Phase II study of oxaliplatin, irinotecan and S-1 therapy in patients with advanced gastric cancer: the Korean Cancer Study Group ST14-11.

BACKGROUND: Doublet chemotherapy of platinum and 5-fluorouracil is a standard first-line treatment for patients with unresectable gastric cancer. Although the addition of taxane or irinotecan to this regimen has yielded promising efficacy, its use has been limited due to severe toxicities. To overcome this limitation, we evaluated the efficacy and safety of the combination of irinotecan, oxaliplatin, and S-1 (OIS) for the treatment of advanced gastric cancer. METHODS: Chemotherapy-naïve patients with pathologically proven advanced gastric adenocarcinoma were assessed for eligibility. Irinotecan (135 mg/m2) and oxaliplatin (65 mg/m2) were administered intravenously on day 1, and S-1 (80 mg/m2/day) was administered orally on days 1-7 of every 2-week cycle. RESULTS: Forty-four patients (median age 57 years) were enrolled and all but one patient had a good performance status (ECOG 0 or 1). A total of 529 cycles were administered, with a median of 9.5 (range 1-31) cycles per patient. The overall response rate was 61.4% (95% confidence interval [CI] 46.6-74.3). The median progression-free survival and overall survival were 10.8 months (95% CI 7.6-14.0) and 15.4 months (95% CI 12.6-18.2), respectively. Major toxicities included grade 3/4 neutropenia (38.6%), febrile neutropenia (13.6%), abdominal pain (9.1%), and diarrhea (9.1%). CONCLUSION: These data suggest that the OIS regimen is effective and relatively well tolerated in patients with advanced gastric cancer. Given that all the patients treated, but one, had a good performance status, these results must be confirmed in a patient population more representative of regular clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02527785.

Trends in the Aggressiveness of End-of-Life Care for Advanced Stomach Cancer Patients.

PURPOSE: It is important to balance the appropriateness of active cancer treatments and end-of-life care to improve the quality of life for terminally ill cancer patients. This study describes the treatment patterns and end-of-life care in terminal gastric cancer patients. MATERIALS AND METHODS: We retrospectively analyzed the records of 137 patients with advanced gastric cancer receiving chemotherapy and dying between June 1, 2006 and May 31, 2011. We recorded interval between last chemotherapy dose and death; frequency of emergency room visits or admission to the intensive care unit in the last month before death; rate of hospice referral and agreement with written do-not-resuscitate orders; and change in laboratory values in the last three months before death. RESULTS: During the last six months of life, 130 patients (94.9%) received palliative chemotherapy; 86 (62.7%) during the final two months; 41 (29.9%) during the final month. During the final month, 53 patients (38.7%) visited an emergency room more than once; 21 (15.3%) were admitted to the intensive care unit. Hospice referral occurred in 54% (74 patients) of the patients; 93.4% (128 patients) gave written do-not-resuscitate orders. Platelets, aspartate aminotransferase and creatinine changed significantly two weeks before death; total bilirubin, one month before; and C-reactive protein, between four and two weeks before death. CONCLUSION: Our results demonstrated that a significant proportion of gastric cancer patients received palliative chemotherapy to the end of life and the patients who stopped the chemotherapy at least one month before death had a lower rate of intensive care unit admission and longer overall survival than those who sustained aggressive chemotherapy until the last months of their lives.

Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer.

PURPOSE: The purpose of this study was to evaluate efficacy and toxicity of irinotecan, leucovorin and 5-fluorouracil (FOLFIRI) as second-line treatment after failure of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) for advanced gastric cancer. MATERIALS AND METHODS: Patients who received modified FOLFOX-4 as first-line treatment and then received sequential modified FOLFIRI for disease progression were included in this study. The modified FOLFIRI regimen consisted of irinotecan 150 mg/m(2) in a 90-minute intravenous infusion on day 1, leucovorin (LV) 20 mg/m(2) and 5-fluorouracil (5-FU) 400 mg/m(2) as a bolus followed by 600 mg/m(2) as a 22-hour infusion on days 1 and 2 with the same dose of 5-FU/LV of modified FOLFOX-4 every 2 weeks. RESULTS: A total of 32 patients received 126 courses of FOLFIRI chemotherapy. No complete response was achieved. Three patients (9.4%; 95% confidence interval [CI], 0 to 20.1%) achieved partial response, whereas 11 (34.4%; 95% CI, 17.0 to 51.8%) patients showed stable disease. Disease control rate (complete response, partial responses and stable diseases) was 43.8% (95% CI, 25.6 to 61.9%) and median follow up duration was 11.3 months (range, 2.23 to 37.9 months). Median time to progression was 2 months (95% CI, 1.49 to 2.51 months), and median overall survival from the start of FOLFIRI was 5.84 months (95% CI, 4.34 to 7.34 months). Toxicities were tolerable. CONCLUSION: Modified FOLFIRI as second-line chemotherapy after failure of the modified FOLFOX-4 in advanced gastric cancer was tolerable but showed a lower response rate. Further study about retrying 5-FU/LV with irinotecan after failure of the 5-FU/LV combined regimen is necessary in advanced gastric cancer.

Primary cutaneous Ewing's sarcoma/primitive neuroectodermal tumor manifesting numerous small and huge ulcerated masses: its complete remission by chemotherapy and magnetic resonance imaging findings.

Extraskeletal Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are widely regarded as clinically and histologically identical tumors which consist of small blue round cells. Extraskeletal ESs/PNETs usually occur in the deep soft tissues of the paraspinal region, chest wall, or lower extremities. However, superficially located cases, so-called cutaneous ESs/PNETs, are exceedingly rare, and the vast majority of the reported cases present as a single small mass. We present magnetic resonance imaging (MRI) findings and clinical course of a unique case of primary cutaneous ES/PNET presenting as numerous huge masses with severe ulceration on them.

[Therapeutic effect of allogenic bone marrow transplantation in acute TNBS-induced colitis].

BACKGROUND/AIMS: Bone marrow-derived cells (BMDC) contribute to tissue maintenance under many kinds of pathologic conditions. We carried out a study to see how BMDC play a role in the treatment of experimental murine colitis. METHODS: We divided the animals into 3 groups and treated them with 50% ethanol (control group), 2,4,6-trinitrobenzene sulfinic acid colitis (TNBS group), and TNBS+bone marrow transplant (BMT group). To induce colitis, TNBS (5.0 mg/mouse) dissolved in 50% ethanol was injected into anus weekly for two weeks. Bone marrow transplantations were performed using bone marrow of male transgenic mouse (donor) with green fluorescence protein (GFP) into female wild type mouse (recipient) three weeks before TNBS instillation. All animals were sacrificed, and colons were extracted one week after the last TNBS instillation. We measured microscopic scores of mucosal injury and investigated the GFP expression for bone marrow engraftment. The immunostaining of vimentin and alpha-smooth muscle actin (alpha-SMA) for myofibroblasts was performed. RESULTS: The score of mucosal injury in the TNBS group was much more severe than those in control, and reduced significantly by BMT (p<0.05). GFP-positive cells were almost deposited in pericryptal niche of BMT group but not at all in both control and TNBS group. Most of myofibroblasts stained with both vimentin and SMA also infiltrated into pericryptal niche. But, the number of myofibroblasts stained with vimentin and SMA in both control and TNBS group was smaller than that in BMT group. CONCLUSIONS: BMDC deposited on pericryptal niche might have a significant role in repairing acute experimental murine colitis.

Primary adenocarcinoma of the small intestine: presentation, prognostic factors and clinical outcome.

BACKGROUND: Malignant small intestine tumor accounts for 0.1-0.3% of all malignancies. Although primary adenocarcinoma is the most common histologic subtype, there is no report of the clinical characteristics and natural history in the Asian population. METHODS: We conducted retrospective analysis for the patients with the small intestine adenocarcinoma to explore the clinical characteristics and prognosis. All patients with adenocarcinoma of small intestine diagnosed between March 1997 and March 2007 in the Catholic Medical Center in Korea were identified through the cancer registry. The medical records were reviewed for patient characteristics, treatment and outcome data. RESULTS: Data on 53 patients were available. Twenty-six patients (49.0%) underwent curative resection and 13 patients receiving adjuvant chemotherapy. Fifteen patients received palliative chemotherapy. Median of overall survival of all patients was 12 months (95% confidence interval (CI): 8.5-15.1 months). Three-year survival and relapse-free survival rates after curative resection was 66.1 and 50.8%, respectively. Median survival of patients received palliative chemotherapy was 8.0 months (95% CI: 3.5-12.4). CONCLUSIONS: The prognosis of primary adenocarcinoma of small intestine was poor, especially in cases where curative resection could not to be performed. Further study on the methods for early detection and effective systemic chemotherapy should be investigated.

Thalidomide effect in endothelial cell of acute radiation proctitis.

AIM: To determine whether thalidomide prevents microvascular injury in acute radiation proctitis in white rats. METHODS: Fourteen female Wistar rats were used: six in the radiation group, six in the thalidomide group, and two in normal controls. The radiation and thalidomide groups were irradiated at the pelvic area using a single 30 Gy exposure. The thalidomide (150 mg/kg) was injected into the peritoneum for 7 d from the day of irradiation. All animals were sacrificed and the rectums were removed on day 8 after irradiation. The microvessels of resected specimens were immunohistochemically stained with thrombomodulin (TM), von Willebrand Factor (vWF), and vascular endothelial growth factor (VEGF). RESULTS: The microscopic scores did not differ significantly between the radiation and thalidomide groups, but both were higher than in the control group. Expression of TM was significantly lower in the endothelial cells (EC) of the radiation group than in the control and thalidomide groups (P<0.001). The number of capillaries expressing vWF in the EC was higher in the radiation group (15.3+/-6.8) than in the control group (3.7+/-1.7), and the number of capillaries expressing vWF was attenuated by thalidomide (10.8+/-3.5, P<0.001). The intensity of VEGF expression in capillaries was greater in the radiation group than in the control group and was also attenuated by thalidomide (P=0.003). CONCLUSION: The mechanisms of acute radiation-induced proctitis in the rats are related to endothelial cell injury of microvessel, which may be attenuated with thalidomide.

Vascular endothelial growth factor levels in ascites between chemonaive and chemotreated patients.

PURPOSE: Vascular endothelial growth factor (VEGF) levels in malignant ascites have high diagnostic value for their discrimination from ascites of non-malignant origin. However, there have been no reports on the comparison of VEGF levels between malignant ascites of chemonaive and chemotreated patients. MATERIALS AND METHODS: VEGF levels were measured in 44 ascites patients (cirrhosis ascites, 10; chemonaive patients, 21; chemotreated patients, 13) and compared to the level of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9). The diagnostic parameters of sensitivity, specificity, and correlation among 3 markers were evaluated. RESULTS: VEGF levels in malignant ascites of chemonaive and chemotreated patients were significantly higher than those in cirrhotic ascites (p<0.05). VEGF levels in ascites of chemonaive patients were significantly higher than those in chemotreated patients (p<0.05). A cutoff value of 10.4 pg/mL was calculated using receiver operating characteristic curves (ROCs) for VEGF in chemotreated and chemonaive patients, which gave sensitivities of 75.0% and 53.8% and specificities of 69.6% and 47.1%, respectively. Positive correlations were observed between VEGF and CEA (r=0.353, p<0.05) as well as between VEGF and CA19-9 (r=0.367, p<0.05) in ascites. CONCLUSION: VEGF levels could be a useful tumor marker for malignant ascites, but its value should carefully be interpreted because of lesser reliability in chemotreated ones.

Autologous stem cell transplantation using a modified TAM conditioning regimen for clinically aggressive non-Hodgkin's lymphoma.

PURPOSE: High-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) have been used for the treatment of clinically aggressive non-Hodgkin's lymphoma (NHL). However, the superiority of specific conditioning regimens has not yet been established. The present study evaluated the efficacy and toxicity of a conditioning regimen involving fractionated total body irradiation (TBI), and the use of Ara-C and melphalan (TAM) for clinically aggressive NHL. MATERIALS AND METHODS: Between March 2002 and December 2004, 31 patients with aggressive NHL received fractionated TBI with a dose of 12 Gy over 3 days, and were administered 9 g/m(2) Ara-C and 100 mg/m(2) melphalan followed by autologous peripheral blood stem Cell Transplantation at the Catholic Hematopoietic Stem cell transplantation Center Korea. Patients that responded to first line chemotherapy and achieved complete remission (CR), or were in a first sensitive relapse were defined as having less advanced disease, while the other patients were defined as having more advanced disease. RESULTS: Objective responses were obtained in 24 of 31 patients (77.4%), comprising complete remission in 19 patients (61.3%) and partial remission in 5 (16.1%) patients. The median follow-up time was 28 months (range 1 approximately 62 months). At 3 years, the overall survival and event-free survival (EFS) rates were 62.3% and 47.3%, respectively. Patients with less advanced disease and more advanced disease showed 3-year EFS rates of 73.3% and 22.5 %, respectively (p=0.006). Early (within the first 100 days) treatment-related mortality occurred in 3 (9.7%) patients. Of the 31 total patients, 15 (48.4%) developed grade 3 mucositis, 22 (70.9%) developed neutropenic fever, and two (6.5%) developed interstitial pneumonia syndrome>grade 3. CONCLUSION: The modified TAM conditioning regimen and ASCT appear to be a feasible treatment regimen for clinically aggressive NHL, particularly for patients with less advanced disease.

Pretreatment serum endostatin as a prognostic indicator in metastatic gastric carcinoma.

Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The presence of serum endostatin in patients with gastric cancer has not been reported. The authors assessed the serum levels of endostatin in patients with gastric carcinoma and evaluated their association with the levels of vascular endothelial growth factor (VEGF) and the clinical outcome. A total of 107 patients with gastric cancer were included in the study. Pretherapeutic serum levels of endostatin and VEGF were measured using an ELISA, and compared with those in 23 healthy controls. The serum levels of endostatin and VEGF were higher in gastric cancer patients than in healthy controls (endostatin, 70.1 +/- 16.6 vs. 52.2 +/- 6.2 ng/mL [p < 0.001]; VEGF, 55.1 +/- 7.6 vs. 32.1 +/- 2.4 ng/mL [p < 0.001]; mean +/- SD). Serum endostatin levels were significantly associated with the presence of distant metastases (r = 0.556, p < 0.001) and VEGF levels (r = 0.335, p < 0.001), but not with the depth of tumor invasion, differentiation, or regional lymph node status. A serum endostatin level above the 75th percentile of the distribution for the patients (79.2 ng/mL) was associated with a poor outcome (last follow-up at 42 months; median survival time, 9 vs. 20 months [log-rank, p = 0.017]; median time to progression, 5 vs. 10 months [log-rank, p = 0.022]) in the patients with metastatic gastric cancer. The results suggest for the first time that an elevated serum level of endostatin at the diagnosis of metastatic gastric cancer could be predictive of a poor outcome.