Usefulness of staging laparoscopy for advanced gastric cancer.

PURPOSE: The aim of this study was to clarify the usefulness of staging laparoscopy for planning the treatment strategy in patients with advanced gastric cancer. METHODS: This was a retrospective study of patients with gastric cancer who underwent staging laparoscopy. The patients were divided into three groups according to the presence/absence of peritoneal metastasis (P) and positive peritoneal cytology (CY): P negative (0) CY0, P0CY positive (1), and P1CY1. The treatment strategy after staging laparoscopy was as follows: (1) surgery for the P0CY0 group, (2) surgery with neoadjuvant chemotherapy (NAC) for the P0CY1 group, and (3) chemotherapy for the P1CY1 group. Survival was estimated by the Kaplan-Meier method and statistical differences were analyzed by the log-rank test. RESULTS: Thirty-four patients were included in this study: 11 in the P0CY0 group, 13 in the P0CY1 group, and 10 in the P1CY1 group. A gastrectomy was done in 11, 10, and no patients, respectively. The survival rate of the P0CY0 patients was significantly better than that of the P0CY1 or P1CY1 patients (P = 0.0106 and 0.0031, respectively). CONCLUSION: Staging laparoscopy is useful for planning the treatment strategy and estimating the prognosis of patients with advanced gastric cancer.

[A case of unresectable advanced gastric cancer successfully treated with continuous S-1 + CPT-11 chemotherapy accompanied by dose reduction against grade 4 hematological adverse event].

We report a successful case of chemotherapy accompanied with grade 4 adverse events for unresectable advanced gastric cancer. A 73-year-old man was admitted to our hospital with complaint of abdominal pain in July 2007. The detailed examination had revealed advanced gastric cancer, lymph node metastasis, and multiple hepatic metastases. Performance status (PS) was level 0, and oral intake of medications was possible. Combined therapy with S-1 and CPT-11 (IRIS regimen) was performed from August as the first-line therapy. As a consequence of first course, grade 4 hematological adverse events (AEs) appeared and an urgent hospitalization was required. With whole body supportive care against grade 3 non-hematological AEs, which were diarrhea, anorexia, and fatigue, G-CSF, the broad-spectrum antibiotic were administered at the clean-room. After 1 course, cyto-reductive change was confirmed at the primary lesion and hepatic metastases. We continued the same regimen with dose reduction (S-1: 2 level dose down, CPT-11: 10% dose down). Although the regression of hepatic metastases was seen, we repeated the dose reduction of CPT-11 and the dose down level was reached to 40% for prolonged grade 2 neutropenia. After 6th courses, complete responses at primary lesion, lymph node, and hepatic metastases were achieved. The patient has received the same regimen of 9th course continuously as an outpatient, and CR has been maintained.

[A case of liver and lung metastases in gastric cancer successfully treated with S-1 and paclitaxel mono-therapy].

A 65-year-old male underwent a curative distal gastrectomy for advanced gastric cancer in June 2000. S-1 mono- therapy (80 mg/m2, day 1-28/42 days) for liver metastasis in S6 started as the first-line chemotherapy in October 2004. After 3 courses, complete response (CR) was observed for liver metastasis which had continued until January 2007. During the first-line chemotherapy, grade 2 non-hematological toxicities occurred and the S-1 dose reduction was required. Thereafter, no more grade 2 non-hematological toxicities were observed. Paclitaxel mono-therapy (80 mg/m2, day 1, 8, 15/28 days) for multiple lung metastases started as the second-line chemotherapy in February 2007. After 4 courses, complete response (CR) was observed for lung metastasis which has continued until now, May 2008. During the second- line chemotherapy, grade 3 neutropenia and grade 2 leukopenia occurred and a 10% dose reduction of paclitaxel was required three times. Consequently, the hematological toxicities have not occurred.

[Management of hand-foot syndrome in patient treated with capecitabine].

Capecitabine is one of the most effective oral regimens of chemotherapy against advanced or recurrent breast cancer. In addition, capecitabine could widely be used for treatment of colon cancer. It appears that more patients will be administered capecitabine because of its QOL benefits. However, Hand-Foot Syndrome(HFS)may appear to be about 50% of the patients who take this regimen. As a result, the patient's QOL is hindered and led to a reduction of the dosage or discontinuation of the treatment depending on the grade of adverse event. This time, we evaluated the efficacy of topical emollients, creams and vitamin B6 for prevention and reduction of HFS symptoms for patients who received capecitabine. We found the efficacy of preventative measures that the occurrence of HFS grade 1 or above could be decreased and delayed. We also noticed that these preventative measures appear to be decreased the occurrence of HFS grade 2 or above, which led to a reduction of dosage or discontinuation of the treatment. For continuation and completion of the treatment and securing of patient's QOL, the supportive measures are needed to control a variety of side effects, such as HFS and others, and a team care support is indispensable.

[A case of advanced gastric cancer treated with chemo-radiotherapy as the fourth-line therapy].

A 69-year-old female patient with type 2 advanced gastric cancer (s-T4N0M0H0Cy0P0, f-Stage IIIA) located from lower corps to antrum underwent a distal gastrectomy with D2 lymphandectomy in May 2006. After surgical treatment, S-1+ docetaxel combined chemotherapy was started for pEM (+) due to direct invasion to pancreas head as the first-line chemotherapy. However, the local recurrence whose diameter was 24 mm at pancreas head was detected with enhanced CT in December 2006. Moreover, nevertheless CPT-11+CDDP combined chemotherapy or paclitaxel monotherapy as the second or the third-line chemotherapy, respectively, the diameter of the local recurrence enlarged to 38 mm in November 2007. Therefore, chemo-radiotherapy using with S-1 and CDDP was started in December 2007 and the diameter of local recurrence was reduced to 25 mm in January 2008. No adverse event of grade 3 or more occurred during chemo-radiotherapy except for grade 3 of neutropenia. Chemo-radiotherapy for this gastric-cancer patient with local recurrence of multiple anti-tumor drug resistance was effective and safe.

[Equalization of spread of breast cancer chemotherapy regimen at general hospitals--with EC and FEC regimens].

We investigated the differences in safety and management of adverse events of chemotherapy among three hospitals, Sakai Municipal Hospital, Takarazuka Municipal Hospital and National Hospital Organization Osaka-minami Medical Center. The main purpose of this study was to equalize the spread of breast cancer chemotherapy regimen. The following three regimens were evaluated; epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) (EC75), epirubicin (75 mg/m(2)) /cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC75) and epirubicin (100 mg/m(2)) / cyclophosphamide (500 mg/m(2)) /5-fluorouracil (500 mg/m(2)) (FEC100). Sixty-three patients were evaluated. We studied the level of myelosuppression after each regimen. As a result, there was no significant difference in neutrocyte counts at nadir after chemotherapy among hospitals and regimens. However, the values tended to be ranked EC75>FEC75>FEC100. In addition, we examined the risk of febrile neutropenia (FN) according to the multi- national association for supportive care in cancer (MASCC) scoring system. Almost all patients (61/63) were in the low risk group of FN, and only two patients had developed FN. At one hospital, patients receiving chemotherapy were prescribed ciprofloxacin tablets prophylactically for prexia over 38 deg C, and the patients learned from it. Thus, no marked difference in the safety (side effects such as myelosuppression) was recognized. However, management of side effects was different among these hospitals. In conclusion, it is very important to provide patients with adequate information on side effects.

[A case of unresectable gastric cancer successfully treated with combination chemotherapy of S-1 + CPT-11].

A 70-year-old female, with type III gastric cancer underwent a staging laparoscopy in September 2004. Judging from the results of endoscopy, enhanced CT and staging laparoscopy, we finally diagnosed the patient with stage IV (T3N2MOHOP1CY1), and we started a combination chemotherapy of S-1 + CPT-11 (S-1: 80 mg/m2, day 1-21/35 days, CPT-11: 80 mg/m2, day 1, 15/35 days) from October 2005 to January 2007. Enhanced CT after 2 courses of the combination chemotherapy showed partial response (PR) in the primary lesion. PR continued up to the 13 courses. The CT and gastro fiberscope finally showed complete response (CR) with Group I in biopsy. During these procedures, the grade 3 of neutropenia, grade 1 of diarrhea and grade 1 of fatigue occurred as adverse events. In January 2007, Virchow and, abdominal lymph node metastases were detected, and that we judged the metastases as progressive disease (PD). Nevertheless, the second-line of paclitaxel chemotherapy (70 mg/m2, days 1, 8,15/28 days) has started and she was being judged PD after 2 courses, she died in April 2007.

[A case of S-1 resistant multiple lung metastases after curative total gastrectomy for gastric cancer successfully treated by S-1 combined with CPT-11 as the third-line chemotherapy].

A 78-year-old female underwent a curative total gastrectomy with D2 lymphandectomy for advanced gastric cancer in March 2003. S-1 mono-therapy (80 mg/m2, day 1-28/42 days) began as the first-line chemotherapy from October 2004 when multiple lung metastases were detected by CT. Paclitaxel mono-therapy (80 mg/m2, days 1, 8, 15/28 days) began as the second-line chemotherapy from April 2005 when prior S-1 mono-therapy judged as progressive disease (PD) by CT. Paclitaxel mono-therapy judged it as partial response (PR) in June, but the final judgement was as PD in September 2005. S-1 + CPT-11 combination therapy (S-1: 80 mg/m2, day 1-21, CPT-11: 80 mg/m2, days 1, 15/35 days) began as the third-line chemotherapy from September 2005. After 10 courses, multiple lung metastases were judged as complete response (CR) in September 2006. During the third-line chemotherapy, any adverse event of grade 2 or more did not occur. After judgment of CR, the patient has been followed without chemotherapy due to patient's desire, and is still alive without any recurrence in July 2007.

[A case of advanced gastric cancer which has kept partial response with the fifth-line chemotherapy].

We report a case of a 48-year-old male with advanced gastric cancer. A total gastrectomy was performed for cancer of remnant stomach. S-1 was administered for cytological cancer cells detected by abdominal cavity lavage as the first-line chemotherapy. After 2 cycles of S-1, cervical lymph nodes were enlarged, and the patient underwent paclitaxel monotherapy as the second-line chemotherapy. After 8 cycles, Virchow lymph nodes were enlarged. The regression of Virchow lymph nodes were observed with a S-1 /CPT-11 combination therapy as the third-line chemotherapy and DOC/CPT-11 as the fourth-line chemotherapy. We then used a combination chemotherapy of CPT-11 60 mg/m2 and CDDP 30 mg/m2 at day 1 and 15, every 4 weeks as the fifth-line chemotherapy. A partial response was achieved after 2 cycles, and has been continued for 7 months. The hematological toxicities and the non-hematological toxicities of grade 2 or higher were not observed. This regimen may be effective for patients with advanced gastric cancer resistant to prior chemotherapy with several agents.

[A case of advanced gastric cancer with obstructive jaundice due to liver metastases successfully treated with chemotherapy].

We report a successful case of chemotherapy for primary far-advanced gastric cancer accompanied with poor general condition related to jaundice due to hepatic metastasis. A 54-year-old man, who had been admitted to another hospital in October 2006 with a complaint of tarry stool, was referred to our hospital. The result of detailed examination revealed an advanced gastric cancer, multiple lymph node metastases and jaundice (T-Bil 3.3 mg/dL) due to multiple hepatic metastases. The performance status (PS) was level 4. In parallel with a whole body control, a combined therapy with S-1 and CPT-11 was performed from October 27 as the first-line therapy. As a consequence of the first course, the jaundice disappeared. After the second course, the patient left the hospital. However, the patient was re-admitted to hospital in January 2007 by a reason of fever and a deterioration of PS. As exacerbation of cancerous peritonitis and the primary tumor were seen, a weekly paclitaxel therapy was performed as the second-line therapy. Two courses of treatment resulted in the disappearance of ascites and a reduction of hepatic/lymph node metastasis. PS was improved to level 0 as well. After these therapies, the patient was discharged from the hospital. As of June 2007, he continuously receives chemotherapy as an outpatient.

[Neoadjuvant therapy with imatinib mesilate for gastrointestinal stromal tumor of the stomach before subsequent successful surgical resection].

A 65-year-old man is presented here with a huge mass of 13 cm in diameter in the left upper abdomen. Histopathologic assessment of endoscopic forceps biopsy revealed a c-kit positive gastrointestinal storomal tumor (GIST) of the stomach. Abdominal computed tomography (CT) showed a direct invasion to the pancreas. Imatinib mesilate was administered as neoadjuvant therapy according to the NCCN Guidelines. Imatinib mesilate therapy was stopped within 2 weeks because of adverse events such as Grade 2 of facial edema and dizziness. However, no hematological adverse event was shown. After three months of treatment (relative dose intensity was 87.5%), CT revealed a reduction in tumor diameter of 35.6% and showed no longer a direct invasion to the pancreas. The radical operation was considered feasible and partial gastrectomy was performed. The tumor was well encapsulated and radical surgery was possible without rupture. Adjuvant therapy was not performed. The patient has now been in good health without a recurrence for three months after the surgery.

[A case of an elderly patient with gastric cancer successfully treated with TS-1 considering impaired renal function caused by aging].

A 75-year-old female patient with impaired renal function caused by aging was treated with TS 1 for gastric cancer with extensive multiple liver metastases. TS-1 contains CDHP, which inhibits DPD activity and maintains a high blood concentration of 5-FU. Because CDHP is excreted from the kidney, a careful TS-1 administration is necessary for patients with impaired renal function considering an occurrence of severe adverse events. Based on the result previously reported by us about pharmacokinetic study and recommended administration dosage of TS-1 for patients with impaired renal function, we administered 50 mg/day of TS-1 for four weeks followed by two weeks rest per one course for this patient. The patient's creatinine clearance calculated by the Cockcroft-Gault method was 38 ml/min, and we reduced the administration dosage in consideration of her impaired renal function, although normal dosage of TS-1 calculated from body surface area for this patient was 100 mg/day. As this patient underwent TS-1 treatment, sizes of multiple liver metastases and the blood concentration level of CEA were gradually reduced, and the reductive rate of the former was more than 90% and the level of the latter fell to a normal range after 12 courses of TS 1 treatment. Through all the treatment courses, relative drug intensity was 100% and the performance status of this patient was kept 0 without any grade 3 or more adverse events under ambulatory treatment. A successful treatment for this patient might indicate that it was important to consider the appropriate reduction of the dosage of TS-1 administration for elderly patients with gastric cancer, because there is a reverse correlation between aging and renal function. To clarify this problem, a multicenter prospective phase II study about TS-1 reductive administration depending on the renal function for elderly patients with gastric cancer (OGSG0404) is ongoing in our clinical study group (OGSG; Osaka Gastrointestinal Chemotherapy Study Group).

[A case of complete remission of carcinomatous ascites refractory for TS-1 monotherapy treated with TS-1 plus paclitaxel combined therapy for gastric cancer].

A 38-year-old female patient with gastric cancer, of which histological type was a poorly differenciated adenocarcinoma and a clinical finding was T3N1MO (Stage IIIA), underwent total gastrectomy with D2 lymphadenectomy as the surgical treatment. However, CY1 was detected during the operation and the final finding was T3N1MOHOPOCY1 (Stage IV). Because this surgical treatment ended in curative C, we administered 80 mg/m2/day of TS-1 for four weeks followed by two weeks rest per one course for CY1 after the surgical treatment. After two courses of TS-1 monotherapy, extensive carcinomatous ascites appeared and blood concentration level of CA19-9 increased. We next treated this patient with TS-1+paclitaxel as a second line chemotherapy, because both of them have been reported to migrate to peritoneal very well and to be effective for peritoneal dissemination. The regimen of this combined therapy consisted of four weeks administration of TS-1 (80 mg/m2/day) followed by two weeks rest and injections of paclitaxel (50 mg/m2) at day 1 and 8 for 21 days as one course. When this patient underwent TS-1+paclitaxel combined treatment, the amount of carcinomatous ascites and blood concentration level of CA19-9 were gradually reduced and the former completely disappeared, and the latter fell to a normal range after five courses. Through all treatment courses, a performance status of this patient was kept 0 without a severe adverse event under ambulatory treatment. After 29 courses, the blood concentration level of CA19-9 rose again and local recurrence was detected at the lesion of esophagoenterostomy, though carcinomatous ascites had been kept in complete remission. We treated surgically for this local recurrence because of CY0 at the operation. At the present, 3 years and 8 months have passed since the first treatment started. This patient is still alive without cancer in ambulatory.

Changes over time in thymidine phosphorylase and dihydropyrimidine dehydrogenase when colon cancer samples are left at room temperature.

The changes over time in thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) were studied when colon cancer samples were left at room temperature. The TP levels and the TP/DPD ratio showed no changes over time in either the tumor or normal tissues. DPD levels increased over time in the normal tissues (P = 0.015), but showed no changes in the tumor tissues. When the DPD level in normal tissues is to be examined, the samples should be frozen as soon as possible. In all other cases, the ELISA results will not be affected if the samples are frozen within 6 h after collection.

[Chemotherapy for patients with advanced/recurrent gastric cancer and the practice at our institute].

Chemotherapy results for all 157 patients with advanced/recurrent gastric cancer at our institute were analyzed based on survival duration. The median survival time (MST) of all 157 patients was 426 days. The break down of the 157 patients are as follows: 59 patients with recurrence after curative operation, 47 patients with a radical grade C after non-curative operation and 51 patients with unresectable gastric cancer, and whose MST's were 590, 610 and 215 days, respectively. The standard chemotherapy for advanced/recurrent gastric cancer has not been established. Our data showed that chemotherapy for gastric cancer should be performed as a means of clinical study. If the patients had any exclusion criteria of clinical study or a proper clinical study did not exist, we would have recommended the TS-1 based regimen as the first-line chemotherapy, and the taxane based regimen as the second-line chemotherapy.

[The appreciation and limitation of regional gastrectomy for early gastric cancer].

We performed limited surgical treatments, including modified radical gastrectomy (D1+ alpha) for 7 patients, segmental gastrectomy for 9 patients and regional gastrectomy for 13 patients from September 1999 to December 2004. Eligibility criteria were as follows: 1) mucosal gastric cancer without an ulcer and/or scar; 2) contraindication to EMR; 3) located at M or L area; 4) negative for lymph node metastasis in clinical and surgical findings. Regional gastrectomy, especially in the patients whose gastric cancer located at the side of greater curvature, improved postoperative remnant gastric function according to the average of half-emptying times determined by RI scintigraphy, endoscopic examination and so on. However, the accuracy of mucosal cancer without lymph node metastasis in clinical and surgical findings was 69% and there was a patient with recurrence of lymph node after regional gastrectomy. These limited surgical treatments were thought to be limited due to more careful diagnosis as to sentinel lymph node navigation surgery in the future.

[A trial of TS-1 administration on the basis of the pharmacokinetic study for an advanced gastric cancer patient with impaired renal function].

TS-1 is an antitumor drug including 5-chloro-2,4 dihydroxypyridine (CDHP), which inhibits dihydriopyrimidine dehydrogenase (DPD) activity selectively in metabolism of 5-FU. However, TS-1 therapy tends to increase adverse events for patients with impaired renal function due to excessively high blood concentration of 5-FU, because CDHP is mainly excreted into the urine. In a 67-year-old male with advanced gastric cancer, renal dysfunction occurred during TS-1 administration as its adverse event. We studied the pharmacokinetics of 5-FU, which were analyzed on the T1/2 value and the AUC (0-infinity) of 5-FU with a single and consecutive TS-1 administration, and estimated an optimal TS-1 administration regimen for this patient. The regimen is 60 mg/body/day given in one divided dose for 28 days consecutively followed by 14 days rest. This regimen enabled a continuation of TS-1 treatment for the patient. In conclusion, individual dose adjustment using pharmacokinetic study of 5-FU might be beneficial to patients with impaired renal function.

[A case of pseudo aneurysm of common hepatic artery related to hepatic arterial infusion chemotherapy].

A 87-year-old male underwent the extended hepatic left lobectomy and the partial hepatectomy (S7, S8) for liver hepatic metastasis from the rectal cancer in March 2003. The reserver was implanted by the GDA-coil method from the right femoral artery, and WHF was enforced 10 times. Epigastric and back pain appeared from January 2004. The pain became strong gradually. MRI and CT scan were examined after hospitalization. These imaging tests showed the pseudo aneurysm of common hepatic artery. Therefore, an emergency angiography was performed, and pseudo aneurysm of the common hepatic artery was embolized with 36 metallic coils. After the embolization, the pain had disappeared suddenly. The patient was discharged the 7th day after embolization. Hepatic arterial infusion chemotherapy is considered safe with respect to blood and non blood toxicity, which was compared with systemic chemotherapy. However, there were also complications like this case, and caution is required.

[A case of peritoneal dissemination disappeared by CPT-11 + TS-1 combination chemotherapy].

A patient is a 35-year-old man. By a diagnosis of descending colon cancer, descending colon ablative operation and D1 lymph node dissection were performed on April 22, 2004. It was P3H0N1SE, Stage IV in perioperative findings. Abdominal CT showed peritoneal dissemination of 1.7 cm at the right under the abdominal wall wound and 1.2 cm in the rectovesical pouch on May 18, 2004. CPT-11 + TS-1 combination chemotherapy was started on June 22nd. In the five weeks of the combination chemotherapy, continuous infusion of CPT-11 (150 mg/body day 1 and 15) was twice administered, and oral administration of TS-1 (120 mg/body/day) was given for 3 weeks (day 1-21). Peritoneal dissemination disappeared after the two-course end, and we judged it as CR. Furthermore, we were certain that we obtained CR after the three course end. The adverse event was only neutropenia of grade 1. The fourth course was not administered, but recurrence has not been observed. Abdominal CT showed no recurrence on March 3, 2005 since the combination chemotherapy ended 6 months ago.

Ki-67 and CEA expression as prognostic markers in Dukes' C colorectal cancer.

This study investigated the relationship between clinicopathological or immunohistochemical factors and postoperative prognosis for Dukes' C colorectal cancer. Short-term survivors died from cancer within 2 years of surgery, whereas long-term survivors were disease-free for over 10 years. The groups differed in Ki-67 antigen and CEA expression in colon cancer, and CEA expression in rectal cancer that was limited to the metastatic lymph nodes. The immunohistochemical scores were higher in short-term survivors. Our data suggest that the characteristics of metastatic lymph nodes are important as a predictor of the aggressiveness of tumor behavior and that the expression of Ki-67 antigen or CEA there may be a useful indicators of patients' survival in Dukes' C colorectal cancer.