Gastric Tumorigenicity of 1,2-Dimethylhydrazine on the Background of Gastric Intestinal Metaplasia Induced by X-Irradiation in CD (SD) Rats

Five-week-old male CD (SD) rats were X-irradiated with a total of 20 Gy in 2 equal fractions with a 3-day interval. After the second irradiation, rats were fed normal diet supplemented with 1% sodium chloride, which is known to increase intestinal metaplasia. 1,2-Dimethylhydrazine (DMH) solution was injected i.m. into the back musculature at a dose of 20 mg/kg body weight weekly for 10 weeks, beginning 20 weeks after the final irradiation. Twelve months after the initial carcinogen treatment, gastric tumors in the glandular stomach were observed in 2 (3 lesions) of 30 animals in the X-irradiated and DMH-treated group fed diet supplemented with 1% sodium chloride. No gastric tumors were observed in the group which excluded X-irradiation from the experimental protocol.     

Gastric tumor induction by 1,2-dimethylhydrazine in Wistar rats with intestinal metaplasia caused by X-irradiation.

Five-week-old male Wistar rats were X-irradiated with a total of 20 Gy in 2 equal fractions at a 3-day interval. 1,2-Dimethylhydrazine (DMH) solution was injected i.m. into the back musculature at a dose of 20 mg/kg body weight weekly for 10 weeks, beginning 20 weeks after the final irradiation. Twelve months after the initial carcinogen treatment, tumors in the fundus of the glandular stomach were observed in 5 of 23 animals receiving both X-irradiation and DMH treatment. No tumors of the glandular stomach were observed in the DMH and X-ray alone or nontreatment groups. It is concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by carcinogens like DMH.     

Gastric Tumor Induction by 1,2-Dimethylhydrazine in Wistar Rats with Intestinal Metaplasia Caused by X-Irradiation

Five-week-old male Wistar rats were X-irradiated with a total of 20 Gy in 2 equal fractions at a 3-day interval. 1,2-Dimethylhydrazine (DMH) solution was injected i.m. into the back musculature at a dose of 20 mg/kg body weight weekly for 10 weeks, beginning 20 weeks after the final irradiation. Twelve months after the initial carcinogen treatment, tumors in the fundus of the glandular stomach were observed in 5 of 23 animals receiving both X-irradiation and DMH treatment. No tumors of the glandular stomach were observed in the DMH and X-ray alone or nontreatment groups. It is concluded that the presence of intestinal metaplasia may increase sensitivity to the induction of gastric tumors by carcinogens like DMH.     

Cyclophosphamide plus 5-FU versus 5-FU alone in advanced gastric carcinoma

30 patients with advanced metastatic gastric adenocarcinoma, having a measurable indicator lesion, were randomized (1:2) to receive (intravenously) either weekly 5-fluorouracil alone (15 mg/kg) or combination treatment with cyclophosphamide (20 mg/kg) given on day 1 and 5-FU (15 mg/kg) given weekly on weeks 2-5, beginning on day 8. The combination cycle was repeated at 6-week intervals. Although the toxic effects of therapy were similar in both arms, the addition of cyclophosphamide to the single-agent 5-FU regimen did not increase either the frequency of objective response (5-FU 18%, combination 16%) or improve the median survival of patients with advanced measurable gastric carcinoma (5-FU 4.4 months, combination 5.2 months). Patients with pretreatment weight loss greater than 10% had significantly (p less than 0.05) shorter median survival (2.8 versus 5.6 months) compared to patients without weight loss.     

Weekly high-dose 5-fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer

BACKGROUND: A phase II clinical trial was performed to evaluate the activity and toxicity of bimonthly cisplatin and weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with advanced gastric cancer. PATIENTS AND METHODS: From September 1997 to March 1998, 23 chemo-naive patients of advanced gastric cancer were enrolled in this study. The regimen consisted of weekly 24-h infusion of 5-FU (2,600 mg/m2) and LV 150 mg and bimonthly cisplatin (25-50 mg/m2) bolus for 12 weeks followed by a 2-week break. RESULTS: There were 10 male and 13 female patients with a median age of 52 years. A total of 428 chemotherapy treatments were given with a mean of 11. Seventeen patients were evaluable for response. There were 41% (7/17) partial response, 18% (3/17) stable disease and 41% (7/17) progressive disease. The grade III or IV toxicity included anorexia 35% (8/23), fatigue 26% (6/23), vomiting 17% (4/23) and mucositis 9% (2/23). One patient developed perforated duodenal stump after chemotherapy. One patient died of hyperammonemia-related coma. The median times to disease progression and overall survival were 3.5 and 7 months, respectively. CONCLUSIONS: This regimen showed modest activity against gastric cancer. However, there was no survival advantage and there was greater toxicity than with weekly high-dose 5-FU-LV alone.     

Two cases of gastric cancers with lung metastases responding to weekly administration of paclitaxel

We report two cases of gastric cancer with multiple lung metastases responding well to weekly administration for 3 weeks followed by a week discontinuation of paclitaxel (80 mg/m2). Case 1, a 73-year-old man, was diagnosed as multiple lung metastases 1 year and 4 months after total gastrectomy for Borrmann 1 type gastric cancer (7.5 x 6.5 cm, pap, P0 cy(-) H0 mpn2, stage III A, ly2, v2). After 8 weekly administrations of paclitaxel 110 mg (80 mg/m2), the lung tumor diminished from 5 cm to a linear scar in size, and dyspnea needing inhalation of oxygen at home disappeared. Case 2, another 73 year-old man with multiple lung metastases at 7 months after distal gastrectomy for Borrmann 3 type gastric cancer (4 x 3.5 cm, muc, P0 cy(-) H0 sen2, stage III B, ly1, v0) received weekly paclitaxel 110 mg (80 mg/m2). Lung tumors disappeared after 27 administrations of paclitaxel, and CT scans have showed CR for 8 months until now after 44 administrations. Therefore, we recommend weekly administration of paclitaxel for lung metastases from gastric cancer.     

Phase I trial of weekly docetaxel with a 4-weekly cisplatin administration in patients with advanced gastric carcinoma

The docetaxel-cisplatin combination is active against several tumors including gastric cancer but it is followed by severe myelosuppression. Recent experience with weekly taxanes has demonstrated a mild myelotoxicity with high dose intensity. We investigated in a phase I study a weekly schedule of docetaxel on days 1, 8 and 15 and cisplatin on day 1 every 4 weeks in 19 patients with advanced gastric cancer with no prior chemotherapy. Cohorts of patients were treated with escalating doses of docetaxel (starting dose 30 mg/m² per week and increments of 10 mg/m² per week) and cisplatin (starting dose 70 mg/m² and increments of 5 mg/m²). Febrile neutropenia was the only dose-limiting event occurring in four (20%) patients; the dose-limiting toxicity was reached at dose level three (docetaxel 40 mg/m² per week and cisplatin 75 mg/m²). The maximum-tolerated dose was 40 mg/m² per week for docetaxel and 70 mg/m² every 4 weeks for cisplatin. Grade 3/4 neutropenia occurred in six patients (30%); early death occurred in one patient with septic shock because of neutropenia and another with acute coronary ischemia. Two (11%) complete and two (11%) partial responses were documented (ORR 22%; 95% CI 3–39%), with a median response duration of 5 months and median time to progression of 7 months. In conclusion, the combination of weekly docetaxel plus cisplatin is feasible with moderate toxicity and merits further investigation in phase II studies in advanced gastric cancer.Presented as an abstract at the 15th International Congress on Anti-Cancer Treatment, Paris, 9–12 February 2004.     

周剂量多西紫杉醇联合卡培他滨治疗晚期胃癌的临床观察

目的观察周剂量多西他赛联合卡培他滨治疗晚期胃癌的近期疗效和不良反应。方法 37例晚期胃癌患者采用多西他赛35mg/m2,静脉滴注,第1,8天;卡培他滨1250mg/m2,bid,口服,1～14d,21d为1周期。3周期后评价疗效和不良反应。结果全组37例患者均可评价疗效,其中CR3例（8.1%）,PR19例（51.3%）,SD10例（27.0%）,PD5例（13.5%）,总有效率59.5%。中性粒细胞减少发生率54.0%。中位TTP为6.5个月（3.2～11.5个月）,中位MST为10.3个月（5.8～14.7个月）。结论多西他赛联合卡培他滨治疗晚期胃癌有效率较高,血液学毒性低,近期疗效较好,用药方便、安全,明显提高了患者的生活质量。     

Complete response of gastric cancer with interaorticocaval lymph node recurrence to weekly administration of paclitaxel--a case report

We report a case in which weekly administration of paclitaxel produced a complete response for gastric cancer with interaorticocaval lymph node recurrence. A 55-year-old man who underwent total gastrectomy for advanced gastric cancer had pathological findings of tub2, se, n2, ly2, v2, stage IIIB. As an outpatient, he was first treated with TS-1 (100 mg/day) for 5 cycles. CEA increased gradually however, and 7 months postoperatively he was found to have interaorticocaval lymph node swelling in upper abdominal CT and was diagnosed with a recurrence of gastric cancer. He underwent weekly administration of paclitaxel as second-line chemotherapy. Paclitaxel was administered by 1-hour intravenous infusion at a dose of 90 mg/body weekly after short premedication as an outpatient. This was continued for 3 weeks followed by 1 week of rest. CEA decreased gradually, and the swollen lymph node had responded completely after 10 cycles. The only toxic side effect was alopecia (grade 1). No major adverse effects such as hypersensitivity, leukopenia or peripheral neuropathy were observed.     

High-dose leucovorin and 5-FU]

Leucovorin (LV), given intravenously the orally becomes 5, 10-methylene tetrahydrofolate in both cancer and normal cells. FdUMP which is an active metabolite of 5-FU binds tightly to thymidylate synthase in the presence of the cofactor 5, 10-methylene tetrahydrofolate. This interaction leads to potentiate the cytotoxic effect of 5-FU by prolonged inhibition of thymidylate synthase. Clinically, the combination of LV and 5-FU is given parenterally by two schedules; 5 consecutive days schedule and weekly schedule. Five 5 consecutive days-schedule is divided into 2 methods. One is a 200 mg/m2/day of LV by Machover, and the other is 20 mg/m2/day of LV by O'Connell. The weekly schedule is a 2-hour infusion of dl-LV (500 mg/m2) and iv bolus of 5-FU (600 mg/m2), given 1 hour after the beginning of LV infusion by Petrelli. A multicenter cooperative study in Japan was conducted to evaluate the clinical efficacy of LV and 5-FU using the weekly schedule by Petrelli. Response rates were 31.5% and 41.2% against advanced gastric and colorectal cancer respectively. Then, we carried out a randomized early phase II study using 250 mg/m2 of l-LV weekly (similar to the schedule of Petrelli's, armA) and 100 mg/m2 (similar to the schedule of Machover's, arm B) or 10 mg/m2 (similar to the schedule of O'Connell's, arm C) of l-LV for 5 consecutive days against gastric cancer. The response rate was 33.3% in arm A, 24.1% in arm B and no response in arm C. Toxicity was within acceptable limits, Toxic effects included diarrhea, stomatitis, anorexia and myelohypoplasia. Our data suggests that high-dose LV and 5-FU seems to be a very promising combination but, there was no responder using low dose (10 mg/m2) of l-LV schedule against gastric cancer patients.     

S-1 combined with weekly dosing of cisplatin for metastatic gastric cancer

We developed a combination chemotherapy, comprising weekly dosing of iv cisplatin (days 1 and 8) combined with a fixed dose (70 mg/m2/day) of S-1 (days 1-14) for patients with metastatic gastric cancer. The treatment was repeated every 3 weeks. Twenty patients were studied. Dose-limiting toxicities of grade 3 diarrhea and stomatitis were observed in one patient at the dose of cisplatin 20 mg/m2. Grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in approximately half of patients at this dose level within the first two treatment cycles. This was the maximum acceptable level. The overall response rate in 18 patients evaluated was 61%. The median survival was 11 months, despite including 11 pre-treated patients. S-1 given with weekly cisplatin was a feasible and promising combination regimen for an outpatient setting.     

A case of advanced gastric cancer with multiple liver metastases successfully treated with TS-1/low-dose CDDP/lentinan combination chemotherapy

We report herein a case of advanced gastric cancer successfully treated with TS-1/low-dose CDDP/Lentinan combination chemotherapy. A 74-year-old male suffering from anorexia was admitted to our hospital and diagnosed as having type 2 gastric cancer metastasizing to the liver. TS-1 was orally administered at 100 mg/body/day for 28 days with a 14-day interval as one session. During the second session, because grade 1 thrombocytopenia was noted, administration of TS-1 was rescheduled to every other day. CDDP was infused at 10 mg/body/day on day 6 to 10, 13, 15, and 17. After his discharge, CDDP at 10 mg/body and Lentinan at 2 mg/body were weekly infused as ambulant patient chemotherapy. The abdominal CT scan showed reduction of hepatic tumors by 86% in three months and 97% in 16 months. Metastatic lymph nodes disappeared in 4 months. The primary tumor was reduced and flattened to a cicatrix, and endoscopic biopsy revealed no cancer cells. The tumor markers, CEA (716.9 ng/ml) and CA 19-9 (57.2 U/ml), were reduced to normal range. The therapeutic efficacy was judged as a partial response (PR), which lasted for 16 months without severe adverse effects. He maintained good quality of life. This combination chemotherapy was thought to be beneficial for patients with advanced gastric cancer.     

周剂量多西紫杉醇联合顺铂、氟尿嘧啶二线治疗晚期胃癌32例

[目的]研究周剂量多西紫杉醇（TXT）联合顺铂（DDP）、氟尿嘧啶（5-Fu）持续滴注二线治疗晚期胃癌的疗效和不良反应。[方法]32例晚期胃癌患者接受DCF方案二线化疗：TXT30mg/m2,d1,8,15,DDP25mg/m2,d1～3,5-Fu500mg/m2持续静脉滴注,d1～5,28d为1个周期。至少完成2个周期后评价有效率、不良反应、疾病进展时间（TTP）和总生存时间（OS）。[结果]32例患者均可评价疗效,客观缓解率21.9%（7/32）,中位TTP及OS分别为2.7个月和7.6个月。主要不良反应为骨髓抑制、胃肠道反应和脱发。[结论]周剂量TXT联合DDP、5-Fu持续滴注二线治疗晚期胃癌疗效显著,不良反应可以耐受。     

A case of non-curatively resected scirrhous gastric cancer successfully treated over 2 years with weekly administration of paclitaxel

We report a patient with far-advanced gastric cancer treated by weekly administration of paclitaxel (TXL) over 2 years. The patient was a 66-year-old female with peritoneal metastasis and remarkable lymph node metastasis of scirrhous gastric cancer. She underwent a non-curative resection with total gastrectomy and splenectomy in May 2002. Postoperative chemotherapy with TS-1 (80 mg/body) was performed. Due to grade 4 neutropenia and grade 2 anorexia, this treatment could not be continued. Three months after surgery, the tumor marker (CA19-9) had elevated to an abnormal level. Alternatively, TXL was administered at a weekly dose of 70 mg/m2 for 3 weeks followed by 6 weeks rest from September 2002. The tumor marker (CA19-9) gradually decreased to the normal level. Because of the long rest interval, 10 courses of treatment could be continued, and the patient has been alive over 2 years with the cancer controlled. There have been few effective chemotherapies for gastric cancer with peritoneal metastasis. Weekly paclitaxel therapy is considered to be effective for the treatment of advanced scirrhous gastric cancer with peritoneal metastasis.     

Phase I trial of weekly docetaxel with concurrent three-dimensional conformal radiation therapy in the treatment of unfavorable localized adenocarcinoma of the prostate.

PURPOSE: A phase I trial was conducted to determine the maximally tolerated dose (MTD) of concurrent weekly docetaxel and three-dimensional conformal radiation therapy (3-D CRT) in unfavorable localized adenocarcinoma of the prostate. PATIENTS AND METHODS: Patients with unfavorable localized adenocarcinoma of the prostate underwent daily 3-D CRT to a total dose of 70.2 Gy at 1.8 Gy/fraction and concurrent docetaxel given once a week for 8 to 9 weeks. The initial weekly docetaxel dose level was 5 mg/m(2) and the docetaxel doses were escalated as follows: 8, 12, 16, 20, and 25 mg/m(2). RESULTS: Between January 2000 and August 2002, 22 men completed the chemoradiation therapy protocol. The dose-limiting toxicity was grade 3 diarrhea, which occurred in the first two patients treated at the 25 mg/m(2) docetaxel dose level. The MTD of weekly docetaxel was determined to be 20 mg/m(2). The overall incidence of grade 2 diarrhea and grade 2 dysuria was 36% and 23%, respectively. Seven (32%) and 15 (68%) patients did not experience any diarrhea or dysuria, respectively. No neutropenia or thrombocytopenia was observed. One patient required intermittent urinary catheterization 10 months postcompletion of therapy, which resolved without any surgical intervention. Seventeen patients remain in prostate-specific antigen remission. At a median follow-up interval of 8 months (range, 2 to 27 months), all patients are alive. CONCLUSION: Concurrent weekly docetaxel in conjunction with 3-D CRT is well tolerated with acceptable toxicity. The MTD of weekly docetaxel was determined to be 20 mg/m(2) with concurrent 3-D CRT.     

A prospective randomized comparison of protracted infusional 5-fluorouracil with or without weekly bolus cisplatin in metastatic colorectal carcinoma. A Mid-Atlantic Oncology Program study

One hundred eighty-four patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to assess the value of weekly cisplatin (20 mg/m2) when added to a protracted schedule of 5-fluorouracil (5-FU) infusion (PIF) at 300 mg/m2/d for 10 weeks of every 12 weeks. The liver was the primary indicator lesion in approximately 75% of the study group. All tumor measurements required radiographic confirmation. The response rate in the PIF alone arm was 35% (29 of 83; 95% confidence interval [CI], 25% to 46%) compared with 33% (28 of 85; 95% CI, 23% to 44%) for the arm in which weekly cisplatin was added to PIF. The median survival times were 11.8 and 11.2 months in the two groups. Weekly cisplatin does not appear to add to the effectiveness of PIF in colorectal carcinoma.     

周剂量多西紫杉醇联合顺铂和5-氟尿嘧啶治疗晚期胃癌

  目的 观察周剂量多西紫杉醇联合顺铂（DDP）、5-氟尿嘧啶（5-Fu）治疗晚期胃癌的临床疗效和毒副作用。方法 晚期胃癌患者28例，给予多西紫杉醇35 mg／m2，静脉滴注1 h，第1、8、15天；DDP 75 mg／m2，均分第1 ~ 3天静脉滴注，5-Fu 500 mg／m2，24 h中心静脉置泵持续滴注，第1 ~ 5天，28 d为1个周期。化疗2 ~ 6个周期后按WHO实体瘤疗效评价标准（RECIST）评定疗效，按WHO标准评价不良反应。结果 全组28例均可评价疗效，其中完全缓解（CR）2例，部分缓解（PR）13例，稳定（SD）7例，近期客观有效率53.4 %，中位疾病进展时间（TTP）为8.7个月，中位生存期（MS）为11.8个月，1年生存率为47.8 %。主要不良反应为骨髓抑制和胃肠道反应。但Ⅲ ~ Ⅳ度发生率较低。结论 周剂量多西紫杉醇联合DDP和5-Fu治疗晚期胃癌疗效较好，患者毒副作用轻，耐受性好，值得进一步推广使用。     

Randomized-controlled study of treatment with UFT-MMC or UFT-ACR in advanced gastric cancer. Tohoku Study Group of Cancer Treatment for the Digestive Organs

The effect of UFT-MMC- or UFT-ACR-therapy on the unresectable or recurrent gastric cancer was studied by a multicenter, randomized-controlled trial. All the patients who were randomly divided into the two groups were administered orally with 400 or 600 mg/day of UFT everyday. In addition, the UFT-MMC group was intravenously injected weekly for three weeks and then triweekly after six weeks with 6 or 8 mg/body of MMC, while the UFT-ACR group was intravenously injected with 20 mg/body of ACR for 5 serial-days every three weeks. Out of 88 cases registered, 75 (85.2%) were evaluable, consisting of 40 (31 complete cases) in UFT-MMC and 35 (27 complete cases) in UFT-ACR. There was no difference in various background factors between the two groups. PR, NC and PD was 10/31, 15/31 and 6/31 in the UFT-MMC group, whereas 0/27, 22/27 and 5/27 in the UFT-ACR group, respectively. The efficacy in the former group was higher, though not significant (U-test, p = 0.052), than that in the latter group. However, there was no difference in the 50% survival time (4.9 months in UFT-MMC vs. 5.4 months in UFT-ACR) of the either group.     

Efficacy and Tolerability of Weekly Docetaxel,Cisplatin, and 5-Fluorouracil for Locally Advanced or Metastatic Gastric Cancer Patients with ECOG Performance Scores of 1 and 2

Background: Docetaxel, cisplatin, 5-fluorouracil (DCF) given every three weeks is an effective, but palliativeregimen and significantly toxic especially in patients who have a low performance score. Here, we aimed to evaluatethe efficacy and tolerability of a weekly formulation of DCF in locally advanced and metastatic gastric cancerpatients. Materials and Methods: 64 gastric cancer patients (13 locally advanced and 51 metastatic) whose ECOG(Eastern Cooperative Oncology Group) performance status (PS) was 1-2 and who were treated with at least twocycles of weekly DCF protocol as first-line treatment were included retrospectively. The weekly DCF protocolincluded 25mg/m2 docetaxel, 25mg/m2 cisplatin, and 24 hours infusion of 750mg/m2 5-fluorouracil, repeated everyweek. Disease and patient characteristics, prognostic factors, treatment response, grade 3-4 toxicity related totreatment, progression free survival (PFS) and overall survival (OS) were evaluated. Results: Of the patients, 41were male and 23 were female; the median age was 63 (29-82) years. Forty-one patients were ECOG-1 and 23were ECOG-2. Of the total, 81.2% received at least three cycles of chemotherapy. Partial response was observedin 28.1% and stabilization in 29.7%. Overall, the disease was controlled in 57.8% whereas progression was notedin 42.2%. The median time to progression was 4 months (95%CI, 2.8-5.2 months) and median overall survivalwas 12 months (95%CI, 9.2-14.8 months). The evaluation of patients for grade 3-4 toxicity revealed that 10.9%had anemia, 7.8% had thrombocytopenia and 10.9% had neutropenia. Non-hematologic toxicity included renaltoxicity (7.8%) and thrombosis (1.6%). Conclusions: In patients with locally advanced or metastatic gastriccancer who were not candidates for DCF administered every-3-weeks, a weekly formulation of DCF demonstratedmodest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment optionfor such patients.     

Five-day continuous infusion of 5-fluorouracil for advanced colorectal, gastric, and pancreatic adenocarcinoma.

In a retrospective study, 58 patients with advanced colorectal carcinoma received one or more 5-day infusions of 5-FU at 20 mg/kg per 24 hours followed by weekly IV 5-FU at 15 mg/kg. In 36 patients who received the infusion as first treatment (Group A), the response rate was 23% with a median duration of response of 8.0 months. No improvement in survival was noted. In 22 patients treated with the infusion after relapse on weekly 5-FU (Group B), the response rate was 10.5% with a median duration response of 4.5 months. Stable disease for 3-6 months was seen in 21%. Survival in Group B was improved when compared with a similar group of patients treated by weekly 5-FU without infusion (Group CB), but statistical significance was not obtained. Twenty percent of patients were alive two years after relapsing on weekly 5-FU when given the five-day infusion 5-FU and re-initiated on weekly 5-FU. Toxicity to the five-day infusion of 5-FU was minimal. Three of 69 (4.3%) infusions were not completed because of toxicity. A separate review of procarbazine indicated that it was minimally active in colorectal carcinoma. Other patients with gastric and pancreatic carcinoma were reviewed but no statistical significance for 5-FU infusion was seen for survival. A five day continuous infusion of 5-FU is recommended for colorectal cancer patients who relapse on weekly 5-FU therapy. Further study of the infusion in combination with other chemotherapy is warranted.