Search

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/m 2 /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.

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.

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: 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.

Background: Watering eyes is a common late adverse event associated with S-1 chemotherapy; however, the frequency and predictive factors are not known., Methods: This study included 304 consecutive gastric cancer patients treated with adjuvant S-1 monotherapy for 1 year at Shizuoka Cancer Center. We retrospectively evaluated the frequency of watering eyes, and explored other nonhematological adverse events during the first course of S-1 monotherapy which could become predictive factors for watering eyes., Results: The severest grade of watering eyes during S-1 monotherapy was grade 2 in 41 patients (13.5 %) and grade 3 in 36 patients (11.8 %). The median time to onset of grade 2 and grade 3 watering eyes was 82 days (range 6-344 days) and 249 days (range 84-653 days), respectively, and the median cumulative S-1 dose at the onset of grade 2 and grade 3 watering eyes was 4174 mg/m(2) (range 491-16,095 mg/m(2)) and 10,243 mg/m(2) (range 4943-16,341 mg/m(2)), respectively. Multivariate analysis showed that anorexia (odds ratio 2.37, P = 0.008), oral mucositis (odds ratio 3.86, P = 0.0003), skin hyperpigmentation (odds ratio 3.84, P = 0.0001), and rash (odds ratio 3.76, P = 0.01) observed during the first course were significantly associated with watering eyes., Conclusion: The risk of watering eyes was higher in patients who also had anorexia, oral mucositis, skin hyperpigmentation, or rash during first course of S-1 monotherapy than in those without them.

Background: We evaluated the efficacy and feasibility of docetaxel, cisplatin, and 5-fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy (CRT) for locally advanced head and neck squamous cell carcinoma (HNSCC) with a high risk of distant metastases compared with CRT alone., Methods: We retrospectively analyzed 29 HNSCC patients with clinical nodal stage N2c, N3, or N2b disease and supraclavicular lymph node metastases receiving CRT alone (CRT group; n = 16) or TPF induction chemotherapy followed by CRT (TPF group; n = 13) between April 2008 and May 2012., Results: The median follow-up periods were 14.5 (range 5.0-65.0) and 25.0 (range 14.0-32.0) months for CRT and TPF groups, respectively. A greater proportion of patient characteristics in the CRT group had advanced T and N stages. The overall response rate to induction TPF was 50.0%; grade 3-4 toxicities included neutropenia, febrile neutropenia, anorexia, and hyponatremia. Complete response rates after CRT completion were 55.5% in the TPF and 42.9% in the CRT group; median overall survival was not reached in the TPF group and was 14.0 months in the CRT group (p = 0.037). Multivariate analysis revealed that induction TPF and T stage were independent prognostic factors [hazard ratio (HR) = 0.196; 95% confidence interval (CI) 0.043-0.898; p = 0.036, HR = 9.966; 95% CI 2.270-43.75; p = 0.002, respectively)., Conclusion: TPF followed by CRT is tolerated and may be an option for the treatment of locally advanced stage N2c, N3, or N2b HNSCC.

Background: The influence of resection of the primary lesion on the prognosis of patients with incurable stage IV colorectal cancer is unclear., Methods: We retrospectively analyzed 158 asymptomatic patients with incurable stage IV colorectal cancer who received systemic chemotherapy in our center from 2002 to 2009, either without (chemotherapy group; n = 112) or after (resection group; n = 46) primary tumor resection. Primary tumor resection was performed if the fiberscope did not pass through the primary lesion. Survival was compared between the 2 groups, and the actual surgical intervention was assessed., Results: At a median follow-up period of 26 months (range 7-91 months), the median survival times were 19.9 months in the resection group and 19.0 months in the chemotherapy group (HR = 0.81, 95 % CI 0.53-1.19, p = 0.29). Among the tumor resection group, 8 (17 %) experienced postoperative complications, with all showing improvement after conservative treatment. In the chemotherapy group, 18 patients (21 %) required surgical interventions for symptoms associated with progression of the primary tumor., Conclusions: Resection of the primary tumor in asymptomatic patients with incurable stage IV colorectal cancer was safe, but had no effect on prognosis.

Background: The number of cases of metastatic colorectal cancer treated by chemotherapy without primary tumor resection has recently increased. However, evaluation of primary tumor response by computed tomography is difficult in such cases. In this study, the usefulness of evaluation of primary tumor response to chemotherapy by endoscopy was investigated., Methods: This retrospective analysis was performed at the Shizuoka Cancer Center and included 31 patients (88 evaluations) with metastatic colorectal cancer. Computed tomography and endoscopy were performed concomitantly between September 2002 and June 2006. Patients were treated by systemic chemotherapy without prophylactic primary tumor resection. Definitions of primary tumor response were as follows: (1) complete response, confirmed by colorectal biopsy; (2) progressive disease, enlargement of at least one of five tumor parameters; and (3) neither (1) nor (2). Computed tomography was performed to evaluate primary tumor response according to the Response Evaluation Criteria in Solid Tumors and to identify colorectal stenosis secondary to primary tumors., Results: The rate of concordance between endoscopy and computed tomography for evaluation of primary tumor response was 75%. Colorectal stenosis was detected 14 times by endoscopy (9 cases) and 3 times by computed tomography (3 cases). Of the 7 patients in whom surgery was required, 6 exhibited stenotic symptoms before endoscopic detection., Conclusions: With regard to primary tumor response evaluation, a high concordance rate was observed between endoscopy and computed tomography, although endoscopic evaluation appeared more sensitive in detecting colorectal stenosis requiring surgical treatment.

Background: Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently., Methods: We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m(2), bid) was administered for 3 weeks and cisplatin (60 mg/m(2)) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m(2), bid) was administered for 4 weeks, every 6 weeks., Results: SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively., Conclusion: SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.

Background: The prophylactic effect of postoperative interferon on recurrence and distant metastasis in stage II or III renal cell carcinoma is unclear. In most studies, interferon has been administered for 6 months or less. Therefore, we performed a clinical study of the efficacy of 1-year postoperative administration of natural interferon α, which is generally used in Japan., Methods: The subjects were patients diagnosed with stage II or III renal cell carcinoma who underwent radical nephrectomy. The subjects were randomly allocated to receive an intramuscular injection of natural interferon α (3 million to 6 million units) 3 times a week for 1 year or to receive follow-up observation until recurrence or metastasis occurred. Chest and abdominal CT were performed once yearly for all patients. The primary endpoint was progression-free survival., Results: From September 2001 to August 2006, a total of 107 patients were registered, but 7 subsequently withdrew from the study. Therefore, 100 patients were included in the analysis. The primary endpoint of progression-free survival did not differ significantly between the groups that received natural interferon α or follow-up observation (p = 0.456, log-rank test). However, peak hazards of progression in the interferon group were delayed for about 6-10 months compared with the observation group., Conclusion: Progression-free survival showed no improvement after administration of natural interferon α to patients with stage II or III renal cell carcinoma for 1 year after radical nephrectomy. The peak hazards of progression might be delayed by about 6 months by interferon administration.

Background: Leptomeningeal carcinomatosis (LMC) is a rare but devastating complication of gastric cancer., Methods: The subjects were 12 gastric cancer patients who were diagnosed as having LMC at the Shizuoka Cancer Center between October 2002 and March 2009. We conducted a retrospective survey of the medical records of the study subjects and collected data on the clinical features, treatment modalities employed/outcomes, and survival of the patients., Results: Of the 12 patients, 9 (75%) were male, and the median age was 63 years. Histopathologically, the majority of the patients (83%) had diffuse-type adenocarcinoma. At the time of diagnosis of the LMC, the other major sites of metastasis were the peritoneum (75%) and lymph nodes (50%). The median duration from the diagnosis of gastric cancer to the diagnosis of LMC was 15.6 months. While the treatment strategy changed with time, intrathecal chemotherapy (n = 10), followed by whole brain irradiation (n = 7) and subsequent ventriculo-peritoneal shunt (n = 3) was performed in 10 of the patients. Improvement of neurological functions was observed in 6 of the 10 patients. The median overall survival time from the diagnosis of LMC in all the 12 patients was 60 days. One patient survived for a considerably long period of 532 days., Conclusions: Multidisciplinary treatment, including ventriculo-peritoneal shunt for LMC secondary to gastric cancer, may benefit selected patients, but further accumulation of clinical cases is necessary.

Background: Although concurrent chemoradiotherapy (CRT) is a standard treatment for esophageal cancer invading adjacent structures (T4-EC), arterio-esophageal fistula (AEF) occurs occasionally as a critical adverse event of T4-EC with CRT. The frequency, clinical course, and risk factors of AEF related to CRT are not well known., Methods: We retrospectively analyzed 48 patients with T4-EC invasion of the aorta who were treated with 5-fluorouracil, cisplatin, and concurrent radiotherapy at our institution between September 2002 and April 2009. Treatment-related AEF was defined as AEF without obvious tumor progression. We evaluated the frequency, clinical courses, and risk factors of AEF., Results: The median survival time was 10.6 months with a median follow-up time of 33.3 months. The 2-year survival rate was 25%. Treatment-related AEF was observed in 7 patients (14.6%) and 4 of them died of massive bleeding due to aortic AEF. In the other 3 patients with non-aortic AEF, hemorrhage could be arrested by transcatheter arterial embolization (TAE). In the univariate analysis of risk factors for AEF, lower serum cholesterol level was a risk factor for AEF (OR 14.7; 95% CI 1.58-137; P = 0.008)., Conclusions: Although CRT has a curative potential even for patients with T4-EC invading the aorta, we should be aware of the relatively high incidence of treatment-related AEF. TAE may be successful in rescuing a non-aortic AEF patient. Low serum cholesterol level may be a risk factor for AEF, but further investigation is needed.

Background: Although S-1 is effective against advanced gastric cancer (AGC), its efficacy in elderly patients has not yet been investigated sufficiently. We assessed the efficacy and safety of S-1 monotherapy in elderly patients with AGC., Methods: We conducted a retrospective review of the data of 153 patients with unresectable/recurrent gastric adenocarcinoma who received S-1 monotherapy as first-line chemotherapy at our institution. S-1 was administered orally twice daily at the dose of 40 mg/m², on days 1-28, every 6 weeks. We categorized the patients into three groups, the young (≤65 years old), the middle-aged (66-75 years old), and the elderly (≥76 years old); and the drug toxicity, objective responses, progression-free survivals, and overall survivals were compared among the three groups., Results: The incidence of leukopenia of grade 3 or greater in the three groups was 7%, 5%, and 13%, and that of anemia was 9%, 18%, and 27%, respectively. In regard to nonhematological toxicities, the incidence of nausea of grade 3 or greater was 3%, 5%, and 13%; that of fatigue was 5%, 11%, and 20%; and that of anorexia was 5%, 6%, and 27%, respectively. As for the treatment efficacy, the objective response rates, median progressionfree survivals, and overall survivals in the young, middle-aged, and elderly groups were 53%, 46%, and 33%; 7.8, 5.6, and 3.9 months; and 16.9, 17.1; and 7.7 months, respectively., Conclusion: Although S-1 monotherapy showed moderate efficacy in elderly (≥76 years) patients with AGC, patients in this age group showed higher incidences of severe toxicities than the younger patients.

Background: Efficacy and safety of irinotecan and cisplatin administration every 2 weeks (biweekly regimen) or 4 weeks (4-weekly regimen) in patients with pretreated unresectable or recurrent gastric cancer was retrospectively evaluated., Methods: Study patients comprised two cohorts: cohort 1, consisting of 31 patients received chemotherapy on a 4-weekly regimen; and cohort 2, consisting of 32 patients received chemotherapy on a biweekly regimen. In cohort 1, patients received irinotecan (70 mg/m(2)) on days 1 and 15 and cisplatin (80 mg/m(2)) on day 1 every 4 weeks; in cohort 2, patients received irinotecan (60 mg/m(2)) on day 1 and cisplatin (30 mg/m(2)) on day 1 every 2 weeks., Results: Response rates were for cohorts 1 and 2 were 26% (7/27) and 28% (7/25) in patients with measurable lesions, median progression-free survivals were 3.5 and 4.3 months, and median survival times after irinotecan and cisplatin initiation were 9.5 and 10.1 months, respectively. The incidence of grades 3 and 4 hematological toxicities in cohorts 1 and 2 were 74% and 44% for leukopenia, 81% and 53% for neutropenia, and 45% and 28% for anemia, respectively. Incidences of grades 3 and 4 nonhematological toxicities were 23% and 12% for nausea, 23% and 9% for vomiting, 19% and 12% for anorexia, and 6% and 6% for febrile neutropenia, respectively., Conclusion: Irinotecan plus cisplatin chemotherapy administered on a biweekly regimen was comparable in efficacy to a 4-weekly regimen and might be more feasible than the 4-weekly regimen.

Background: Although triweekly administration of paclitaxel is approved for gastric cancer in Japan, currently, the drug is often delivered with a weekly schedule because of the equivalent efficacy and lesser toxicity of this dosing schedule as compared with the triweekly administration schedule. Weekly administration of paclitaxel as second-line or first-line chemotherapy for gastric cancer has been reported to yield a response rate of about 20%. Because there has been no report of the efficacy of weekly paclitaxel in the third-line setting, this retrospective study investigated the efficacy and toxicities of weekly paclitaxel used in the third-line setting for the treatment of gastric cancer refractory to all three key drugs, fluorouracil, irinotecan, and cisplatin, used in clinical practice., Methods: In 85 patients with advanced or recurrent histologically confirmed gastric adenocarcinoma who had failed to respond to prior chemotherapy regimens containing fluorouracil, irinotecan, and cisplatin, paclitaxel (80 mg/m(2)) was administered weekly, three times, for 3 weeks out of 4., Results: The median number of courses was 3 (range, 1-38). The overall response rate was 23.2% (19/82) in the patients with measurable lesions, and ascites disappeared in 15 of 48 patients (31.3%). Progression-free survival was 105 days and the median survival time was 201 days from the initiation of paclitaxel administration. Grade 3 or 4 leukopenia, neutropenia, anemia, and thrombocytopenia were observed in 25 (29%), 25 (29%), 37 (44%), and 3 (4%) patients. Other, nonhematological, toxicities were nausea, vomiting, anorexia, sensory neuropathy, fatigue, and febrile neutropenia., Conclusion: Weekly paclitaxel administration shows activity against advanced gastric cancer also in the third-line setting.

Background: Cyclin E and p27 play pivotal roles in cancer development and progression. We investigated whether the prognosis in cases of non-small cell lung cancer without lymph node metastases that underwent complete resection could be associated with tissue expression of cyclin E, p27, and Ki-67., Methods: Tumors from 62 patients at least 5 years after surgery were assessed by immunohistochemistry for expression of cyclin E, p27, and Ki-67. Disease-free survival (DFS) after surgery was used to evaluate disease prognosis. We also investigated the relationship between expression of these factors and postoperative recurrence., Results: In non-small cell lung cancer, p27-negative expression and pT factor were significantly unfavorable prognostic factors in multivariate analysis. The DFS rate in cyclin E-positive expression was significantly lower than in cyclin E-negative expression. Similarly, p27-negative expression and high Ki-67 expression correlated with a shortened DFS rate. In combinations of expression of cyclin E and p27, the cyclin E-negative/p27-positive group had a significantly higher DFS rate than did the other groups. According to histological type, there were correlations between the risk of postoperative recurrence and expression of these three biological factors, especially in adenocarcinoma., Conclusion: By analyzing the expression of cyclin E, p27, and Ki-67 of tumor cells, it was possible to extract the patient group for whom closer follow-up and postoperative treatment is necessary to improve survival rate.