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.     

PMC (pharmacokinetic modulating chemotherapy) for advanced gastric cancer

We performed pharmacokinetic modulating chemotherapy (PMC) postoperatively in patients with advanced gastric cancer and examined its antitumor and the side effects. Nineteen patients with advanced gastric cancer (all were above Stage II) were treated: 10 had undergone total gastrectomy and 9 distal gastrectomy. UFT (400 mg/day) was orally administered daily and a continuous infusion of 5-FU (600 mg/m2/24 hr) was given once a week. The average observation period was 14.26 months (4-30 months). All patients with Stage II or III disease have survived, but two patients with Stage IV disease died. One patient received insufficient PMC and the other had a liver metastasis. Two patients experienced Grade 3 inappetence, but all other side effects were Grade 2 or lower and the incidence was less than 25%. In conclusion. PMC has tolerable side effects and may be effective in postoperative chemotherapy for advanced gastric cancer.     

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.     

Treatment results of peritoneal dissemination from gastric cancer by neoadjuvant intraperitoneal-systemic chemotherapy

No standard treatment exists for peritoneal dissemination from gastric cancer. We reviewed our experience using a novel treatment consisting of peritonectomy and intraoperative chemo-hyperthermic peritoneal perfusion (CHPP). Records of all patients who underwent CHPP and cytoreductive surgery from 1992 to 2001 were reviewed. RESULTS: Data from 107 patients (average age, 52 years) were available. P3 dissemination was found in 72 patients, and 8 and 27 patients showed P1 or P2 dissemination, respectively. Peritoneal metastasis was synchronous in 75 and metachronous in 32 patients. All patients received CHPP after cytoreductive surgery. Peritonectomy was performed in 42 patients. Complete cytoreduction (CC-0) was achieved in 47 patients (44%). Peritonectomy, resulted in CC-0 in 69% (29/42), but CC-0 was achieved in 18 of 65 (28%) patients by ordinary surgical techniques. There were 23 postoperative complications (21%) after operation. The overall operative mortality was 2.8% (3/107). Median follow-up for the entire study group was 46 months. Seventeen patients (15%) were disease-free, and 90 patients were dead at the time of analysis. Eighty-seven deaths were related to progression of disease. The median survival of all patients was 16.2 months, with an actual 5-year survival of 6%. Median survival of CHPP plus ordinary cyoreduction was 12.0 months and that after CHPP and peritonectomy was 22.8 months. Completeness of cytoreduction and peritonectomy were significant prognostic factors on univariate analysis and 5-year survival rate was 27%. Lymph node status, grade of peritoneal dissemination (P1-2 vs P3), age (>60 years vs <60 years), tumor volume of dissemination (>2.5 cm vs <2.5 cm in diameter), and histologic type (differentiated vs. poorly differentiated type) did not affect survival. The cox proportional model demonstrated that completeness of cytoreduction was the strongest prognostic factor. Patients who had an incomplete resection had 2.8-fold higher risk of dying from disease than patients who underwent complete cytoreduction. The 5-year survival after complete cytoreduction was 12%, compared with 2% for incomplete resection. Four patients lived more than 5 years. Cytoreduction was incomplete in one 5-year survivor who showed complete response to CHPP. CONCLUSION: Complete cytoreduction using peritonectomy and CHPP may improve survival of patients with peritoneal dissemination from gastric cancer. This procedure is most appropriate for highly motivated patients who are committed to survive as long as possible.     

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.     

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.     

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.     

Modified pharmacokinetic modulating chemotherapy using 5-fluorouracil,UFT, and taxotere (docetaxel) for advanced gastric cancer

The efficacy of neoadjuvant chemotherapy for advanced gastric carcinoma is controversial. Moreover, a standard regimen for such chemotherapy has not been clearly established. Pharmacokinetic modulating chemotherapy (PMC), a combination of infused 5-fluorouracil and oral uracil-tegafur, has been proven to be highly effective for the treatment of colorectal carcinoma. We report two patients with advanced gastric carcinoma successfully treated with PMC and infused taxotere (TXT; docetaxel). Preoperative treatment with PMC and TXT significantly decreased the depth of wall penetration of the tumor in one patient and reduced the size of the tumor in the other patient. In both patients, there were significant chemotherapeutic effects on the primary tumor and on regional lymph nodes pathologically. Preoperative PMC plus TXT produced primary tumor downstaging, leading to improved resectability. The responsiveness of metastatic cancer cells in the regional lymph nodes suggested the possibility of nodal downstaging by this regimen.     

A case of nonresectable scirrhous type gastric cancer treated by hypertensive subselective chemotherapy with pharmacokinetic modulating chemotherapy

There have been few effective chemotherapeutic regimens for scirrhous type gastric cancer. A 62-year-old male patient was admitted to our hospital because of anorexia and abdominal discomfort. Gastroendoscopy showed a type 4 advanced gastric cancer in the upper gastric body. Histologic study of biopsy specimens from the tumor revealed poorly differentiated adenocarcinoma. Examination by computed tomography and ultrasonography revealed swollen paraaortic lymph nodes and peritonitis carcinomatosa. The patient was diagnosed as having a nonresectable scirrhous type gastric cancer with peritonitis carcinomatosa and paraaortic lymph node metastasis. This patient was treated weekly with an intraarterial 5-FU (500 mg) and MTX (100 mg) including AT-II by a subcutaneously implanted port system placed into the thoracic aorta. Furthermore, he was administered tegafur/uracil (400 mg/day) 5 days weekly as a pharmacokinetic modulating chemotherapy (PMC). After eight courses of treatment of PMC, paraaortic lymph node swelling and ascites decreased. This chemotherapy produced a partial response in the peritonitis carcinomatosa and paraaortic lymph nodes. This chemotherapy was repeated preoperatively. We reconsidered this case to show indications for operation. The patient died suddenly of acute heart failure before the operation. This therapy was considered an effective treatment for nonresectable gastric cancer.     

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.     

Effective therapy for peritoneal dissemination in gastric cancer

Peritoneal dissemination is the most frequent cause of death from gastric cancer, accounting for death in 20% to 40% of patients. Preoperative intraperitoneal chemotherapy, peritonectomy, intraoperative chemohyperthermic perfusion, and early postoperative intraperitoneal chemotherapy are treatment modalities specifically designed to eliminate peritoneal dissemination and progression. Preoperative intraperitoneal chemotherapy is for containment of peritoneal free cancer cells, and also may facilitate complete eradication of visible peritoneal dissemination by peritonectomy. Further, complete cytoreduction can be achieved more often when peritonectomy is included in the surgical treatment of gastric cancer with peritoneal dissemination. Phase III data shows prolonged survival attributed to complete cytoreduction. Aggressive cytoreduction of peritoneal dissemination by peritonectomy can reduce residual tumor burden to micrometastases on the peritoneal surface that can be treated by intraoperative intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. Among all these modalities, surgical cytoreduction is probably the most important for survival benefit. If the surgical cytoreduction is visibly incomplete, prolonged survival cannot be expected, despite subsequent treatment. The surgeon's goal is to reduce the cancer cell burden to a microscopic level. Continued refinement of phase II studies is needed for maximal benefit and to standardize the technical and chemotherapeutic options of each modality.     

Safety of intraperitoneal chemotherapy with paclitaxel in gastric cancer patients with peritoneal dissemination

We evaluated the safety of paclitaxel (TXL) via intraperitoneal (i.p.) administration in 6 patients with peritoneal dissemination of gastric cancer. Four patients were treated with TXL via i.p. administration at a dosage of 80-90 mg/m2 every 1 to 2 weeks. Grade 4 leukopenia was observed in 1 patient, accompanied with massive ascites. Two other patients, who also had malignant peritoneal effusion, were treated with TXL via i.p. administration at a dosage of 60 mg/m2 every 1 to 2 weeks. All toxicities were mild in those two patients. TXL via i.p. administration at a dosage of less than 90 mg/m2 has never been reported to cause a grade 4 leukopenia. These results suggest that a phase I/II study of TXL via i.p. administration should be tried in gastric cancer patients with malignant peritoneal effusion.     

Cytoreductive surgery and sandwich therapy with chemohyperthermic peritoneal perfusion and intra-aortic chemotherapy for peritoneal dissemination in gastric cancer

Cytoreductive resection (RST), chemohyperthermic peritoneal perfusion (CHPP) and/or intra-aortic chemotherapy (IA-chemo) were performed for peritoneal dissemination in gastric cancer. Ninety-six patients with peritoneal dissemination were grouped into tubercular (TB), 40; nodular (ND), 31; diffuse (DF) type, 19; and others, 6, respectively, by the gross findings. Sixty-three patients underwent RST. Fifty-nine patients received CHPP by 10-liter heated saline. Thirty patients underwent intra-aortic catheterization for the IA-chemo. The 1-year and 2-year survival rate (1-ysr and 2-ysr) of the RST(+) group were 47% and 10% significantly greater than the 9% and 0% of the RST(-) group (p<0.001). The 1-ysr and 2-ysr of the CHPP(+) group were 37% and 11% significantly greater than the 27% and 0% of the CHPP(-) group (p=0.04). In the TB type the 1-ysr and 2-ysr of the former was 43% and 8% significantly greater than the 15% and 0% of the latter (p=0.04). But there was no significant difference in survival time between the CHPP(+) and the CHPP(-) group in the ND type (p=0.22) or in the DF type (p=0.42). The 1-ysr and 2-ysr of the IA-chemo(+) group were 49% and 19% significantly greater than the 27% and 2% of the IA-chemo(-) group (p<0.01). In the DF type the 1-ysr and 2-ysr of the former was 50% and 33% significantly greater than the 8% and 0% of the latter (p=0.02). However, there was no significant difference in survival time between the IA-chemo(+) and the IA-chemo(-) group in the TB type (p=0.06) or in the ND type (p=0.50). Moreover, the effect of the combination therapy of CHPP and IA-chemo (the sandwich therapy, SDW) were examined. The 1-ysr and 2-ysr of the SDW(+) group were 49% and 22% significantly greater than the 24% and 0% of the SDW(-) group (p=0.002). The sandwich therapy should be performed in addition to cytoreductive surgery for improvement of prognosis in the patient with intractable peritoneal dissemination.     

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.     

Treatment strategy for primary gastric cancer with peritoneal dissemination

Curative resection is considered to be a standard therapy for gastric cancer with localized peritoneal metastases. For tumors with diffuse dissemination, chemotherapy may play a major role, however, the benefits of reduction surgery and standard chemotherapy have not yet been clarified. Median survival time after reduction surgery was reported to be 4-13 months for patients diagnosed by surgery and/or CT and 5-6 months for chemotherapy for those diagnosed by CT alone. Reduction surgery has a high risk, with a morbidity of 12-44% and a mortality of 3-14%. Palliative surgery should be indicated for stenosis or bleeding due to primary tumors. 5-FU, MTX-5-FU, TS-1, paclitaxel, and their combination are candidates for practice and clinical trials. It is important to evaluate the severity of peritoneal dissemination by diagnostic laparoscopy or laparotomy for decision making.     

Neoadjuvant chemotherapy with S-1 and surgical resection for a mucinous gastric cancer with peritoneal dissemination

We herein report the case of a patient with mucinous gastric carcinoma with peritoneal dissemination that disappeared after neoadjuvant chemotherapy with S-1 alone. The patient has survived for over 23 months after surgery, without recurrence. A 60-year old man was referred to our hospital because of an advanced gastric cancer, detected by upper gastrointestinal endoscopy at another hospital. Staging laparoscopy was performed on October 25, 2002, and revealed massive peritoneal dissemination. Two courses of neoadjuvant chemotherapy with S-1 were administered, at 120mg/day for 28 days, as one course. Total gastrectomy, with D2 lymph node dissection, was performed on January 24, 2003. The peritoneal dissemination had macroscopically disappeared and the cytology of the peritoneal lavage fluid was class III. His final diagnosis was gastric carcinoma, MLU, type 3, T2(SS), P0, H0, M0, N3, CY0, stage IV.     

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.     

Effectiveness of continuous hyperthermic peritoneal perfusion for the peritoneal dissemination of gastric cancer

We investigated the effectiveness of continuous hyperthermic peritoneal perfusion (CHPP) for the peritoneal dissemination of gastric cancer. A total 124 patients with advanced gastric cancer were enrolled in this study. Prophylactic CHPP (P-CHPP) was performed in 45 patients who had macroscopic serosal invasion without peritoneal dissemination, and 79 patients without CHPP were a control group. Therapeutic CHPP (T-CHPP) was performed in 21 patients with peritoneal dissemination, and 52 patients without CHPP were a control group. There was no significant difference in 5 year survival between patients treated and not treated with P-CHPP. Univariate analysis showed that location of tumor, tumor diameter, and lymph node metastasis influenced prognosis, but there was no prognostic factor in the Cox proportional regression hazard model. There was no significant difference in 5-year survival between patients treated and not treated with T-CHPP. Univariate analysis showed that degree of peritoneal dissemination and adjuvant chemotherapy influenced prognosis, and the Cox proportional regression hazard model showed that the macroscopic types and degree of peritoneal dissemination affected prognosis. In the patients with CHPP, the incidences of respiratory failure and renal failure were each statistically greater than in the patients undergoing CHPP.