrospective analysis of 142 patients with locally advanced head and neck or esophageal cancer treated with TPF between January 2009 and March 2017. Among them, 116 patients started TPF without primary prophylactic G-CSF (control group) while 26 patients were given primary prophylactic G-CSF from day 7 of the first cycle of TPF (prophylactic group). RESULTS: The incidence of grade 4 neutropenia during the first cycle of TPF was significantly higher in the control group than in the prophylactic group [58.6% (n = 68) vs. 30.8% (n = 8), p = 0.02]. However, the incidence of FN in the first cycle was not significantly different between the two groups [32 patients (27.5%) in the control group and 8 patients (30.8%) in the prophylactic group (p = 0.62)]. In addition, the mean relative dose intensity throughout all cycles of TPF, as well as the survival time and response after TPF, were also not significantly different between the two groups. CONCLUSIONS: Primary prophylactic G-CSF from day 7 of the first cycle of TPF did not reduce the incidence of FN. Our findings suggest that the timing of primary prophylactic G-CSF, as recommended by the American Society of Clinical Oncology guidelines, should be modified to reduce the incidence of FN in TPF.

Survival benefit of adding docetaxel, cisplatin, and 5-fluorouracil induction chemotherapy to concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma with nodal Stage N2-3.

BACKGROUND: Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CCRT-AC) has been established as the standard of care in locally advanced nasopharyngeal carcinoma (LA-NPC). The survival benefit of induction chemotherapy (ICT) for LA-NPC remains controversial. We analyzed the efficacy and feasibility of docetaxel, cisplatin and 5-fluorouracil (TPF) ICT followed by CCRT for LA-NPC with nodal Stage N2-3. METHODS: We performed a retrospective analysis of 28 LA-NPC patients with nodal Stage N2-3 receiving induction TPF followed by CCRT (TPF group; n = 12) or CCRT-AC (CCRT group; n = 16) between October 2006 and May 2016. RESULTS: The median follow-up periods were 36.4 (range 6.7-55.2) and 40.1 months (range 4.3-99.0) for the TPF and CCRT groups, respectively. One- and three-year overall survival for the TPF group vs. the CCRT group were 100% and 100% vs. 94% and 75%, respectively (P = 0.21). The cumulative one- and three-year incidences of locoregional recurrence or progression for the TPF group vs. the CCRT group were 10% and 21% vs. 16% and 32% (P = 0.49), and those of distant metastasis were 0% and 0% vs. 26% and 26%, respectively (P = 0.08). The common Grade 3-4 acute toxicities were neutropenia, anorexia, febrile neutropenia, and stomatitis in the TPF group. The Grade 3-4 late toxicities did not differ significantly between the two groups. CONCLUSIONS: This study suggests that induction TPF followed by CCRT might reduce distant metastasis, so this combination may be feasible for the treatment of LA-NPC with nodal Stage N2-3.

A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

Two cases of liver cirrhosis with hyperammonemic encephalopathy caused by urease-producing bacteria in the urinary tract.

Hyperammonemia is often experienced as a complication of liver cirrhosis, but it is not well known that hyperammonemic encephalopathy is induced by urease-splitting bacteria in the urinary tract. We report two cases of hyperammonemia in two women in their 80s with liver cirrhosis. Both cases were treated as hepatic encephalopathy with usual treatment, but there was no improvement. Urinalysis showed marked alkalinuria and urine culture showed urease-splitting bacteria, which were thought to be related to the pathology. After drainage of urine and administration of antimicrobials, the blood ammonia level decreased and the urine pH level normalized. The mechanism of this is that ammonia is produced by the degradation of urinary urea by urease-producing bacteria in the bladder, and in the presence of dysuria, it is absorbed into the blood circulation from the bladder venous plexus, leading to hyperammonemia.Urine findings should be confirmed when a patient with liver disease develops hyperammonemia or is unresponsive to conventional hepatic encephalopathy treatment.

Analysis of factors affecting progression-free survival of first-line chemotherapy in older patients with advanced gastrointestinal cancer.

OBJECTIVES: Few studies have investigated factors influencing the efficacy of chemotherapy in older patients with cancer. This study aimed to evaluate the usefulness of G8, geriatric assessment (GA), and factors measured in general clinical practice for evaluating progression-free survival (PFS) of first-line palliative chemotherapy in older patients with advanced gastrointestinal cancer. MATERIALS AND METHODS: This was a prospective observational study of older patients (age ≥70 years) with advanced gastrointestinal cancer. The modified cut-off value of G8 was determined by referring to two or more abnormal GA conditions. The usefulness of baseline GA and G8 (conventional and modified cut-off value) was assessed according to the efficacy (PFS and disease control rate) of the administered first-line palliative chemotherapy. RESULTS: Overall, 93 patients were evaluated between March 2017 and February 2019. A modified G8 cut-off value of ≤12 had a sensitivity and specificity of 68.9% and 46.9%, respectively. PFS was significantly prolonged in the patients with G8 > 12, serum albumin ≥3.5 g/dl, and in whom grade ≥3 adverse events occurred. There was no significant difference in the PFS between monotherapy and combination therapy. GA was not useful for predicting PFS prolongation or the occurrence of serious adverse events in first-line treatment. CONCLUSION: Among older patients with advanced gastrointestinal cancer who receive first-line chemotherapy, a modified G8 cut-off value of 12 points, occurrence of grade 3 or higher adverse events, albumin levels, rather than age or performance status were predictors of PFS prolongation.

Efficacy and safety of irinotecan monotherapy as third-line treatment for advanced gastric cancer.

PURPOSE: Although irinotecan monotherapy is often used in third-line treatment after the failure of taxanes in Japanese clinical practice, its survival benefit is still unclear. The aim of this study is to investigate the efficacy and safety of irinotecan monotherapy as third-line treatment. METHODS: Clinical data from consecutive patients in whom irinotecan had been initiated as third-line treatment between December 2003 and July 2015 in Shizuoka Cancer Center were retrospectively analyzed. Patients who were refractory or intolerant to fluoropyrimidine with or without platinum in first-line treatment and subsequent therapy with taxanes were included in this study. Irinotecan was administered at 150 mg/m(2) every 2 weeks. RESULTS: The data of 50 patients who met the inclusion criteria were analyzed. The overall response rate was 18.4 % (7/38) among the patients with measurable disease. The median progression-free survival time was 66 days, and the median survival time was 180 days from the initiation of irinotecan therapy. The major grade 3 or 4 adverse events including neutropenia, fatigue, and anorexia were observed in 12 (24 %), 8 (16 %), and 7 (14 %), respectively. No treatment-related deaths occurred. Thirteen patients (26 %) required a dose reduction to 120 mg/m(2) or less from the initiation of irinotecan. CONCLUSIONS: This study suggests that irinotecan as third-line treatment has an anti-tumor effect and is feasible with optimal dose modification for advanced gastric cancer.