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Background: Previously reported results from phase III KEYNOTE-048 demonstrated similar or improved overall survival (OS) with pembrolizumab or pembrolizumab-chemotherapy versus cetuximab-chemotherapy (EXTREME) in Japanese patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). We report results in Japanese patients from KEYNOTE-048 after 5 years of follow-up., Methods: Patients with R/M HNSCC of the oropharynx, oral cavity, hypopharynx, or larynx were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or EXTREME. Primary endpoints were OS and progression-free survival. Efficacy was evaluated in the programmed cell death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, PD-L1 CPS ≥ 1, and total Japanese populations., Results: In Japan, 67 patients were enrolled (pembrolizumab, n = 23; pembrolizumab-chemotherapy, n = 25; EXTREME, n = 19). Median follow-up was 71.0 months (range, 61.2-81.5); data cutoff, February 21, 2022. 5-year OS rates with pembrolizumab versus EXTREME were 35.7% versus 12.5% (hazard ratio [HR] 0.38; 95% CI 0.13-1.05), 23.8% versus 12.5% (HR 0.70; 95% CI 0.34-1.45), and 30.4% versus 10.5% (HR 0.54; 95% CI 0.27-1.07) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively. 5-year OS rates with pembrolizumab-chemotherapy versus EXTREME were 20.0% versus 14.3% (HR 0.79; 95% CI 0.27-2.33), 10.5% versus 14.3% (HR 1.18; 95% CI 0.56-2.48), and 8.0% versus 12.5% (HR 1.11; 95% CI 0.57-2.16) in the PD-L1 CPS ≥ 20, CPS ≥ 1, and total Japanese populations, respectively., Conclusion: After 5 years of follow-up, pembrolizumab and pembrolizumab-chemotherapy showed long-term clinical benefits; results further support these treatments as first-line options for Japanese patients with R/M HNSCC., Clinical Trial Registration: NCT02358031., Competing Interests: Declarations. Conflict of interest: Nobuhiko Oridate has received honoraria from MSD, Ono Pharmaceutical, Bristol Myers Squibb Japan, Merck Biopharm Japan, and Taiho Pharmaceutical. Shunji Takahashi has received honoraria from MSD, Eisai, and Ono Pharmaceutical and grants from Taiho Pharmaceutical, Daiichi Sankyo, Novartis, Ono Pharmaceutical, Eisai, BMS, Bayer, and Astra Zeneca. Kaoru Tanaka has received personal fees from Astra Zeneca, Merck Biopharma, Eisai, Bristol Myers Squibb, Ono Pharmaceutical, MSD, Kyowa Kirin, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, and Novartis Pharma, outside the submitted work. Yasushi Shimizu has received research funding from MSD. Koji Matsumoto has received honoraria from MSD, Kyowa Kirin, Daiichi Sankyo, Eli Lilly, and Chugai Pharmaceutical Co. and received trial fee from Daiichi Sankyo, MSD, Eli Lilly, Gildea Sciences, and Eisai. Tomoya Yokota has received research funding from MSD. Masanobu Takahashi has received lecture fees from Daiichi Sankyo, Ono Pharmaceuticals, Bristol Myers Squibb, Taiho Pharmaceutical Co. and research funding from Ono Pharmaceutical, Chugai Pharmaceutical, and MSD, outside the submitted work. Tsutomu Ueda has received research funding from Lilly and personal fees from Rakuten Medical, Merck Biopharma, Mitsubishi Tanabe Pharma, MSD, and Bristol Myers Squibb. Nobuhiro Hanai has received honoraria from Rakuten Medical K.K. and research funding from MSD K.K. and Adlai Nortye USA Inc. Hiroki Hara has received honoraria from Bristol Myers Squibb, Chugai, Daiichi Sankyo, Lilly, Merck Biopharma, Miyarisan, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, and Yakult Honsha and research funding from ALX oncology, Amgen, Astellas, Astra Zeneca, Bayer, BioGene, Chugai, Daiichi Sankyo, Janssen, Jazz Pharma, MSD, Ono Pharmaceutical, and Taiho Pharmaceutical. Kenichi Takahashi is an employee of MSD K.K., Tokyo, Japan and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Nijiro Nohata is an employee of MSD K.K., Tokyo, Japan and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Burak Gumuscu is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Nati Lerman is an employee of Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and owns stock/stock options in Merck & Co., Inc., Rahway, NJ, USA. Makoto Tahara has received honoraria from Eisai, MSD, Merck Biopharma, Lilly and research funding from Bayer, Astra Zeneca, Ono Pharmaceutical, and Pfizer. Yasushi Fujimoto, Tomoko Yamazaki, Hironori Yamaguchi, Tomokazu Yoshizaki Ryuji Yasumatsu, Masahiro Nakayama, Kiyoto Shiga, Takashi Fujii, and Kenji Mitsugi declare they have no conflicts of interest., (© 2024. The Author(s).)

Background: Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen., Methods: We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center., Results: We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014)., Conclusions: Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen., (© 2023. The Author(s).)

Purpose: This study aimed to evaluate the effectiveness and safety of gemcitabine (GEM) plus nab-paclitaxel (GnP) in patients aged ≥ 75 years with advanced pancreatic cancer and compare it with monotherapy (GEM or S-1)., Methods: We retrospectively reviewed the data of consecutive patients with advanced pancreatic cancer aged ≥ 75 years who received either GnP or monotherapy (GEM or S-1) between January 2014 and May 2020. The primary efficacy outcome was overall survival (OS)., Results: A total of 96 patients were included in this study; 51 were treated with GnP and 45 with monotherapy (31 with GEM and 14 with S-1). The median OS and progression-free survival were 10.8 and 6.7 months in the GnP group and 10.7 and 4.3 months in the monotherapy group, respectively. The treatment effect on OS was consistently favorable in the GnP group across most subgroups, particularly in patients with locally advanced cancer, modified Glasgow prognostic score of 0 or 1, and neutrophil/lymphocyte ratio < 3.1. The disease control rates were 76% and 48% in the GnP and monotherapy groups, respectively, and grade 3 or 4 neutropenia occurred in 23 (45%) and 11 (24%) patients of the GnP and monotherapy groups, respectively., Conclusions: This study demonstrated that GnP was not superior to monotherapy with regard to OS. However, multivariate analysis showed that GnP treatment positively affected the OS and could be considered as a treatment option, even for elderly patients., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The aims of this study are to evaluate the efficacy and safety of first-line treatment with chemotherapy plus cetuximab in real-world patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and to identify prognostic factors for overall survival (OS)., Methods: This is a prospective observation study involving 20 oncology institutions in Japan. Patients with RM-SCCHN treated with a first-line therapy consisting of cetuximab plus any chemotherapy regimen between December 2013 and February 2017 were enrolled. The primary objective of the study was 1-year OS. Secondary objectives included response rate and adverse events., Results: Of 120 patients recruited, 114 patients were analyzed. Median age was 64 years. Cetuximab in combination with platinum plus 5-FU (EXTREME regimen) was chosen in 86 patients (75.4%). The median OS was 12.4 months. A point estimate of the 1-year survival rate was 51.1%. Overall response rate was 26.3%. Grade 3 or worse adverse events included neutropenia (22.8%), hypokalemia (9.6%), acneiform rash (7.0%), pneumonitis (1.8%), and infusion-related reaction (0.9%). On multivariate analysis, regional lymph node metastasis, absence of intervention by dermatologists, lack of response to therapy, skin metastasis, and non-EXTREME regimen were identified as independent unfavorable prognostic factors for OS., Conclusion: The combination of cetuximab plus chemotherapy was tolerable and efficacious in patients with RM-SCCHN in a real-world setting. Clinical outcomes and prognostic factors extracted from this study provide a reference of the current clinical practice as well as for the future development of novel therapy in RM-SCCHN.

Background: Docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy (ICT) is a treatment option for locally advanced unresectable head and neck squamous cell carcinoma (LA-HNSCC). However, patients with advanced age, or renal, cardiac or neurogenic dysfunction are ineligible for ICT-TPF., Methods: We retrospectively assessed 24 unresectable LA-HNSCC patients who received paclitaxel, carboplatin and cetuximab (PCE) as ICT at the Shizuoka Cancer Center between April 2013 and October 2018., Results: Patient characteristics were as follows: median age, 72 years (range 60-81); 0, 1, and 2 performance status (PS), 1, 15, and 8 patients, respectively, and creatinine clearance ≥ 60 mL/min or < 60 mL/min, 8 and 16 patients, respectively. The main reasons for PCE selection were renal impairment, older age, cardiac dysfunction, poor PS, and cerebral infarction. Twenty-two patients (92%) completed two or three cycles of ICT-PCE. After ICT-PCE, one patient (4%) and 20 patients (83%) achieved a complete response and partial response, respectively. Twenty-one patients (87%) advanced to definitive locoregional treatment. Median observation period was 25.2 months. The 12-month progression-free and overall survival rates were 75 and 92%, respectively. Median progression-free survival and overall survival were 29.4 and 34.8 months, respectively. Grade 3 or 4 toxicities included neutropenia (58%), oral mucositis (8%), and febrile neutropenia (4%)., Conclusions: ICT-PCE may be a tolerable and potential option for unresectable LA-HNSCC patients ineligible for TPF.

Background: A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS., Methods: Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse., Results: The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2-63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%)., Conclusions: Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.

Purpose: To evaluate the efficacy and safety of nab paclitaxel (nab-P) plus gemcitabine (GEM) in elderly patients ≥ 75 years old with unresectable pancreatic cancer (PC) compared with younger patients., Methods: The data of 27 unresectable PC patients treated with nab-P plus GEM as first-line chemotherapy were retrospectively analyzed. The patients were divided into two groups according to their age at inclusion: an elderly group (9 patients ≥ 75 years old) and a younger group (18 patients <75 years old). We compared the disease control rate, median overall survival (OS), and adverse events (AEs) between the two groups. Predictive factors for the OS were also evaluated., Results: The clinical characteristics of patients of the two groups were not significantly different except for the age. The respective values for the disease control rate (66.7% vs. 77.8%, P = 0.542) and median OS (277 days vs. 312 days, P = 0.722) were also not significantly different between the elderly and younger group, although the relative dose intensity of GEM/nab-P in the elderly group (56.6%/53.1%) was significantly lower than that in the younger group (67.3%/63.1%) (P = 0.016/0.04). The absence of biliary drainage and CEA ≥ 6.5 were found to be poor prognostic factors in a multivariate analysis. The most common grade ≥ 3 AE was neutropenia (44% in both groups). No significant differences in the frequency of all AEs were observed between the two groups., Conclusions: Nab-P plus GEM appears effective and well-tolerated for elderly patients ≥ 75 years old with unresectable PC.

A conditioning regimen with fludarabine and myeloablative dose of busulfan (FLU/BU4) has been commonly used in allogeneic hematopoietic cell transplantation (allo-HCT). However, there are two major problems with this regimen: insufficient anti-leukemic effect, especially in advanced cases, and slow time to complete donor-type chimerism, especially T-cell chimerism. To overcome these issues, we designed a combination regimen with FLU (150 mg/m 2 ), intravenous BU (12.8 mg/kg), and melphalan (100 mg/m 2 ) (FLU/BU4/MEL) and conducted retrospective analyses of treatment outcomes at our institute. Forty-two patients with myeloid malignancies received allogeneic bone-marrow transplantation or peripheral blood stem-cell transplantation (allo-BMT/PBSCT) with FLU/BU4/MEL regimen. The median age of patients was 46.5 years (20-63 years). Thirteen patients (31%) did not achieve complete hematological remission at transplantation. All patients examined achieved complete whole and T-cell chimerism within 1 month after allo-HCT. The 4-year overall survival and disease-free survival rates were 66.0% [95% confidence interval (CI) 49.4-78.3%] and 59.5% (95% CI 43.2-72.6%) in all patients, and 49.4% (95% CI 19.7-73.6%) and 38.5% (95% CI 14.1-62.8%) in patients who were not in remission. In conclusion, FLU/BU4/MEL showed curative potential, even in patients with advanced myeloid malignancies, accompanied by achievement of rapid complete chimerism after allo-BMT/PBSCT.

A 42-year-old woman was referred to our hospital for the treatment of pyloric stenosis. Esophagogastroduodenoscopy (EGD) and computed tomography (CT) revealed the presence of type 4 advanced gastric cancer with bladder metastasis and peritoneal dissemination. Biopsy specimen examination revealed poorly differentiated adenocarcinoma with signet ring cell carcinoma. Thus, two cycles of chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin were administered. Subsequently, the gastric lesion and bladder metastasis reduced as detected using EGD and CT. Consequently, she achieved adequate oral intake. After changing the regimen to tegafur/gimeracil/oteracil and oxaliplatin, she was discharged. Currently, she continues to receive chemotherapy.

Purpose: Although oxaliplatin 130 mg/m 2 every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m 2 (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer., Methods: Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0-1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥ 80% relative dose intensity of oxaliplatin., Results: Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8-86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1-19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9-8.5) and 13.1 months (95% confidence interval 7.4-19.0), respectively., Conclusion: Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

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.

A 61-year-old man was referred to the urology department in our hospital with gross hematuria and hydro nephrosis. Cystoscopy revealed a smooth mass lesion in his bladder, and a transurethral biopsy was performed. Signet ring cell carcinoma was found in the submucosa. Upper gastrointestinal endoscopy revealed an ulcerated lesion in his gastric body. Biopsy specimens obtained from the ulcerated lesion showed signet ring cell carcinoma. No other primary lesions were detected using colonoscopy, gallium scintigraphy, or computed tomography of the chest. He was ultimately diagnosed with advanced gastric cancer with bladder metastasis. He was prescribed combination chemotherapy of cisplatin and tegafur, gimeracil, oteracil potassium, and trastuzumab. After 2 courses of chemotherapy, there was a decrease in the size of both the gastric and bladder lesions. There was also a significant decrease in the tumor marker levels. He is currently alive after 7 courses of chemotherapy.

Background: Standard treatment for unresectable esophageal squamous cell carcinoma (ESCC) without distant metastasis is definitive chemoradiotherapy (dCRT), in which the incidence of esophageal fistula (EF) is reported to be 10-12%. An ad hoc analysis of JCOG0303, a phase II/III trial of dCRT for patients with unresectable ESCC (including non-T4b), suggested that esophageal stenosis is a risk factor for EF. However, risk factors for EF in patients limited to T4b ESCC treated with dCRT have yet to be clarified. The aim of this study was to investigate risk factors for EF in T4b thoracic ESCC treated with dCRT., Methods: We retrospectively analyzed the data of consecutive T4b thoracic ESCC patients who were treated with dCRT (cisplatin and fluorouracil) at Shizuoka Cancer Center between April 2004 and September 2015., Results: Excluding 8 patients with esophageal fistula clearly attributable to other iatrogenic interventions, the data of 116 patients who met the inclusion criteria were analyzed. Esophageal fistula was observed in 28 patients (24%). Although the fistula was closed in 5 patients, overall survival was significantly shorter in patients who experienced esophageal fistula (8.0 vs. 26.8 months; p < 0.0001). Among four potential variables extracted in univariate analysis, namely, total circumferential lesion, elevated CRP level, elevated white blood cell count, and anemia, the first two were revealed as risk factors for esophageal fistula in multivariate analysis., Conclusions: This study demonstrated that total circumferential lesion and CRP ≥1.00 mg/dL are risk factors for esophageal fistula in T4b thoracic ESCC treated with dCRT., Trial Registration: This study was retrospectively registered.

Background: The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN., Patients and Methods: Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients., Results: Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia., Conclusions: The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population., Registered Clinical Trial Number: UMIN000010507.

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., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: The efficacy of chemotherapy for unresectable pancreatic cancer has improved. However, it is occasionally difficult to make treatment decisions for elderly patients. We reviewed the outcomes of elderly patients with unresectable pancreatic cancer by using a large cohort and evaluated whether they had received chemotherapy and the reason why., Methods: Data for 895 pancreatic cancer patients who were treated using chemotherapy or best supportive care were analyzed considering demographics, clinical stage, treatment, and outcome. Data were analyzed using the chi-square test, Student t-test, or Mann-Whitney U-test, as appropriate. Outcomes were analyzed using the Kaplan-Meier method. Differences in survival were analyzed using the log-rank test., Results: The median survival time was significantly shorter in elderly patients (≥65 years) than in younger patients (<65 years) (181 vs. 263 days, P = 0.0001). The median survival time of patients treated with chemotherapy was not significantly different between the elderly and the younger group (274 days vs. 333 days, P = 0.09), and nor was that of patients choosing best supportive care (84 days vs. 78 days, P = 0.83). These results held true even when the age cut-off between younger and elder patients was increased to 70, 75, and 80 years. Elderly patients treated with chemotherapy had a significantly longer median survival time than those choosing best supportive care (274 vs. 86 days, P < 0.0001); a significantly greater proportion of elderly patients chose best supportive care compared to younger patients (47.8 vs. 25.8%, P < 0.0001). The reason for choosing best supportive care was established in 261 elderly patients (82.9%); 133 (51.0%) met the eligibility criteria for chemotherapy, but of these, 78 (58.6%) were not informed about their disease. The treatment preferences of elderly patients were not always considered; they often received only best supportive care per family members preference (N = 65, 48.8%) or because the physician based their treatment decision only on the patient's age (N = 68, 51.1%)., Conclusions: Chemotherapy appears effective for elderly pancreatic cancer patients with unresectable disease, but treatment needs to be optimized to improve prognosis.

Background: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus., Methods: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30-40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS)., Results: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy., Conclusions: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Purpose: Standard care for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is concurrent chemoradiotherapy, but survival remains limited. Neoadjuvant chemotherapy with docetaxel, cisplatin and fluorouracil (DCF) has demonstrated promising activity, with a pathological complete response (CR) of 17 % for resectable stage II/III ESCC. Here, we conducted a multicenter study to assess the efficacy and safety of induction chemotherapy with DCF followed by CRT in patients with unresectable locally advanced ESCC., Methods: Eligibility criteria included clinical T4 and/or M1 lymph node ESCC, PS 0-1 and age 20-70 years. Treatment consisted of docetaxel 70 mg/m(2) and cisplatin 70 mg/m(2) on day 1, and fluorouracil 750 mg/m(2) on days 1-5, repeated every 3 weeks for three cycles, followed by cisplatin 70 mg/m(2) on days 64 and 92, and fluorouracil 700 mg/m(2) on days 64-67 and 92-95, concurrently with radiotherapy (60 Gy in 30 fractions, 5 days/week). Primary endpoint of the phase II part was CR rate., Results: Thirty-three patients were enrolled. The completion rate of protocol treatment was 88 %. Thirteen patients (39.4 %) achieved a CR. With a median follow-up period of 41 months (range 24-49 months), median progression-free survival was 12.2 months, and median survival was 26.0 months, with a survival rate of 40.4 % at 3 years. The most common grade 3 or 4 toxicities were neutropenia, leukopenia, anorexia and dysphagia. No treatment-related death was observed., Conclusion: Induction chemotherapy with DCF followed by CRT is tolerable and shows promising efficacy for unresectable locally advanced ESCC.

Background: The oncological outcomes of transthoracic esophagectomy (TTE) and definitive chemoradiotherapy (dCRT) as initial treatment in patients with esophageal squamous cell carcinoma (ESCC) who could tolerate TTE remains unclear., Methods: Consecutive patients histologically diagnosed with stage I/II/III ESCC (excluding cT4 or cN3) or stage IV ESCC due to supraclavicular lymph node metastasis were eligible for inclusion in this retrospective study. To select patients who could tolerate TTE, respiratory function, Eastern Cooperative Oncology Group performance status, and preoperative complications were considered. Patient characteristics, recurrence-free survival (RFS), 3- and 5-year overall survival (OS), pattern of recurrence, and treatments after initial treatment failure were investigated., Results: Overall, 112 patients were included in the TTE group and 65 were included in the dCRT group. No significant differences were observed in patient characteristics and clinical stage between the TTE and dCRT groups (stage I/II/III/IV of 29/27/46/10 in the TTE group and 23/15/20/7 in the dCRT group). The R0 resection rate was 87 % in the TTE group, and complete response rate was 68 % in the dCRT group. In intention-to-treat analysis, there was no significant difference in RFS. In contrast, 3-year OS of non-stage IA patients was significantly longer in the TTE group than the dCRT group (TTE 66.9 %; dCRT 49.8 %; p = 0.023). In non-stage IA patients, after initial treatment failure significantly more patients could undergo local treatment (radiotherapy or surgery in the TTE group; surgery or endoscopic resection or photodynamic therapy in the dCRT group) in the TTE group than the dCRT group (TTE 74 %; dCRT 40 %; p = 0.003)., Conclusions: In locally advanced ESCC patients who could tolerate TTE, TTE extended 3-year OS, which might have been encouraged by utilizing local treatment after initial treatment failure.

Objective: Neoadjuvant chemotherapy with 5-fluorouracil plus cisplatin and subsequent esophagectomy with two- to three-field lymphadenectomy is a standard treatment for patients with clinical stage II/III squamous cell carcinoma (SCC) of the esophagus. This study investigates the prognostic factors for patients who received neoadjuvant chemotherapy., Methods: Of 164 patients assigned to receive neoadjuvant chemotherapy in the JCOG9907 trial, multivariate analyses were performed for 159 and 149 patients to evaluate the preoperative and the combined preoperative and postoperative prognostic factors, respectively., Results: The multivariate analyses using preoperative factors showed that clinical stage T3 [vs. cT1-2; hazard ratio (HR) 3.60, p = 0.0007] and serum albumin (Alb) <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.29, p = 0.0005) were associated with a poor prognosis. Four independent prognostic factors were identified by multivariate analysis of both preoperative and postoperative factors: pathological curability B (pB; R0 with stage IV or pD < pN) or pC [microscopic or macroscopic residual tumor (R1/R2)] [vs. pA (R0); HR 1.93, p = 0.015], pathological stage N1 (vs. pN0; HR 3.86, p = 0.0012), cT3 (vs. cT1-2; HR 2.80, p = 0.0073), and serum Alb <4.0 g/dl (vs. ≥ 4.0 g/dl; HR 2.03, p = 0.0069)., Conclusions: Preoperative cT stage, Alb, and postoperative pathological findings are independent prognostic factors for patients undergoing neoadjuvant chemotherapy for advanced thoracic esophageal SCC. This analysis may aid in stratification according to individual patient risk., (© 2015 S. Karger AG, Basel.)

Objective: Breast, gastric and lung cancers are the most common cancers that cause pulmonary lymphangitis carcinomatosa. However, little is known about the clinical features of pulmonary lymphangitis carcinomatosa in advanced gastric cancer., Methods: We retrospectively reviewed the data throughout the clinical courses of 33 patients with gastric cancer who developed pulmonary lymphangitis carcinomatosa. Pulmonary lymphangitis carcinomatosa was confirmed by both a pulmonologist and a diagnostic radiologist on the basis of computed tomography findings of interstitial patterns such as thickening or irregularity of interlobular septa and bronchovascular bundles., Results: The median age of the 33 patients was 55 years old (range, 25-73 years). The percentages of female patients, those with performance status 3 or 4, and those with respiratory symptoms at diagnosis were 70, 36 and 76%, respectively. The histologically diffuse type of gastric cancer accounted for 85% of cases. Mediastinal lymph node, peritoneal and bone metastases were found in 64, 61 and 39% of patients, respectively. Disseminated intravascular coagulation was noted in 21% of patients. The median survival time of the 18 chemotherapy-naïve patients treated with chemotherapy was 5.7 months (range, 0.4-37.0 months). Two patients obtained symptomatic relief, and one patient treated with S-1 + cisplatin + sunitinib survived >3 years., Conclusions: Pulmonary lymphangitis carcinomatosa caused by gastric cancer has some specific clinicopathological features. While the prognosis of gastric cancer patients with pulmonary lymphangitis carcinomatosa is extremely poor, some patients may have survival benefit from chemotherapy., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Since 2007, S-1 plus cisplatin therapy has been recognized as the standard first-line treatment for advanced gastric cancer in Japan. However, no standard regimen has been established for patients refractory to first-line treatment. Furthermore, irinotecan and paclitaxel are considered key drugs for second-line treatment. Several studies have investigated the efficacy and tolerability of combination therapy with oxaliplatin, 5-fluorouracil and leucovorin (modified FOLFOX-6) for advanced gastric cancer. Here, we examined the efficacy and toxicity of modified FOLFOX-6 therapy in heavily pretreated patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes., Methods: Fourteen patients with advanced gastric cancer refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes were included in the study. In modified FOLFOX-6 therapy, 85 mg/m(2) oxaliplatin, 400 mg/m(2) 5-fluorouracil and 200 mg/m(2) leucovorin on Day 1 were administered biweekly by intravenous infusion, followed by the administration of 2400 mg/m(2) 5-fluorouracil by a 46-h continuous infusion., Results: The median age of the patients was 59 years (range, 22-74). A median of 5.5 (range, 1-13) chemotherapy cycles were administered. The overall response rate was 23.1% in patients with measurable lesions. Of the 12 patients with advanced gastric cancer refractory to cisplatin, 2 showed partial response (response rate, 18.2%). The progression-free survival was 90 days, and the median survival time from the initiation of modified FOLFOX-6 therapy was 268 days. Grade 3-4 toxicities most commonly observed included neutropenia (57%), anaemia (14%), thrombocytopenia (21%) and hyperammonaemia (7%)., Conclusions: Modified FOLFOX-6 therapy in patients refractory to 5-fluorouracil, irinotecan, cisplatin and taxanes may be a potential advanced gastric cancer therapeutic strategy.

The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with every second week cetuximab and irinotecan in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with wild-type KRAS metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. Cetuximab was administered at 500 mg/m(2) biweekly with irinotecan. The primary endpoint was response rate. The pharmacokinetics of cetuximab was also evaluated in 5 patients. From May 2009 to February 2010, a total of 31 patients were enrolled from five institutions. One patient was not eligible. Among the 30 patients who were treated with biweekly cetuximab plus irinotecan, partial response was observed in 9 patients. The objective response rate was 30.0% (95% confidence interval [CI], 14.7%-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 76.7% (95% CI, 57.7%-90.0%). The median progression-free survival was 5.3 months and median overall survival was 10.8 months. Grade 3 skin toxicity was observed in 3 patients (10.0%) and one treatment related death due to pneumonia was observed. Combination chemotherapy with biweekly cetuximab and irinotecan was effective for pretreated metastatic colorectal cancer with wild-type KRAS.

Disseminated intravascular coagulation (DIC) is a complication that may be experienced by patients with solid tumors. The prognosis of solid tumors with DIC is much poorer than those without DIC. Although treatment of the underlying disease is critical for improvement of DIC, the efficacy and safety of chemotherapy in patients with DIC associated with colorectal cancer are not clear. A 50-year-old man with advanced rectal cancer and multiple liver metastases experienced DIC during third-line treatment with cetuximab plus irinotecan, following 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) plus bevacizumab and 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus bevacizumab. Combination chemotherapy consisting of FOLFOX plus bevacizumab was reintroduced. Although platelet and fresh-frozen plasma transfusions were required daily before chemotherapy, the patient's laboratory values improved after two cycles of chemotherapy, without severe toxicity. The patient was discharged, and FOLFOX plus bevacizumab has been continued on an outpatient basis without sign of recurrence of DIC as of December 2010 (4 months after initiation of chemotherapy). This case suggests that reintroduction of combination chemotherapy with FOLFOX plus bevacizumab is effective and feasible in patients with colorectal cancer with DIC and that chemotherapy may be a treatment option for such patients.

The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n=60) and a group given off-protocol treatment (n=27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n=23), stable disease (n=38), or progressive disease (n=26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (ρ) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (ρ=0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: This study aimed to evaluate the efficacy of docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy for locally advanced borderline-resectable T4 esophageal cancer., Patients and Methods: We retrospectively analyzed data regarding thirty patients with borderline-resectable T4 tumor who received either DCF or cisplatin plus 5-fluorouracil (FP) as induction chemotherapy., Results: The overall response rate was significantly better for the DCF group than the FP group. In the DCF group, 6/16 patients achieved a grade 2 histological post-chemotherapeutic effect after treatment, compared to 1/14 in FP group. Except for myelotoxicity, no other significant differences in toxicity were observed during induction chemotherapy between groups. The DCF regimen did not result in increased postoperative complications compared to the FP regimen. Postoperative recurrence or distant metastasis was observed in 7/10 of FP patients and 5/12 of DCF patients., Conclusion: DCF induction chemotherapy may be an option for conversion therapy of initially unresectable, locally advanced esophageal cancer.

The aim of this study was to prospectively evaluate the efficacy of combination irinotecan and cetuximab chemotherapy in patients with pretreated metastatic colorectal cancer harboring wild-type KRAS. Patients with metastatic colorectal cancer that had progressed after chemotherapy with irinotecan, oxaliplatin, and fluoropyrimidine were included. KRAS status was evaluated using the Cycleave PCR method; only patients without KRAS mutations were included. Cetuximab was administered initially at 400 mg/m² followed by weekly 250 mg/m² infusions. Irinotecan was administered biweekly. From October 2008 to April 2009, a total of 30 patients were enrolled. The objective response rate was 30.0% (95% confidence interval [CI], 14.7-49.4%) and the disease control rate (complete response, partial response, or stable disease) was 80.0% (95% CI, 61.4-92.3%). Among the 15 patients with stable disease, 11 patients experienced >10% tumor shrinkage. Median progression-free survival was 5.8 months (95% CI, 4.1-7.6). Median overall survival was not reached at a median follow-up of 10.1 months. Grade 2 skin toxicity was observed in 23 patients, while no grade 3 skin toxicity was observed. Combined irinotecan and cetuximab is effective for pretreated metastatic wild-type KRAS colorectal cancer.

The prognosis of patients with advanced colorectal cancer with icterus is dismally poor, and adequate chemotherapy for these patients has not been established yet. A 59-year-old male with fatigue, anorexia and icterus with serum total bilirubin 9.7 mg/dL was referred to our institution. He was diagnosed with advanced sigmoid colon cancer with multiple liver metastases. A biopsy specimen of the primary tumor showed well-differentiated adenocarcinoma without KRAS mutation. Since biliary drainage was impossible due to diffuse liver metastases, we initiated combination chemotherapy with 5-fluorouracil, Leucovorin, oxaliplatin (modified FOLFOX6) and cetuximab. The doses of 5-fluorouracil and oxaliplatin were reduced, but cetuximab was administered at the standard dosage. After 3 courses of chemotherapy, total bilirubin dropped to 0.8 mg/dL. No significant toxicity other than grade-2 skin toxicity and neuropathy was observed, and the patient has continued chemotherapy on an outpatient basis. Combination chemotherapy with mFOLFOX6 plus cetuximab was effective and feasible in this case of metastatic colon cancer with icterus due to diffuse liver metastasis.

A 57-year-old female with advanced gastric cancer was referred to our hospital. She underwent neoadjuvant chemotherapy with S-1 plus cisplatin followed by curative gastrectomy. Weekly paclitaxel and combination chemotherapy with irinotecan plus cisplatin were administered for lymph node recurrence, but the tumor progressed. Since the human epidermal growth factor receptor 2 status of her gastric cancer specimen was strongly positive, docetaxel plus trastuzumab was administered for three cycles. However, the lymph node metastasis appeared to enlarge and abdominal pain worsened. Therefore, combination chemotherapy with lapatinib and weekly trastuzumab was initiated. A computed tomographic scan after 3 months of treatment showed stable disease. Although dose reduction of lapatinib was necessary due to Grade 3 diarrhea, the patient has continued this treatment on an outpatient basis without signs of disease progression for 8 months after initiation. In this case, trastuzumab plus lapatinib resulted in durable stable disease, despite the appearance of progression during prior chemotherapy with trastuzumab.

Objective: To retrospectively compare docetaxel (DTX) with paclitaxel (PTX) with regard to efficacy and safety in advanced or recurrent esophageal cancer patients who previously received platinum-based chemotherapy., Methods: We retrospectively analyzed 124 advanced or recurrent esophageal cancer patients who had received platinum-based chemotherapy and then received DTX or PTX from April 2006 to November 2010., Results: Eighty-six patients (69.4%) received DTX and 38 patients (30.6%) received PTX monotherapy. Due to toxicity, dose reduction was needed in 36.0 and 27.8% of patients and treatment was discontinued in 10.5 and 2.6% of patients receiving DTX and PTX, respectively. The objective response (25.7 vs. 10.3%, p = 0.03) and disease control rates (60.0 vs. 34.6%, p = 0.01) were higher in the PTX group than in the DTX group, respectively. There were no significant differences in median progression-free survival (2.1 vs. 3.5 months) and overall survival (6.1 vs. 7.2 months) between the DTX and PTX groups, respectively. Grade 3-4 neutropenia (48.8 vs. 21.1%, p = 0.003) and febrile neutropenia (20.9 vs. 5.3%, p = 0.029) were more frequent in the DTX patients than in the PTX patients, respectively., Conclusion: Although the efficacy of DTX and PTX for advanced or recurrent esophageal cancer patients after platinum-based chemotherapy was not significantly different in terms of survival, PTX was a more feasible treatment. PTX provided similar efficacy to DTX with less febrile neutropenia., (Copyright © 2011 S. Karger AG, Basel.)

Objective: S-1 plus cisplatin is standard treatment for advanced gastric cancer in Japan. Triplet therapy with docetaxel, cisplatin and fluoropyrimidine showed a survival benefit over doublet therapy, but was associated with substantial toxicities. We investigated the maximum tolerated dose of combination chemotherapy with divided-dose docetaxel added to standard-dose S-1 plus cisplatin in advanced gastric cancer patients., Methods: Patients with advanced gastric cancer, naive to chemotherapy or not refractory to fluoropyrimidine, were enrolled. Fixed doses of S-1 (40 mg/m(2) twice daily for 3 weeks) and cisplatin (60 mg/m(2) on day 1) were administered with increasing docetaxel dose levels of 20 mg/m(2) (dose level 1), 25 mg/m(2) (dose level 2) and 30 mg/m(2) (dose level 3) on days 1, 8 and 15, or 40 mg/m(2) (dose level 4) on days 1 and 15 of a 5-week cycle. Treatment cycles were repeated until disease progression, patient's refusal or unacceptable toxicity occurred., Results: Fifteen patients were enrolled. During the first cycle, no dose-limiting toxicity was observed at dose levels 1 and 2. At dose level 3, grade 3 febrile neutropenia was seen in one patient. At dose level 4, grade 3 infection and grade 3 abdominal pain were observed. Thus, dose level 4 was determined to be the maximum tolerated dose. The response rate was 54% (7/13), and median progression-free survival and overall survival were 243 and 383 days, respectively., Conclusions: The recommended dose of docetaxel added to standard-dose S-1 (80 mg/m(2) days 1-21) plus cisplatin (60 mg/m(2) day 1) was 40 mg/m(2) on days 1 and 15 of a 5-week cycle.

Standard weekly cetuximab and irinotecan is an effective regimen in heavily pre-treated patients with metastatic colorectal cancer. The aim of this study is to prospectively evaluate the efficacy of combination chemotherapy with biweekly cetuximab and irinotecan in patients with pre-treated metastatic colorectal cancer harboring wild-type KRAS. A total of 30 patients will be enrolled at four medical institutions. The primary endpoint is response rate. The secondary endpoints include adverse events, progression-free survival and overall survival. The pharmacokinetics of cetuximab will also be evaluated in five patients.

Background: A relationship between dietary folate intake and efficacy of fluorouracil (FU) is supported by preclinical data. Furthermore, there are several reports that evaluated genetic polymorphisms of MTHFR (methylenetetrahydrofolate reductase) or TYMS (thymidylate synthase) and efficacy of FU. However, to our knowledge, there are no reports that evaluate simultaneously the effects of folate intake and genetic polymorphisms on clinical outcome of gastric cancer patients., Methods: We retrospectively analyzed the survival impact of estimated folate intake by a food frequency questionnaire and MTHFR and TYMS polymorphisms in 132 patients with advanced gastric cancer who were treated with first-line FU-based chemotherapy., Results: Median overall survival was 11.3 months (95% confidence interval, 9.4-13.4 mo) and median progression-free survival was 5.2 months (95% confidence interval, 4.1-6.3 mo). Patients with folate intake of >260 microg/day (n=88) showed longer overall survival compared with low folate intake (n=44; overall survival, 12.2 versus 8.4 mo). In a multivariate Cox model, patients who had folate intake of >260 microg/day, MTHFR 677 TT polymorphism, and TYMS-3' untranslated region 6-bp insertion were associated with better survival. Similar tendency was observed in progression-free survival. No interaction was observed between folate intake and favorable genotypes., Conclusion: Folate intake and genetic polymorphisms of MTHFR and TYMS were associated with better clinical outcome by FU-based chemotherapy in advanced gastric cancer., Impact: Our results suggested folate intake and folate-related genetic polymorphisms may play an important role in efficacy of FU-based chemotherapy in advanced gastric cancer., (Copyright (c) 2010 AACR)

Objective: Tumor cells that overexpress P-glycoprotein (Pgp) may be resistant to several anticancer agents due to altered pharmacokinetics and reduced intracellular concentrations of the anticancer agents. Pgp is encoded by the ATP binding cassette gene B1 (ABCB1). To our knowledge, only one previous report has evaluated the effect of ABCB1 gene polymorphisms on clinical outcomes of gastric cancer. The purpose of this analysis was to evaluate the impact of genetic polymorphisms of the ABCB1 gene on clinical outcomes in patients with advanced gastric cancer (AGC) treated with second-line chemotherapy., Methods: We retrospectively analyzed the impact of ABCB1 gene polymorphisms (ABCB1 3435C>T) on clinical outcomes in 100 patients with AGC who received second-line chemotherapy., Results: Median overall survival (OS) since the initiation of second-line chemotherapy was 6.0 months (95% confidence interval [CI], 4.8 to 8.0 months), and median progression-free survival (PFS) was 2.7 months (95% CI, 2.1 to 3.4 months). In a multivariate analysis of PFS, a 3435 CC polymorphism (n=45) was significantly associated with longer PFS compared with the CT/TT type polymorphism (n=55), with borderline significance (PFS of 3.2 months vs. 2.2 months, respectively; HR 1.50; 95% CI, 0.98-2.30; P = 0.061). ABCB1 3435 C>T polymorphisms were not associated with OS. No interaction was seen between ABCB1 polymorphisms and treatment regimens., Conclusion: Genetic polymorphisms of ABCB1 3435C>T might have a possible impact on clinical outcomes of second-line chemotherapy in AGC. Further prospective evaluation using a larger sample size is required.

Background: Based on several phase III studies, oral S-1-based chemotherapy has become the standard for treatment of advanced gastric cancer in Japan. However, these studies included patients able to maintain sufficient oral intake, and the effectiveness of chemotherapy for patients unable to eat remained unclear., Methods: We retrospectively analyzed the effect of chemotherapy on patients with advanced gastric cancer who presented with inability to eat. We defined 'inability to eat' as requirement for daily intravenous fluids or hyperalimentation and 'improvement of oral intake' as no such requirement >1 week., Results: Among the 777 patients who received first-line chemotherapy, 100 patients (12.8%) were considered unable to eat and required daily intravenous fluids or hyperalimentation. Performance status was 0-1 in 26 patients and ≥ 2 in the other 74 patients. Seventy-eight patients (78%) had peritoneal metastasis and 62 patients (62%) had ascites. First-line chemotherapy with 5-fluorouracil-based regimens was used in 46 patients, taxane-based chemotherapy in 34 patients, oral fluoropyrimidine-based therapy in 19 patients, and irinotecan-cisplatin combination treatment in 2 patients. Median survival time was 5.0 months (95% confidence interval, CI, 3.9-6.6). Improvement in oral intake with duration for >1 week was achieved in 40 patients (40%) with the median duration of nutritional-support-free time of 3.1 months (95% CI 2.5-4.6)., Conclusion: Chemotherapy is moderately effective in improving oral intake in patients with advanced gastric cancer with inability to eat. Further study is required to improve its prognosis., (Copyright © 2011 S. Karger AG, Basel.)

We retrospectively analysed 153 patients with metastatic colorectal cancer who received FOLFOX with or without bevacizumab as first-line chemotherapy. Several background characteristics and chemotherapy features (grade of neutropaenia, use of bevacizumab or irinotecan, re-introduction of FOLFOX, and tumour progression) as time-varying covariates were analysed as potential prognostic factors. Of the 153 patients, mild neutropaenia (grade 1-2) occurred in 60 patients (39%) and severe neutropaenia (grade 3-4) occurred in 46 patients (30%). The other 47 patients (31%) did not experience neutropaenia. According to a multivariate Cox model with time-varying covariates, hazard ratios (HRs) of death were 0.55 (95% confidence interval (CI), 0.31-0.98; P=0.044) for patients with mild neutropaenia and 0.35 (95% CI, 0.18-0.66; P=0.002) for those with severe neutropaenia. Both mild and severe neutropaenia during chemotherapy are associated with improved survival in patients with MCRC. Prospective trials are required to assess whether dosing adjustments based on neutropaenia may improve chemotherapy efficacy.

We retrospectively analyzed the efficacy of chemotherapy in patients whose gastric cancer recurred after adjuvant chemotherapy with S-1. A total of 51 patients were evaluated. Twenty-one patients received S-1-containing chemotherapy as first-line treatment after recurrence [cohort A: S-1 plus cisplatin (n = 10), S-1 monotherapy (n = 7), S-1 plus irinotecan (n = 3) and S-1 plus docetaxel (n = 1)]. The other 30 patients received a non-S-1-containing regimen [cohort B: paclitaxel or docetaxel (n = 22), irinotecan plus cisplatin (n = 6) and other drugs (n = 2)]. No objective responses occurred in cohort A, while five patients achieved a partial response in cohort B (response rate, 0 versus 16%; P = 0.04). Median progression-free survival was significantly longer in cohort B than in cohort A (4.3 versus 2.3 months, P = 0.02). S-1-containing chemotherapy does not appear to be effective in patients whose gastric cancer recurs after adjuvant S-1 chemotherapy. Other chemotherapeutic agents should be evaluated in this setting.

Purpose: The purpose was to investigate side effects of FEC100 treatment, particularly bone marrow suppression, nausea and vomiting., Patients and Methods: We investigated side effects of FEC100 at the time of initial administration in 49 breast cancer patients (including 3 with recurrence). We used a 5-HT3 receptor antagonist as an antiemetic agent, steroids and Haloperidol, an antidopamine agent. Antibiotics were also administered for five days from day 10., Results: The mean nadir of white blood cell count was 1,492+/-575 microL, and the mean day on which the nadir was reached was the 13.0+/-1.45th day. Leukopenia of less than 1,000 microL (grade 4) was seen in 8 (16.3%) of the 49 patients, and the incidence of leukopenia was particularly high (3/6, 50%) in patients with multiple bone metastases. Febrile neutropenia occurred in 4 (8.1%) of the 49 patients, 2 of those 4 patients having multiple bone metastasis. Fifteen (30.6%) of the 49 patients had nausea, and 3 patients (6.1%) had vomiting., Conclusion: The results indicate that side effects of FEC100 treatment are tolerable. However, care is needed for patients with multiple bone metastases because of the strong bone marrow suppression in such patients.

A 57-year-old female underwent left lower lung lobectomy and was histologically diagnosed as having lymphoepithelioma-like carcinoma. One year and 2 months after surgery, pleural thickening was recognized, so she was administered 4 courses of CBDCA/PTX combined chemotherapy. Toxicity associated with the chemotherapy was very mild. Pleural thickening and effusion disappeared after treatment, so this case was judged to be a complete response. She suffered from left chest pain before chemotherapy, which later lessened. She was thus able to stop taking NSAIDs. Because primary pulmonary lymphoepithelioma-like carcinoma is a rare tumor, there is no standard chemotherapy treatment. CBDCA/PTX combined chemotherapy is effective for pulmonary lymphoepithelioma-like carcinoma and shows good tolerability and improves QOL.

A 59-year-old female complaining of breast tumor with suppurative discharge was diagnosed as having advanced breast cancer (T4cN3M1-StIV), with giant liver metastasis. Seven courses of combined chemoendocrine therapy (CTF + MPA) were used. Following the chemoendocrine therapy, primary tumor, lung, pleural, supraclavicular and parasternal metastasis disappeared, and the liver metastasis was obviously diminished. These effects continued for 1 year 7 months. Although CTF + MPA chemoendocrine therapy is widely used with advanced or recurrent breast cancer, a clearly effective case has almost never been reported. The reason for the remarkable effect in this case was the consistent immunity to breast cancer.

Diarrhea is a common complication of cancer chemotherapy, while bloody stool is rare. Pseudomembranous colitis has been reported as causing bloody diarrhea after chemotherapy. In this report, we describe nine consecutive patients who presented frank bloody stools within one month after cancer chemotherapy. Patients with a history of pelvic irradiation or with a previously identified colorectal tumor were excluded. Among nine patients, bleeding from tumor undetected before chemotherapy was seen in three, pseudomembranous colitis in four, ischemic colitis in one and methicillin-resistant Staphylococcus aureus enterocolitis in one. Of the three tumors, one was an adenomatous polyp and the other two were metastatic tumors. Two of the four patients with pseudomembranous colitis had not received antibiotics before the onset of colitis. Causes of bloody stools after chemotherapy were various and colonoscopy played an important role in diagnosis and prompt therapy.

To ascertain the effect of local treatment for unresectable primary liver tumor, 59 patients were investigated retrospectively. Patients were classified into four groups; transcatheter arterial embolization (TAE) group, intermittent intra-arterial infusion chemotherapy group, combined therapy group (TAE+intermittent intra-arterial infusion chemotherapy) and a group without adjuvant therapy. The results revealed that TAE and intermittent intra-arterial infusion chemotherapy both prolonged the survival period. We found that the survival rate depends largely on the therapeutic method. No correlations were confirmed with the liver function nor stage grouping of the tumor. Therefore, we concluded that intermittent intra-arterial infusion chemotherapy is a beneficial treatment, considering its minimal adverse effect, broad indication and the fact that it does not require hospitalization.

A 67-year-old advanced breast cancer patient with multiple bone metastases showed a remarkable response to the combination therapy of mitoxantrone (MIT) and medroxyprogesteron acetate (MPA) after failure of anthracycline therapy. Eight course of CTF (cyclophosphamide, THP-adriamycin, 5-fluorouracil) and subsequent 4'-epi-adriamycin were performed for locally advanced breast cancer and multiple bone metastases, but the ulcerated breast cancer enlarged. Then the combination therapy of MIT (10 mg/day) and MPA (1,200 mg/day) was carried out. Seven months after treatment, the ulcerated breast cancer disappeared completely and the serum levels of CA 15-3, TPA and CEA decreased within the normal range. These results suggest that combination therapy with mitoxantrone may well be effective against the anthracycline-resistant breast cancer.

A man who had unresectable leiomyosarcoma of the left kidney with skin and lung metastases was treated with intra-arterial infusion chemotherapy consisting of cisplatin and doxorubicin suspended in lipid contrast medium, lipiodol, and oral administration of cyclophosphamide. The tumor responded well to this treatment three times. He is alive and well in remission, the renal tumor decreased in size, and lung metastases became unclear more than 50 weeks after treatment was completed.