Phase II study of paclitaxel with 3-h infusion in patients with advanced gastric cancer

Abstract. Background: To increase the options for agents for gastric cancer chemotherapy, we performed a phase II clinical trial on the use of a 3-h infusion of paclitaxel to confirm its efficacy and the feasibility of its use in patients with advanced gastric cancer. Methods: Thirty-two (32) patients with measurable metastatic gastric cancer were enrolled in this study. Seventeen patients (53%) had received prior chemotherapy for metastatic disease, 4 patients (13%) had adjuvant chemotherapy alone, and 11 patients (34%) were chemotherapy-naive. Paclitaxel was intravenously infused for 3 h, at a dose of 210 mg/m², once every 3 weeks. To prevent hypersensitivity reactions, standard premedication was administered to all patients. Results: Nine (28%; 9/32 ) objective partial responses (PRs) were observed (95% confidence interval [CI], 14%–47%), and the remaining 23 patients showed stable (12 patients; 37.5%) and progressive disease (11 patients; 34.4%). The median time to response was 20 days (range, 14–38 days). The median response duration was 87 days (range, 50–103 days). The median survival of all patients was 234 days (range, 13–646+ days). The major adverse reactions were myelosuppression (grade 3/4 leukopenia and neutropenia were observed in 59% and 88% of the patients, respectively), alopecia, and peripheral neuropathy. Peripheral neuropathy was observed in 19 patients, however, most of the patients recovered after the completion of treatment. Conclusion: A 3-h infusion of paclitaxel is an effective therapy for advanced gastric cancer and is clinically well tolerated by the patients. Received: October 22, 2001 / Accepted: February 21, 2002     

Increased Expression of Toll-like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia

TLRs are important innate immunity receptors. Even though TLR2, 4 and 5 appear to be important for Helicobacter pylori (HP) recognition, their role in the evolution of gastritis to more advanced lesions is still unknown. To compare the expression of TLR2, 4 and 5 in normal gastric mucosa, HP+ gastritis, intestinal metaplasia, dysplasia and adenocarcinoma. Immunohistochemistry for TLR2, 4 and 5 was performed with anti-TLR2-TLR4-TLR5 antibodies in 117 histological samples of normal gastric mucosa (n = 22), HP+ gastritis (n = 20), intestinal metaplasia (n = 33), dysplasia (mucosectomy specimens, n = 20) and intestinal type adenocarcinoma (surgery specimens,n = 22); quantification of expression was performed independently by two pathologists taking into account the percentage of positive epithelial cells and the degree of expression (zero to three score). A statistically significant trend for progressive increase of TLRs expression from normal mucosa to gastric dysplasia was found (mean expression: normal mucosa 0.1; gastritis 1.0; metaplasia 2.2; dysplasia 2.8, p < 0.01). All dysplasia samples presented more than 90% positive epithelial cells with strong expression (2.8;95%CI2.7–3). There was less TLRs expression in carcinomas (TLR2:1.0; TLR4:2.0 and TLR5:1.2, p < 0.05) when compared with dysplasia, with TLR4 being more expressed than TLR2 and 5 in these lesions (p = 0.03). A score of all markers’ expression of eight leads to a low (4%) false positive rate in patients with precancerous conditions. Progression of gastric lesions associated with gastric carcinogenesis is associated with increased TLRs expression. Gastric dysplasia presents a high level of TLRs expression, suggesting that these receptors may play a role in adenocarcinoma development.     

Metachronous gastric cancers after endoscopic resection: how effective is annual endoscopic surveillance?

Background Endoscopic resection (ER) has been widely accepted in Japan as a less invasive treatment for early gastric cancer, but the incidence of subsequent metachronous gastric cancer (MGC) and the appropriate endoscopic follow-up interval after ER have not been determined as yet. In this study, we investigated the incidence of MGC after ER and assessed our annual endoscopic surveillance program after ER. Methods We studied the clinicopathological features of 633 consecutive ER patients (575 with a single lesion and 58 with synchronous multiple lesions) treated at our institution from 1987 through 2002, after excluding 158 patients who underwent additional surgery due to noncurative ERs, 180 patients whose surveillance periods were less than 1 year, 1 patient with hereditary non-polyposis colorectal cancer, and 1 patient with gastric tube cancer. We defined a second cancer found within 1 year after ER as “synchronous” and a second cancer found after 1 year as “metachronous.” Results First MGCs had an overall incidence of 8.2% (52 out of 633 patients); the annual incidence was constant, and the cumulative 3-year incidence was 5.9%. The average time to the discovery of a first MGC after the initial ER was 3.1 ± 1.7 years (range, 1–8.6 years). Almost all first MGCs (96.2%, 50 out of 52 lesions) were treated curatively with repeat ER. Conclusion In order to detect MGC at a stage early enough for a curative repeat ER, an annual endoscopic surveillance program is both practical and effective for post-ER patients.     

Pilot study of intraperitoneal administration of paclitaxel and oral S-1 for patients with peritoneal metastasis due to advanced gastric cancer

Background  There is no standard treatment for peritoneal dissemination from gastric cancer. A novel combination chemotherapy has been introduced for patients with advanced gastric cancer with peritoneal metastasis. Methods  This pilot study was performed on four patients to confirm safety and efficacy. They were diagnosed with unresectable gastric cancer with severe peritoneal dissemination by staging laparoscopy, or with metastasis to the transverse colon. We selected combined chemotherapy with both paclitaxel and S-1. Paclitaxel at 60 mg/m² or 60 mg/body was administered intraperitoneally on days 1 and 8 and S-1, at 80–120 mg/body, was administered orally for 14 days followed by 7 days’ rest, as one course. After five courses of this therapy, the primary gastric tumors were evaluated by conventional examinations, and second-look laparoscopy was performed to assess the efficacy of the treatment against the peritoneal metastases. Results  After five courses, primary tumor reductions were confirmed, and no cancer cells were detected on pathocytological investigation during second-look laparoscopy in any of the patients. Three patients underwent total gastrectomy with lymph node dissection and one underwent left upper abdominal evisceration. Final histological staging showed two stage 3 and two stage 4 patients. The intraperitoneal administration of paclitaxel and the oral administration of S-1 were well tolerated. Three patients died, at 8, 15, and 29 months, respectively, after the initial treatment, and one has been alive for 54 months without recurrence. Conclusion  This chemotherapy can be used in the treatment of patients with peritoneal metastasis of gastric cancer.     

Phase II study of paclitaxel combined with capecitabine as second-line treatment for advanced gastric carcinoma after failure of cisplatin-based regimens

Purpose  To determine the safety and the efficacy of paclitaxel and capecitabine as second-line combination chemotherapy after failure of platinum regimens in advanced gastric cancer. Methods  Patients with histologically proven gastric cancer and measurable metastatic disease received capecitabine 825 mg/m² twice daily (1,650 mg/m² per day) on days 1–14 and paclitaxel 175 mg/m² by intravenous infusion on day 1 every 3 weeks until disease progression or unacceptable toxicities. Results  Between June 2003 and October 2005, 26 patients, of median age 59 years (range 41–84 years) were included in the study and were treated by paclitaxel/capecitabine combination. Overall response rate was 34.6% (95%CI = 17.2–55.7%) with one complete response and 42.3% (95%CI = 17.2–55.7%) of patients achieved a stable disease. Median progression-free survival was 4.5 months (95%CI = 4–4.5 months). Median overall survival was 7.5 months (95%CI = 6–10 months). Cumulated overall survival including cisplatin regimens was 15.5 months (95%CI = 11–18 months). Grade 3/4 adverse events included alopecia (30.8%), neutropenia (11.5%), hand foot skin reaction (11.5%), neuropathy (11.5%), arthralgias (7.5%), and anemia (3.8%). Conclusions  Paclitaxel and capecitabine combination was safe and effective in advanced gastric cancer after failure of cisplatin regimens. The cumulated overall survival of 15.5 months suggests a particular interest of taxanes in second-line treatment after failure of platinum salts.     

豫西地区胃黏膜不典型增生和肠化生的临床流行病学调查

目的:探讨近4年豫西地区胃黏膜不典型增生和肠化生的相关临床流行病学资料的特点及变化趋势。方法:选取2007年1月-2010年6月我院胃镜室行内镜检查的21932例患者为研究对象,对胃黏膜不典型增生和肠化生患者的一般临床资料和病理资料进行回顾性分析。结果:胃黏膜不典型增生和不典型增生伴肠化生有随年龄增加检出率增高的趋势,且不典型增生程度随年龄增加而程度增高。重度不典型增生≥60岁患者比例高于轻、中度不典型增生,(P<0.05),中度不典型增生≥60岁患者比例高于轻度不典型增生;中度肠化生≥60岁患者比例高于轻度肠化生患者(P<0.05)。贲门部不典型增生和肠化生中≥60岁患者比例高于胃角和胃体部(P<0.05),幽门螺杆菌检出率均较单纯慢性浅表性胃炎组高,(P<0.05)差异有统计学意义。结论:胃黏膜不典型增生和肠化生的发生与年龄和幽门螺杆菌感染有关,常发生于贲门部。     

Phase II trial of S-1 for neoadjuvant chemotherapy against scirrhous gastric cancer (JCOG 0002)

Background  The prognosis of scirrhous gastric cancer remains poor despite extended surgery or adjuvant or neoadjuvant chemotherapy. A pilot study of S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan), an oral 5-fluorouracil derivative, for neoadjuvant chemotherapy unexpectedly showed good response and a promising effect on survival. Therefore, the Japan Clinical Oncology Group conducted a phase II trial to confirm the efficacy of S-1 for neoadjuvant chemotherapy against resectable scirrhous gastric cancer. Methods  Patients were eligible if they had typical scirrhous gastric cancer invading more than half of the stomach, and resectable disease confirmed by laparoscopic staging. The treatment schedule consisted of two courses (each, 4-week administration and 2-week withdrawal) of S-1 (100–120 mg/body per day), followed by radical surgery. Results  Fifty-five eligible patients were registered. Three completed only one course of the neoadjuvant chemotherapy, whereas 52 completed two courses. Toxicity was acceptable, with a few grade 3 (5.5%) events, but no grade 4 adverse events. The response rate was 32.6% in 43 evaluable patients. Of the 55 patients, 2 refused operation, 1 developed lung metastasis, and 52 underwent laparotomy. The curative resection rate was 80.8%, with acceptable morbidity and no mortality. The survival curve at 2 years’ follow up showed a better survival rate than that of the historical controls, but did not reach the expected survival rate. Conclusion  S-1 neoadjuvant chemotherapy appeared feasible and showed positive effects against scirrhous gastric cancer; however, the survival rate with S-1 did not reach the expected rate required when selecting an agent for a phase III trial to confirm the effectiveness of neoadjuvant chemotherapy against scirrhous gastric cancer. (on behalf of the Gastric Cancer Surgery Study Group of the Japan Clinical Oncology Group)     

Proliferative epithelial changes in ectopic gastric mucosa of Meckel’s diverticula

Twenty-one Meckel’s diverticula containing an adequate amount of assessable heterotopic gastric mucosa were investigated for epithelial changes. Marked or moderate foveolar hyperplasia was present in 52% and 29% of the cases, respectively. Four cases displayed an excessive epithelial proliferation indefinite for dysplasia. It is pointed out that reflux type gastritis or gastropathy, which is the most common lesion in the ectopic gastric mucosa of Meckel’s diverticulum, can be associated with the same confusing epithelial proliferation as reflux gastritis in the stomach, but these lesions are best regarded as representing atypia of repair. Distinguishing features from dysplasia are maturation towards the surface, lack of hyperchromatism and abscence of atypical mitoses. Negative p53 immunostaining and localization of the Ki-67 positivity to the expanded neck region could be additive clues that can help to classify lesions indefinite for dysplasia as negative for dysplasia. On the basis of the similarities of the ectopic and ortotopic gastric mucosa, it is suggested that these additive clues previously used in other parts of the digestive tract could also apply for the stomach.     

Capecitabine in combination with Oxaliplatin (XELOX) as a first-line therapy for advanced gastric cancer

Purpose We evaluated efficacy and safety of XELOX in previously untreated patients with AGC. Patients and methods Patients received intravenous oxaliplatin 130 mg/m² over 2 h on day 1 plus oral capecitabine 1,000 mg/m² twice daily on days 1–14, every 3 weeks (XELOX). Treatment was continued until disease progression, intolerable toxicities or eight cycles reached. All tumour evaluations were reviewed and confirmed centrally. Design was according to Ensign’s three-stage method. Results Fifty-four patients (37 men) were enrolled; median age 57 years (range 29–70). In total, 311 cycles of XELOX were delivered. Overall response rate was 63% (95% CI, 50–76%), with 3 complete and 31 partial responses. At 13 months’ median follow-up, median progression-free and overall survival were 5.8 (95% CI, 4.4–7.2) and 11.9 months (95% CI, 8.8–15.1), respectively. The most common haematological adverse event was anaemia (70% of patients). Grade 3–4 neutropenia was observed in four patients, with neutropenic fever in only one patient. Most common non-haematological toxicities were neuropathy (70%), vomiting (50%), diarrhoea (33%), and hand-foot syndrome (HFS) (39%). Grade 3–4 toxicities were rare. Treatment was delayed or the dose reduced in 30 and 15% of cycles, respectively. There was one treatment-related death associated with grade 4 neutropenic sepsis. Conclusion XELOX was active and well tolerated as a first-line therapy for AGC.     

豫西地区胃黏膜不典型增生和肠化生的临床流行病学调查

目的：探讨近4年豫西地区胃黏膜不典型增生和肠化生的相关临床流行病学资料的特点及变化趋势。方法：选取2007年1月-2010年6月我院胃镜室行内镜检查的21932例患者为研究对象,对胃黏膜不典型增生和肠化生患者的一般临床资料和病理资料进行回顾性分析。结果：胃黏膜不典型增生和不典型增生伴肠化生有随年龄增加检出率增高的趋势,且不典型增生程度随年龄增加而程度增高。重度不典型增生≥60岁患者比例高于轻、中度不典型增生,（P〈0.05）,中度不典型增生≥60岁患者比例高于轻度不典型增生;中度肠化生≥60岁患者比例高于轻度肠化生患者（P〈0.05）。贲门部不典型增生和肠化生中≥60岁患者比例高于胃角和胃体部（P〈0.05）,幽门螺杆菌检出率均较单纯慢性浅表性胃炎组高,（P〈0.05）差异有统计学意义。结论：胃黏膜不典型增生和肠化生的发生与年龄和幽门螺杆菌感染有关,常发生于贲门部。     

Pathological features of gastric cancer in Zhuanghe high-risk area in China during 1992–2005

Objective  To investigate the pathological features and chronological changes of 1003 cases with gastric cancer in Zhuanghe high-risk area during 1992–2005 and the relationship between the changes and etiology factors in order to make a clue for gastric cancer prevention. Methods  A total of 1003 gastric cancer specimens resected surgically between 1992–2005 in Zhuanghe Center Hospital were studied. The specimens were fixed in formalin and diagnosed by routine pathology. Results  The incidence of patients with gastric cancer was highest at age of 60–69, the next high was at age of 50–59 and it was significantly higher in male than in female (P<0.001), the ratio was 3.0:1. During the past 14 years, there were 159 (15.9%) EGC, 195 (19.4%) moderate and 649 (64.7%) advanced gastric cancer detected. In macroscopical features, type III remained dominant in EGC, the next was mixed type in EGC. In advanced gastric cancer the Borrmann’s type III remained the dominant, the next was type II. For nodal metastasis, positive cases were decreasing and negative were increasing in EGC, moreover negative cases were higher than positive ones each year. There was no obvious trend in advanced cancer but positive cases were higher than negative ones each year. In histological features, papillary, moderately and poorly differentiated tubular adenocarcinoma remained downtrend, mucus adenocarcinoma and undifferentiation cancer remained uptrend year after year. The radio of intestinal to diffuse type decreased from 0.78 to 0.62 during the past 14 years. Conclusion  There were significant chorological trends of pathological characteristic of gastric cancer in Zhuanghe high-risk area during the past 14 years. This work was supported by the National “Tenth-Five” Key Technologies R&D Program of China (2004BA703B04-02)     

Changes in aberrant DNA methylation after Helicobacter pylori eradication: A long‐term follow‐up study

Changes of DNA methylation in gastric mucosae after eradication of Helicobacter pylori have not been clarified yet. From this background, we investigated time course of DNA methylation following H. pylori eradication in 221 successfully H. pylori eradicated subjects with endoscopic follow‐up at least for 6 months, including 114 controls, 53 subjects with gastric dysplasia and 54 patients with early gastric cancer. All dysplasia and gastric cancer patients underwent endoscopic resection at the time of enrollment. The methylation levels in LOX, APC and MOS genes from noncancerous gastric mucosae using quantitative methylation‐specific PCR, as well as the histologic findings of gastric mucosae, were compared before and after eradication. Average follow‐up duration was 26.0 months (range: 6 to 76 months). H. pylori eradication decreased methylation levels in LOX (p‐value for slope < 0.001) but not in APC. In MOS, decrease of its methylation level following H. pylori eradication was significant among controls without intestinal metaplasia (IM) (p‐value for slope < 0.05); however, it was not observed among patients with IM or those with dysplasia or gastric cancer. After H. pylori eradication, methylation level in MOS persistently increased in patients with dysplasia or gastric cancer (p < 0.01). In conclusion, H. pylori eradication decreases aberrant DNA methylation with gene‐specific manner. Methylation level in MOS is associated with IM and may be used as a surrogate marker for gastric cancer risk, regardless of H. pylori eradication history.     

The impacts of breast conserving treatment and mastectomy on the quality of life in early-stage breast cancer patients

The quality of life (QOL) in 55 early-stage breast cancer patients after surgery was prospectively assessed using a newly developed Japanese QOL questionnaire: The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs (QOL-ACD). The impacts of breast conserving treatment (BCT) (22 cases) and modified radical mastectomy (MRM) (33 cases) on the QOL in those subjects were compared. The overall QOL scores were evaluated during four periods (before surgery, 0–2, 3–12, and 13–24 months after surgery). The mean scores of the four categories of the QOL-ACD (activity, physical condition, psychological condition, and social relationships) were also compared. The results demonstrated that a significant improvement was observed in the overall QOL scores among the three periods after surgery (0–2, 3–12, and 13–24 months) only in the BCT group (P<0.05). There were no significant differences between the two groups in the overall QOL scores during any of the three periods after surgery, and the mean score of the ‘psychological condition’ during 0–2 months period in the BCT group was significantly lower than that in the MRM group (P< 0.05).     

Research on serum levels of retinol, α-tocopherol β-carotene,and 12 elements in gastric dysplasia and gastric cancer patients

Serum levers of retinol, α-tocopherol, β-carotene and elements (Zn, Cu, Mn, Ca, Mg, Cr, Co, Cd, Mo, Se) were determined in 45 gastric cancer and 41 gastric dysplasia patients, and 48 normal subjects. The results showed that β-carotene and Se, Co were lower in gastric cancer patients than that in gastric dysplasia patients or in normal subjects, Ni and Cr levels were lower and Mn, Ca and Cd were higher in gastric cancer than in dysplasia patients. Zn, Fe, Cr, Cd were lower and Mn, Ca, Mg, Mo levels were higher in gastric cancer patients than in normal. The differences mentioned are statistically significant. The stepwise discriminant analysis of 10 variables (Mn, Fe, Ca, Cr, Mo, Co, Cd, Se, α-tocophrol, β-carotene) were used in identifying gastric cancer, with 100% of the positive rate. The potential protective effect of β-carotene and Se against gastric cancer is an interesting postulate. We suggest that optimum supplement of β-carotene and Se might will be beneficial to gastric dysplasia patients in preventing the development of gastric cancer.     

胃癌和胃粘膜异型增生核仁组织区嗜银蛋白定量和形态研究

目的探讨核仁组织区嗜银蛋白（ＡｇＮＯＲ）染色技术在胃癌、癌前病变、慢性胃炎中鉴别诊断价值和意义。方法应用ＡｇＮＯＲ染色技术，观察１３２例胃良恶性病变和癌前病变细胞核中ＡｇＮＯＲ颗粒含量和形态。结果胃癌、胃粘膜异型增生、慢性胃炎三组间细胞核内ＡｇＮＯＲ颗粒均数差异非常显著（Ｐ＜０．０１），正常胃壁粘膜与慢性胃炎ＡｇＮＯＲ颗粒均数无明显差异（Ｐ＞０．０５）。胃癌和胃粘膜异型增生ＡｇＮＯＲ颗粒形态以弥散型为主，而慢性胃炎和正常胃粘膜以核仁型为主。结论细胞核内ＡｇＮＯＲ颗粒含量和分型对于区别胃良恶性及癌前病变有重要参考价值。     

Surgery and chemotherapy versus chemotherapy as treatment of high-grade MALT gastric lymphoma

Background and Objectives Treatment of high-grade MALT (mucosa-associated lymphoid tissue) gastric lymphoma remains uncertain. To assess efficacy and toxicity of the most common therapies—surgery followed by chemotherapy or chemotherapy alone—we began a controlled clinical trial in patients in early stage (I and II). Methods One hundred and two patients were randomized to be treated with surgery followed by six cycles of CEOP-Bleo (cyclophosphamide, epirubicin, vincristine, prednisone, and bleomycin at standard doses) (52 cases) or with chemotherapy alone (49 cases). Results Complete response rates were 94% [95% confidence interval (CI): 88–99%] and 96% (93–100%), respectively. Actuarial curves at 5 yr showed that event-free survival were 70% (95% CI: 59–74%) in patients treated with surgery and chemotherapy, that were not statistically significant to 67% (95% CI: 51–69%) in the patients who received chemotherapy (p=0.5). Also, overall survival that was not statistically significant: 78% (95% CI: 70–88%) in the combined treatment and 76% (95% CI: 70–87%) in chemotherapy (p=0.8). Acute and late toxicity were mild and well controlled. No acute leukemia or second neoplasm has been observed. Conclusions The use of surgery and chemotherapy did not improve outcome in patients with early-stage high-grade gastric MALT lymphoma. It is apparent that chemotherapy alone is sufficient treatment in this select group of patients.     

Bcl-2、Bax在胃癌病变过程中的表达及其与凋亡的关系

Objective： To study the expressions of Bcl-2 and Bax proteins and explore the relationships between them and apoptosis in gastric carcinoma and precancerous lesions, Methods： TUNEL method was used to detect apoptosis and immunohistochemical staining method was used to detect the expressions of Bcl-2 and Bax proteins in 70 cases of chronic gastritis, 49 cases of intestinal metaplasia, 64 cases of dysplasia and 81 cases of gastric carcinoma. Results： The positive incidences of Bcl-2 and Bax were the highest in severe dysplasia, In intestinal metaplasia and dysplasia, positive incidences of Bcl-2 and Bax were higher than those in chronic gastritis and gastric carcinoma. During the process of evolvement from chronic gastritis to intestinal metaplasia then to dysplasia, apoptosis indexes gradually rise up to mid-high dysplasia, which reached the highest point, then it began to fall down, when it reached the lowest point in gastric carcinoma. There were negative correlations between the expressions of Bcl-2, Bax proteins and apoptosis. Conclusion： The expression of Bcl-2 may be an early behavior in the gastric carcinogenesis. Bax had antagonistic effect to Bcl-2, Detections of Bcl-2 and Bax may be beneficial to the early diagnosis of gastric tumor and precancerous lesions.     

A phase I/II trial of docetaxel and oxaliplatin in patients with advanced gastric cancer

Purpose  We designed this phase I/II study of docetaxel–oxaliplatin combination chemotherapy to determine the dose-limiting toxicity (DLT), maximum tolerated dose and efficacy as a first-line treatment in patients with advanced gastric cancer. Methods  Patients with histologically proven, chemo-naive gastric adenocarcinoma were eligible. For the phase I part, three dose levels of oxaliplatin and docetaxel every 3 weeks were tested in a cohort of three patients for each level (respectively, 100 and 60 mg/m², 100 and 75 mg/m², 130 and 75 mg/m²). Patients were treated up to a maximum of nine cycles of oxaliplatin and docetaxel unless there was documented disease progression, an unacceptable adverse event, or withdrawal of consent. Results  No DLT was observed at any of the three levels tested in the phase I portion. Therefore, oxaliplatin 130 mg/m² and docetaxel 75 mg/m² were recommended for the phase II study. All 47 patients were evaluable for toxicity and treatment response. The overall response rate was 55.3% (95% CI, 40.6–70.1%) and median duration of response was 4.2 months (range 0.9–9.5 months). After a median follow-up duration of 13.3 months, median overall survival was 12.7 months (95% CI: 10.4–14.9). The median time to progression was 5.0 months (95% CI, 3.4–6.5 months). The main toxicities (grade 3 or 4) were febrile neutropenia (14.9%), neutropenia (23.4%), diarrhea (10.6%) and neurotoxicity (8.5%). Conclusion  The combination of docetaxel and oxaliplatin was feasible with favorable toxicity profile and showed a promising anti-tumor activity in unresectable, metastatic gastric cancer patients.     

Perigastric lymph node metastases in gastric cancer: comparison of different staging systems

Background. Perigastric lymph node metastases in gastric cancer are classified differently by different staging systems: the distance of positive nodes from the primary tumor is considered by the 1987 International Union Against Cancer (UICC)-TNM system, but not by the Japanese staging system (of the Japanese Research Society for Gastric Cancer [JRSGC]); the new UICC-TNM system of 1997 is based on the number of involved nodes without differentiating perigastric from regional nodes. The aim of the present study was to assess which classification was more useful to predict prognosis in gastric cancer patients with metastases to the perigastric nodes. Methods. The results for 107 patients with lymph node metastases to the first and second tiers who underwent curative gastrectomy for gastric cancer from March 1988 to October 1997 were analyzed. In particular, we compared the clinical characteristics and the survival probabilities of: (1) patients with metastases to perigastric nodes located within 3 cm from the primary tumor, classified as N1; (2) patients with metastases to perigastric nodes located 3 cm beyond the primary tumor (N2 in the UICC-TNM and N1 in the Japanese classification), classified by us as N1–N2; and (3) patients with metastases to the second tier (classified by us as N2). We also assessed the number of positive nodes dividing the patients into groups according to the 1997 UICC TNM system. Results. On multivariate survival analysis, the mortality risks in the N1 and N1–N2 patients were comparable (relative risk [RR], N1–N2 versus N1, 1.32; 95% confidence interval [CI], 0.53–3.51) and were half the mortality risk in N2 patients (RR, N2 versus N1, 2.52; 95% CI, 1.33–4.79). The N1 and N1–N2 categories, while presenting markedly different distributions in the number of metastatic nodes (patients with more than seven metastatic nodes constituted less than 20% of the N1 group and more than 60% of the N1–N2 group), showed similar prognostic significance. Conclusion. In the present series, the distance of perigastric nodes from the primary tumor did not seem to exert a significant effect on prognosis, and the use of a combined classification based on anatomical location (JRSGC) and number of node metastases (UICC-TNM 1997) could be more useful than either system alone for prognostic purposes. Received on July 14, 1999; accepted on Nov. 18, 1999     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.