Pharmacologic study of intraperitoneal paclitaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of paclitaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Fourteen patients with peritoneal dissemination were entered in the trial. Three distinct dose levels from 120 to 180 mg/body were studied. A major pharmacokinetic advantage (550-2,000 fold) for peritoneal cavity exposure compared with the systemic compartment was seen following intraperitoneal delivery of paclitaxel. The dose-limiting toxicity was found to be abdominal pain at 180 mg/body. Grade 2 toxicity included 1 episode of neutropenia and grade 1 toxicities included 1 case of finger-numbness and 2 of alopecia. We conclude that intraperitoneal paclitaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

Intraperitoneal chemotherapy in gastric cancer patients with peritoneal dissemination

Peritoneal dissemination is one of the non-curative factors in gastric cancer and colon cancer. Although many treatments have been conducted for peritoneal dissemination, no standard chemotherapy has yet been established. For sometime we had used continuous hyperthermic peritoneal perfusion (CHPP)for peritoneal dissemination in gastric cancer and colon cancer. CHPP has a marked survival benefit for scirrhous type gastric cancer patients without liver metastasis. Patients with prophylactic CHPP have significantly better prognoses than those without prophylactic CHPP, and therapeutic CHPP has a survival benefit for gastric cancer patients with slight to moderate peritoneal dissemination (P 1-2). But CHPP has no significant prognostic benefit for gastric cancer patients with severe peritoneal dissemination (P 3). Therefore, a new cancer treatment is needed for those patients. On the other hand, many kinds of anticancer agents, including cisplatin, via intraperitoneal (ip) administration have been tried thus far for peritoneal dissemination therapy. Especially, intraperitoneal taxane anticancer agent is very effective for the treatment and local control of severe peritoneal dissemination in gastric cancer. A phase I/II study of taxane anticancer agents via ip administration should be tried in gastric cancer patients with peritoneal dissemination.     

Effect of intraperitoneal chemotherapy on experimental peritoneal dissemination of gastric cancer

In vitro chemosensitivity test using a collagen-gel method was done on 165 primary gastric cancers. All of 5-FU, CBDCA, CDDP and docetaxel showed a high sensitivity. The effects of per oral (po) administration of TS-1, a combination of po TS-1 and intraperitoneal (ip) administration of CDDP, ip 5-FU and ip docetaxel, were evaluated in athymic mice bearing peritoneal dissemination of a gastric cancer cell line (MKN-45-P that shows a high rate of metastasis to the peritoneal cavity of nude mice). Nude mice were inoculated by ip with 10(7) MKN-45-P cells. No survival benefit was obtained after po administration of TS-1 (12 mg/kg) alone or ip CDDP alone. However, a combination of po TS-1 (8 mg/kg x 10 days, from day 3) and ip CDDP (3.5 mg/kg, day 6 and 13) showed a significant survival improvement than that of po TS-1 or ip CDDP treatment alone. ip administration of 30 mg/kg (3 times/week x 3 weeks) or 15 mg/kg (6 times/week x 3 weeks) of 5-FU significantly improved the survival of mice bearing MKN-45-P. 5-FU concentration of ascites after ip administration of 30 mg/kg of 5-FU was 600-fold higher than po administration of 12 mg/kg of TS-1 at peak level. ip injections of docetaxel of 8 mg/kg, and 2 mg/kg improved the survival of 4 and 1 mice, respectively, and they were tumor-free on day 90. Survival of mice treated with ip injection of CBDCA (100 mg/kg, on day 3, or 50 mg/ kg on day 3 and 10) was significantly better than the control group. These results suggest the potential of po TS-1 + ip CDDP, ip 5-FU, ip docetaxel and ip CBDCA administration for the treatment of peritoneal dissemination of gastric cancer.     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

Repeated intraperitoneal chemotherapy for peritoneal dissemination from gastric carcinoma

Repeated intraperitoneal chemotherapy (RIC) via i.p. port was carried out in 16 patients with peritoneal dissemination P(+) and 8 with positive washing cytology P0.cy (+). CDDP with/without MMC soluted by physiological saline was periodically administered via i.p. port. The average administration was 5.6 times (2-16, median: 6) and the average dose was 288.0 mg. As the results, negative change of washing cytology after RIC was found in 71%, with a high rate especially in P0.cy (+) cases. Also, median survival time (MST) of responders was statistically longer than that of non-responders (777 days vs 254 days). Although diarrhea and anorexia of grade 3 developed once in each one patient, serious toxicities were not found. In conclusion, RIC is effective for peritoneal dissemination, especially P0.cy (+) cases, from gastric carcinoma.     

Repeated intraperitoneal chemotherapy for peritoneal dissemination from gastric carcinoma

Repeated intraperitoneal chemotherapy (RIC) via an i.p. port system was carried out in 16 patients with peritoneal dissemination (P1) and in 10 with positive washing cytology (P0.CY1) from gastric carcinoma. CDDP dissolved in 500-1,000 ml of physiological saline solution was periodically administered via the i.p. port system. The change of washing cytology (CY), which was obtained from i.p. port, was examined before each administration as a indicator of the response. The average number of administrations was 5.7 and the average total dose was 301.7 mg. As a result, a negative change of CY after RIC was found in 74% of patients, and also more than 80% of the response occurred within three administrations. The prognosis tended to be better in P0.CY1 patients than in P1 patients. In particular, the median survival time of the CY responders markedly improved as compared with non-responders (27.8 months versus 7.1 months). Although diarrhea and anorexia of grade 3 developed once in each patient, serious toxicities were not found. In conclusion, we consider RIC to be an effective therapy for P0.CY1 among cases with peritoneal dissemination from gastric carcinoma.     

Safety and efficacy of hypotonic CDDP intraperitoneal administration for gastric cancer with peritoneal dissemination

We examined safety and efficacy of hypotonic CDDP intraperitoneal administration followed by systemic chemotherapy using MTX/5-FU and UFT. Between 1998 and 2004, seven patients who had histologically proven gastric adenocarcinoma with peritoneal metastases underwent palliative gastrectomy at Niigata University Medical Hospital. For residual peritoneal tumors, 100 mg/body of CDDP diluted with distilled water was intraperitoneally administered to the patients before closure of abdominal wall and was drained 30 to 60 minutes after administration. During the postoperative period, a patient suffered from intraperitoneal abscess and another patient had a renal dysfunction with an increasing level of serum Cr (2.1 mg/dl). As adverse effects of the following systemic chemotherapy, three patients had grade 3 anemia and one had grade 3 leukopenia. The median time to progression was 109 days and the median survival time was 248 days. Although intraperitoneal CDDP administration is safe to be carried out intraoperatively, the effect on survival is not better than new anticancer drugs, such as TS-1 and paclitaxel.     

Neoadjuvant chemotherapy for gastric cancer with peritoneal dissemination

An early detection and treatment of gastric cancer with peritoneal dissemination are rather difficult so that a clinical trial has been neglected. Therefore, we introduced a pre-operative peritoneal lavage diagnosis for gastric cancer patients with serosa-invaded tumors. Neoadjuvant chemotherapy was introduced to patients with positive cytology and with no non-curative factors except peritoneum. The neoadjuvant chemotherapy followed by surgery was done safely. The patients with the disappearance of CY and P factors due to neoadjuvant chemotherapy had a better prognosis than those with positive results of CY or R However, many of the patients with negative results from peritoneum eventually suffered a peritoneal recurrence. We started another protocol study with S-1 and an intra-peritoneal chemotherapy using docetaxel. The efficacy in the protocol result will be expected.     

Effectiveness of intraperitoneal chemotherapy using new-aged drugs for the peritoneal dissemination of gastric cancer

We evaluated the effectiveness of intraperitoneal chemotherapy for peritoneal dissemination of gastric cancer. A total of 104 patients with primary gastric cancer with peritoneal dissemination were enrolled in this study. In 72 of the 104 patients with gastrectomy performed, 5 patients underwent CDDP-ip (50-100 mg/100-200 ml), 16 patients underwent CHPP (CDDP 300 mg, MMC 30 mg, ETP 150 mg/8 l/42-43 degrees C/60 min), and 17 patients underwent CMV-ip (CDDP 150 mg, MMC 20 mg, ETP 100 mg/1 l/60 min). The prognosis of patients who underwent CMV-ip was significantly better than those who received other therapies. In 26 patients with severe peritoneal dissemination who were treated with TS-1 (60 mg/m2) and taxane-ip (docetaxel 40-60 mg/body or paclitaxel 120-180 mg/body), 9 of 18 responders performed complete cytoreduction. The median survival time (MST) in these 9 patients was 944 days and a 2-year survival rate was 63%. A multimodal therapy consisting of systemic chemotherapy, intraperitoneal chemotherapy and complete cytoreductive surgery may provide good prognosis to the gastric cancer patients with peritoneal dissemination.     

Safety and efficacy of chemotherapy using TS-1 followed by paclitaxel for advanced or recurrent gastric cancer with peritoneal dissemination

There has been no standard treatment for gastric cancer with peritoneal dissemination. We have used TS-1 followed by paclitaxel for advanced or recurrent gastric cancer patients with peritoneal dissemination since January 2002. Twenty-three patients were enrolled to our prospective study and 19 of 23 patients completed the protocol. There were less severe adverse events concerning paclitaxel despite of the second line therapy of TS-1, and 80 percent of all therapeutic courses was at an outpatient clinic. The median time to progression was 199 days. The median survival time was 363 days in all the enrolled patients, and was 436 days in 19 patients who completed the protocol. Chemotherapy using TS-1 followed by paclitaxel is considered to be safe and effective for gastric cancer with peritoneal dissemination.     

Intraoperative intraperitoneal administration of CDDP against gastric cancer with peritoneal dissemination

This study was undertaken in order to evaluate the effect of intraoperative intraperitoneal (i.p.) administration of CDDP on patients who underwent gastrectomy for gastric cancer with peritoneal dissemination, compared with MMC or OK-432 i.p. administration group and untreated group. The median survival time was 11 months in CDDP i.p. group (35 patients), 8 months in MMC or OK-432 Ip group (33 patients) and 7 months in untreated group (25 patients). 1- and 2-year survival rates were 30.4% and 12.1% for MMC or OK-432 i.p. group, and 28% and 8% for untreated group, while in CDDP i.p. group, the rates were higher at 46.4% and 14.7%, respectively (CDDP i.p. group vs. untreated group, p less than 0.05). In vitro chemosensitivity test by succinate dehydrogenase inhibition (SDI) test supported the clinical results. CDDP had higher sensitivities than MMC and ADM on poorly differentiated cases as well as peritoneal dissemination cases. Our results suggest that intraoperative i.p. administration of CDDP was useful for the treatment of gastric cancer with peritoneal dissemination.     

Intraoperative chemotherapy against peritoneal dissemination of gastric cancer with intraperitoneal activated carbon particles adsorbing mitomycin C

For prevention and therapy of peritoneal dissemination, a new dosage from (MMC-CH) comprising carbon particles adsorbing mitomycin C was given to 44 patients (the MMC-CH group) undergoing gastrectomy for gastric cancer, of which advancing stage was classified into the category of H0, and S2 or S3, and P0, P1, P2 or P3 according to the General Rules for the Gastric Cancer Study. MMC-CH, principally at 50 mg person in terms of mitomycin C was administered intraperitoneally before the surgical wound was closed. Historical control group was composed of 53 patients not given MMC-CH, who underwent gastrectomy for gastric cancer in the same advancing stage as those of the 44 patients. There was statistically no significant difference of age, sex, depth of infiltration, macroscopically and microscopically defined progression of lymph-nodal metastases, between the MMC-CH group and the historical control group. The survival rate of the overall patients, and each group of the patients with the lesion defined as P0, P1, P2, or P3 was compared with Kaplan-Meier's method between the MMC-CH group and the historical control group. In the MMC-CH group, the survival rates of the overall patients and the patients with P0, P1, or P2 lesion were statistically significantly higher than those in the historical control group. However, the rate of the P3 patients in the MMC-CH group was statistically significantly lower than in the historical control group.     

The current situation and subjects of the intraperitoneal chemotherapy for peritoneal dissemination in gastric cancer

Many different chemotherapeutic modalities have been done for patients with peritoneal dissemination of gastric cancer. However, no regimen of chemotherapy has become the treatment of choice for the control of peritoneal dissemination. It is thought that intraperitoneal chemotherapy is effective to contact lesions directly and reduce its side effects. So, many kinds of anticancer agents, including cisplatin, via intraperitoneal administration have been tried for peritoneal dissemination therapy. However, they were not so effective. Recently, intraperitoneal taxane administration has proven very effective for the treatment and local control of severe peritoneal dissemination in gastric cancer. The response rate, including disappearance of as cites, was higher than that of MTX/5-FU systemic chemotherapy. There is no evidence that intraperitoneal taxane is significantly more effective than systemic chemotherapy in gastric cancer. But we considered that intraperitoneal taxane was promising for peritoneal dissemination therapy and organized the Society for the Study of Peritoneal Dissemination in Gastric Cancer. To determine the safety profile and activity of docetaxel via intraperitoneal administration combined with S-1 for gastric cancer patients with peritoneal dissemination, a multi-centric phase I/II study is being carried out now. A phase III study should be conducted in future for further understanding and cooperation in a smoothly undertaken investigation.     

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves the survival of gastric cancer patients with ovarian metastasis and peritoneal dissemination

The prognosis for ovarian metastasis of gastric cancer is poor. There is no currently available treatment for this disease. The purpose of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) in female gastric cancer patients with metachronous ovarian metastasis. From January 2000 to December 2010, 62 patients developed ovarian metastasis after undergoing gastrectomy with D2 lymphadenectomy. Thirty-two patients underwent CRS plus HIPEC, and 30 patients underwent CRS alone. The median age of all 62 patients was 44 years (range 19–71 years). Metastatic carcinoma involving bilateral ovaries was observed in 50 patients (80.6 %). The median survival time in the CRS?+?HIPEC group was 15.5 months (95 % confidence interval [CI] 12.1–18.9 months) but was only 10.4 months (95 % CI 8.5–12.2 months) in the CRS group (P?=?0.018). Among the 32 patients with pelvic peritoneal metastasis, a stratified analysis revealed that the median survival period for the 15 patients treated with CRS?+?HIPEC was significantly higher than that for the patients treated with CRS alone (P?=?0.046). Among the 30 patients who suffered from ovarian metastasis alone, the median survival times were similar in both groups (P?=?0.141). A multivariate analysis revealed that CRS?+?HIPEC and a low Peritoneal Cancer Index (PCI) were independent predictors for improved survival. In conclusion, our study indicates that employing the HIPEC procedure after CRS could improve the survival time of patients with ovarian metastasis with few complications; however, we do not recommend HIPEC treatment for ovarian metastasis alone.     

A case of gastric cancer with peritoneal dissemination successfully treated by S-1/paclitaxel combination chemotherapy

A 62-year-old woman visited our hospital with diarrhea, bloating, vomiting, and black stool. Borrmann-type 3 gastric cancer with hemorrhaging was revealed by stomach endoscopy. The biopsy showed a poorly-differentiated adenocarcinoma. Moreover, peritoneal dissemination was found by computed tomography and we combined S-1 80 mg/m2(4 weeks administration and week rest)with paclitaxel(PTX)50 mg/ m2 (day 1, 8, 15, 3 weeks rest). After 2 courses, endoscopy showed tumor shrinkage. Therefore, we conducted total gastrectomy with resection of gall bladder and spleen. The final findings were Stage II .We conducted S-1/PTX combination chemotherapy(4 courses)followed by monotherapy as adjuvant chemotherapy. Recently, the woman had been living without relapse four years after operation.     

A phase I study of intraperitoneal plus intravenous paclitaxel against gastric cancer with peritoneal dissemination (HGCG 0301)

The safety of the intraperitoneal (ip) plus intravenous (iv) paclitaxel against gastric cancer with peritoneal dissemination was evaluated on a phase I dose escalation trial. Patients were treated with ip paclitaxel administered in 500 ml of normal saline before closing the abdomen, using the following dose levels: level 1, 50 mg/m(2); level 2, 60 mg/m(2); level 3, 70 mg/m(2); and level 4, 80 mg/m(2), followed by iv infusion of the same doses of paclitaxel on days 14 and 21. Twelve patients were enrolled in this study: 7 underwent reduction surgery,while 5 had only a laparotomy. ip therapy was well tolerated, and did not bring about any postoperative complications even in patients who underwent gastrectomy. Although multiple NCI/CTC grade 1 toxicities and grade 2 anemia (4 of six patients at dose levels 2 and 3) were observed, there was no dose-limiting toxicity. The overall median survival time was 316 days, and that for patients who underwent gastrectomy was 413 days. Paclitaxel at a dose of 80 mg/m(2) can be delivered by the operative ip route with acceptable toxicity profile.     

A case of gastric cancer with peritoneal dissemination responding to combination chemotherapy with oral fluoropyrimidine and weekly paclitaxel

We report a case in which combination chemotherapy with oral fluoropyrimidine and weekly paclitaxel was effective for gastric cancer with peritoneal dissemination. A 44-year-old woman suffering from advanced gastric cancer with peritoneal dissemination underwent total gastrectomy. After surgery, combination chemotherapy with doxifluridine plus weekly paclitaxel was administered on an outpatient basis, and was effective without any sign of relapse of the disease for a year. However, she complained of dull abdominal pain, and ascites was observed 13 months after surgery. She received combination chemotherapy with S-1 plus weekly paclitaxel. The ascites decreased after 3 courses of the chemotherapy. No major adverse effect was observed except for grade 1 anemia and grade 2 hair loss. She has been well with the chemotherapy on an outpatient basis 18 months after surgery.     

A case of recurrent biliary tract cancer with peritoneal dissemination treated with intraperitoneal chemotherapy

We report a case of postoperative dissemination of intrahepatic biliary tract cancer subsequently treated with intraperitoneal chemotherapy combined with systemic chemotherapy. A 61-year-old-woman who underwent hepatic resection 18 months before was admitted for abdominal distension. CT scan revealed a recurrent tumor in her transverse mesocolon. We tried tumor resection but peritoneal dissemination was recognized, and intraperitoneal chemotherapy was started followed by systemic hemotherapy. For 34 months after the diagnosis of postoperative peritoneal dissemination, the patient has not suffered from abdominal distension and stenosis of the gastrointestinal tract. The CA19-9 level remained low for over 30 months. Intraperitoneal chemotherapy followed by systemic chemotherapy in this case seemed to delay the progression of disseminated tumor and to preserve the quality of life of the patient. The present case shows the effectiveness of intraperitoneal chemotherapy with or followed by systemic chemotherapy for patients who had peritoneal disseminations.     

Studies of the effectiveness and optimal administration of repeated intraperitoneal chemotherapy for peritoneal dissemination from gastric cancer

The optimal interval for drug administration was examined for repeated intraperitoneal chemotherapy (IPC). The subjects were 31 patients who underwent curative surgical resection excluding P1 or CY1 factor, followed by IPC. IPC was carried out 180 times in total, and the intervals were divided into three groups: 2-week interval 45 times, 3-week interval 10 times and 4-week or greater interval 94 times. The optimal method of drug administration was evaluated from the therapeutic outcome and the development of adverse effects with each interval time. The cytology of ascites obtained via an i.p. port was examined before each drug administration, and those with a negative change (CY0) were judged as responders. The adverse effects in the patients receiving drugs at 2-week intervals were grade 1 or 2, although the incidence was high compared with other patients. All responders obtained a negative change in CY within six courses. At present, we conclude that it is reasonable for IPC to be carried out six times at 2-week intervals.