Molecular Biomarker Study in a Randomised Phase III Trial of Irinotecan Plus S-1 versus S-1 for Advanced Gastric Cancer (GC0301/TOP-002).

AIMS: Gastric cancer is a common and heterogeneous disease; however, global standard and biomarkers for selecting chemotherapy regimens have not been established. This study was designed retrospectively to identify molecular biomarkers for irinotecan plus S-1 (IRI-S) and S-1 therapy from subset analyses in GC0301/TOP-002, a randomised phase III trial for advanced gastric cancer. MATERIALS AND METHODS: Paraffin-embedded primary tumour specimens were collected from 126 of 326 randomised patients in GC0301/TOP-002. The mRNA was measured for thymidylate synthase, dihydropyrimidine dehydrogenase, topoisomerase I, excision repair cross-complementing gene 1 (ERCC1) and thymidine phosphorylase; categorised into low and high to analyse their association with efficacy end points. RESULTS: There was no significant difference in each mRNA between S-1 and IRI-S groups, whereas there were differences among some clinical characteristics. Multivariate analyses for overall survival showed that mRNA levels were not correlated with prognosis. By comparison, between IRI-S and S-1 arms, low thymidylate synthase, low ERCC1 and high thymidine phosphorylase were associated with better prognosis for IRI-S versus S-1 (hazard ratio = 0.653, 0.702 and 0.709, respectively; P < 0.15 for each interaction). CONCLUSION: Low thymidylate synthase, low ERCC1 and high thymidine phosphorylase are candidates for predictive biomarkers for first-line treatment in advanced gastric cancer by IRI-S. Further study is warranted to confirm these results in other clinical trials and cohort studies.

Impact of intraperitoneal chemotherapy after gastrectomy with positive cytological findings in peritoneal washings.

BACKGROUND: There is no standard treatment available for gastric cancer patients whose sole 'non-curative factor' is positivecytological findings in peritoneal washings (CFPW). The aim of this study was to examine the safety, pharmacokinetics and efficacy for free intraperitoneal cancer cells of intraperitoneal chemotherapy with paclitaxel after gastrectomy with en bloc D2 lymph node dissection in cases of gastric cancer with positive CFPW. METHODS: Ten patients with gastric cancer who underwent gastrectomy and systemic lymphadenectomy with D2 dissection, without any other non-curative factors besides positive CFPW, were treated with early postoperative intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complications were measured using NCI-CTC version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatographic assay. RESULTS: Grade 3/4 toxic effects included anemia (20%) and neutropenia (10%) that required no treatment. Operative complications were, for example, superficial surgical site infections (10%) that were treated with antibiotics. No viable cancer cells were observed in the intra-abdominal fluid 24 h after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve ratio was 2,003.3:1. CONCLUSION: Intraperitoneal chemotherapy with paclitaxel is a safe and effective treatment modality for free intraperitoneal cancer cells.

Prospective randomized trial of short-term neoadjuvant chemotherapy for advanced gastric cancer.

BACKGROUND: We performed short-term neoadjuvant chemotherapy (s-NAC) to examine whether anticancer drugs can change the proliferative ability of cancer cells in gastric cancer patients. METHODS: Chemotherapy was performed for 72 h before gastrectomy in 63 gastric cancer patients. Patients were classed into four groups: Group F, 16 cases who received a single administration of 5-fluorouracil (5-FU); Group C, 15 cases who received a single administration of cis-diamminedichloroplatinum (CDDP; cisplatin); Group FC, 16 cases who received both 5-FU+CDDP; and a Control group, 16 cases who did not receive chemotherapy. We reviewed neoadjuvant biopsy tissue and gastric cancer tissue delivered by operation in these cases. The TUNEL method and immunohistochemistry with an anti-MIB-1 antibody were used to evaluate cellular apoptosis and proliferative ability, respectively. The apoptotic index (AI) and an MIB-1 index (MI) were also calculated. RESULTS: There were no differences in AI or MI in biopsy tissue between the groups. The AI of gastric cancer tissue in Group FC was significantly higher than in the other groups (P < 0.01). The MI of Group FC was significantly lower than in the other groups (P < 0.05). In addition, after s-NAC operation there was a significant inhibition of proliferative potency and an induction of apoptosis in Group FC. CONCLUSION: Combination of CDDP and 5-FU reduced proliferative potency and increased cellular apoptosis in gastric cancer cells.

Esophageal cancer after distal gastrectomy.

The effect of gastrectomy on the subsequent development of esophageal cancer was investigated. Duodenogastroesophageal reflux is thought to be common in patients after distal gastrectomy, but whether this contributes to the development of esophageal cancer in such patients is controversial. We retrospectively evaluated 153 patients who underwent subtotal esophagectomy for thoracic esophageal cancer between January 2002 and July 2005. They were divided into two groups, according to whether or not they had previously undergone a gastrectomy: group 1, comprising 14 patients who had undergone gastrectomy and group 2, comprising 139 patients who had not. Clinical profiles of the patients were obtained from the medical records and the whole resected esophagus was histopathologically examined. The interval between gastrectomy and esophagectomy in group 1 was significantly shorter in the patients who had undergone gastrectomy for gastric cancer (10.5 +/- 4.2 years) than in those who had undergone gastrectomy for a peptic ulcer (28.9 +/- 3.0 years). The interval was also somehow shorter in the patients for whom anastomosis had been performed by Billroth I (21.3 +/- 5.6 years) compared with Billroth II (29.7 +/- 3.2 years), although the difference did not reach its statistical significance (P = 0.11). Moreover, the proportion of lower third tumors in patients after gastrectomy was significantly higher compared with that of the patients with intact stomach. These findings suggest that a history of gastrectomy is associated with more lower-third squamous cell esophageal carcinoma.

Expression levels of thymidine phosphorylase and dihydropyrimidine dehydrogenase in various human tumor tissues.

Thymidine phosphorylase (dThdPase) is the rate-limiting enzyme that metabolizes 5'-deoxy-5-fluorouridine (5'-dFUrd, doxifluridine), an intermediate metabolite of capecitabine, to the active drug 5-fluorouracil (5-FUra), while dihydropyrimidine dehydrogenase (DPD) catabolizes 5-FUra to an inactive molecule. The susceptibility of tumors to fluoropyrimidines is reported to correlate with tumor levels of these enzymes. To obtain some insight into the tumor types susceptible to fluoropyrimidine therapy, we measured expression levels of these two enzymes in various types of human cancer tissues (241 tissue samples) by the ELISA methods. DPD exists in all the cancer types studied, such as bladder, breast, cervical, colorectal, esophageal, gastric, hepatic, pancreatic, prostate, and renal cancers. Among them, the cervical, hepatic, pancreatic, esophageal, and breast cancer tissues expressed high levels of DPD (median >70 U/mg protein), while high concentrations of the dThdPase were expressed in esophageal, cervical, breast, and pancreatic cancers and hepatoma (median >150 U/mg protein). The dThdPase/DPD ratio, which was reported to correlate with the susceptibility of human cancer xenografts to capecitabine, was high in esophageal, renal, breast, colorectal, and gastric cancers (median ratio of >1.5). In any of these three parameters, the inter-patient DPD variability for each cancer type was much larger than the DPD variability among cancer types; highest/lowest ratios for dThdPase, DPD, and dThdPase/DPD were 10-321, 7-513, and 2-293, respectively. These results indicate that measurements of the three parameters, DPD, dThdPase and dThdPase/DPD, would be useful criteria for selecting cancer patients suitable for fluoropyrimidine therapy rather than for selecting cancer types.

[The efficacy and limitation of hepatic arterial infusion chemotherapy for colorectal liver metastases].

We investigated the efficacy and limitation of hepatic arterial infusion (HAI) chemotherapy for colorectal liver metastases. In terms of prophylactic HAI following curative resection of liver, the 5-year disease-free survival of HAI group (12 g of 5-FU administered in 6 weeks) was 66.7%, whereas that of randomly selected control group was 20.0%. The difference was statistically significant (p = 0.045). Recurrent disease was confirmed in three cases of HAI group (one in liver) and in 8 patients of the control group (6 in liver). However, the overall survival was not significantly different between the groups. Thus, the short-term HAI of 5-FU is effective in decreasing the recurrence of disease. As for the treatment of unresectable liver metastases, some patients received HAI of 5-FU (1,000-1,500 mg/w) showed prolonged survival with partial remission of the disease. However, the 1-, 2-, and 3-year cumulative survival of HAI group (n = 27) was 69.3, 34.1 and 11.4%, respectively, against 61.3, 22.6 and 9.4%, respectively, in the transarterial embolization (TAE) group (n = 31). Therefore it is important to estimate the effect in the early phase of HAI, and aggressively continue the treatment in selected patients for whom it is suitable.

[Pharmacological study of weekly docetaxel in patients with metastatic breast cancer].

A pharmacological comparison of weekly administrations of docetaxel (TXT) and standard/conventional TXT was carried out among patients with metastatic breast cancer. Fifteen patients were enrolled in this study of weekly TXT (TXT: 40 mg/body/week x 3 with 1 week interruptions in 10 patients) and standard TXT (TXT: 60 mg/m2/3 weeks in 5 patients). The median dose intensity (DI) of weekly TXT (20.63 mg/m2/week) was similar to that of standard TXT, and the median relative dose intensity (RDI) of weekly TXT was 0.98. The median area under the plasma concentration-time curve (AUC) of weekly TXT (1.20 micrograms.h/ml) was smaller than that of standard TXT (1.87 micrograms.h/ml). Therefore, there were remarkable decreases in both median percent of decrease in neutrophil counts and grade 3, 4 neutropenia with weekly TXT. These pharmacological data show that weekly TXT is a well-tolerated and feasible schedule for the treatment of metastatic breast cancer.

A Case of Advanced Breast Cancer Successfully Treated with Primary Endocrine Therapy.

We present a case of a premenopausal woman with advanced hormone-sensitive breast cancer who was successfully treated with primary endocrine therapy consisting of ovarian ablation followed by a combined endocrine regimen of the aromataseinhibitor fadrozole 2 mg daily and tamoxifen 20 mg daily. During the 5 months treatment period, PR evaluation of the loco-regional lesions was performed. The patient then underwent mastectomy with axillary lymph node dissection followed byfadrozole and tamoxifen therapy. Throughout the treatment course, no adverse events were encountered and the patient has been enjoying a favorable quality of life. As shown by this case, primary endocrine therapy is a promising treatment option for hormonesensitive breast cancer. However, this modality should be continued to be regarded as experimental.

[Intra-arterial chemotherapy to improve quality of life in cases of unresectable advanced or recurrent breast cancer].

We performed repetitive intra-arterial infusion chemotherapy (I.A.) with epirubicin in order to improve the quality of life (QOL) in 3 cases with locally advanced or recurrent breast cancer which were diagnosed as surgically unresectable and seemed uncontrollable by outpatient systemic chemotherapy. The patients were admitted to our hospital for chest wall invasion, lymph node metastasis, bleeding, pain, or edema in upper extremity. Therapeutic effects included 1 case of CR and 2 cases of PR in the primary site, and similar effects were obtained in metastasized lymph nodes. We could perform mastectomy in both of the 2 cases with locally advanced cancer after I.A., Although leukocytopenia, which was the dose limiting factor in this regimen, was observed in all 3 cases, it was Grade 2 or 3 and recovered by G-CSF. With regard to their QOL, symptoms which had driven them to inpatient treatment remarkably improved in all of the cases. Thus, after 2 series of I.A. they could receive maintenance systemic chemotherapy as outpatients. Our findings showed that the I.A. as a local control treatment in patients with unresectable advanced or recurrent breast cancer is useful for the improvement of their QOL.

[Long-term survival in a case of multiple liver metastasis from postoperative gastric cancer effectively treated by hepatic intraarterial infusion chemotherapy using MMC and pirarubicin].

We experienced a case of multiple liver metastasis from postoperative gastric cancer who showed long-term survival with hepatic arterial infusion chemotherapy (HAI) of MMC and pirarubicin. A catheter was inserted into the hepatic artery, and 4 mg of MMC and 20 mg of pirarubicin were administered through an implantable port catheter every two to four weeks. The total dose of MMC and pirarubicin by the time of this report was 164 mg and 820 mg, respectively. The follow-up CT scan 2 months after the beginning of HAI showed a decrement of the liver tumors. The decrease rate at 12 and 17 months was 50% and 70%, respectively, which was diagnosed as partial response (PR). The therapeutic effect at 49 months is still PR without any sign of tumor enlargement of extra hepatic lesion.

[Effects of intravenous infusion of 5-FU and intraperitoneal injection of low-dose CDDP on 3 cases with ascites owing to peritonitis carcinomatosa of postoperative gastric carcinoma and debility].

We examined the effects of intravenous infusion of 5-FU and intraperitoneal injection of low-dose CDDP on 3 cases with ascites owing to peritonitis carcinomatosa of postoperative gastric carcinoma and debility. Intravenous infusion of 5-FU (250-1,000 mg/body) and intraperitoneal injection of CDDP (20-25 mg/body) carried out for 2-5 days. As a result, QOL of 3 cases was fairly improved. The PS (Performance Status) of 2 cases improved from Grade 4 to 2, and another one improved from Grade 4 to 3. Adverse effects of Grade 1 according to the WHO criteria were observed in 1 case (leukocytopenia and diarrhea). This palliative chemotherapy method appeared to be safe and effective for ascites due to peritonitis carcinomatosa of postoperative gastric carcinoma and debility.

[Effect of FUT-187, oral serine protease inhibitor, on inflammation in the gastric remnant].

Excessive enterogastric reflux following partial gastrectomy is believed to be responsible for the cause of inflammation in the gastric remnant. We examined the effect of FUT-187, a synthetic serine protease inhibitor, on symptoms and endoscopic findings in 33 patients who were diagnosed endoscopically as postgastrectomy gastritis. Patients took 50 mg FUT-187 orally after each meal and at bedtime for 8 weeks. Before treatment, 30 patients (91%) suffered from several symptoms including regurgitation and/or bitter taste in the mouth (49%), epigastric pain (42%) and nausea (36%). From endoscopic observation, erythema was detected in 32 patients, edema in 23 patients and erosion and/or ulcer in 9 patients. After treatment the global improvement rating for subjective symptoms was 76.7% (23/30) and the improvement of endoscopic findings was 63.6% (21/33). Diarrhea was observed in one patient but could be easily controlled by discontinuation of the drug. Our results suggest that FUT-187 can be a useful drug for the treatment of postgastrectomy gastritis with its efficacy and safety.

Disorder in ultrastructure of basement membrane and mechanical junction in human esophageal cancer.

The ultrastructure and clinical significance of the basement membrane (BM) are still unclear in esophageal cancer. In this report, we examined the ultrastructure of the BM and microstructures related intercellular adhesion in squamous cell carcinoma of human esophagus using a transmission electron microscope, and investigated their clinical significance. BM was absent in 38% of the examined cases and the frequency or the presence of the microstructures of cancer cells of the infiltrating margin (CCIM) was negatively related to the presence of BM (BM-P); CCIM of BM-P tumors often had smaller number per cell of desmosomes and cytoplasmic processes. These results indicate that CCIM of BM-P tumor are in an 'inconvenient status' for tumor cells to form a firm group. In the intercellular space between CCIM and BM or surrounding stromal cells, all of the CCIM of BM-P tumors had hemidesmosomes, but not those of BM absent (BM-A) tumors. Though no statistical significant difference was found in our clinical observation between BM-P and BM-A tumors, the present study suggested that a considerable proportion of cancer cells have abnormal intercellular adhesiveness via a mechanical mechanism related to the presence or absence of BM.

Endoscopic screening of early esophageal cancer with the Lugol dye method in patients with head and neck cancers.

The poor prognosis for esophageal cancer could be improved if lesions were detected at an early stage. To detect early esophageal cancer, endoscopic screening of the esophagus with the Lugol dye method was performed in patients with head and neck cancers who were asymptomatic but regarded as being at high risk for synchronous or metachronous esophageal cancer. Of 178 patients screened, 9 had esophageal cancer (5.1%). Eight of these patients (89%) were at early stages with no lymph node metastasis. Most of the lesions (9 of 13 lesions) were not detectable by barium studies or ordinary endoscopic study. The epidemiologic statistical analysis of the patients confirmed that they had a significantly high observed and expected number (O/E) ratio (39.7; P less than 0.001). These results demonstrate the value of endoscopic screening of the esophagus with the Lugol dye method in patients with head and neck cancers and imply that endoscopic screening with the Lugol dye method may be useful for detecting early esophageal cancer in individuals at risk for other causes.

Primary small intestinal adenocarcinoma diagnosed by endoscopic examination prior to operation.

Progress in diagnostic procedures has made it possible to diagnose neoplasms of the gastrointestinal tract preoperatively. However, preoperative diagnosis of tumors of the small intestine remains difficult. We report here detection of an adenocarcinoma of the jejunum by endoscopic examination prior to operation. A 73-year-old woman was admitted with complaints of intermittent periumbilical pain, nausea, and vomiting. An upper gastrointestinal series showed an abnormal segmet 10 cm distal to the duodenojejunal flexure. Small intestinal endoscopic examination revealed a tumor with a crater and an irregular surface of mucosa near the duodenojejunal flexure, and annular constriction due to tumor extension, and endoscopic biopsy specimens contained tissue from a poorly differentiated adenocarcinoma. Wide resection, including the duodenum, proximal jejunum, and adjacent mesentery was performed. The resected tumor was confirmed histologically to be a poorly differentiated adenocarcinoma of the jejunum.

[Changes in the chest on CT examinations after endoscopic intravascular sclerotherapy of the esophageal varices].

Between June 1985 and December 1986, 24 endoscopic intravascular sclerotherapies (5% ethanolamine oleate) were carried out in 17 patients. CT examinations were performed prior to and within 48 hours after all procedures. 1. Esophageal wall thickening was demonstrated by CT scanning within 48 hours after all 24 procedures. Mean diameter of the esophagus before sclerotherapy was 27mm, and after operation, 49mm. Changes of esophageal wall were: 1) 8 cases of the homogeneous wall thicking (33%), 2) 4 localized low density lesions in the wall (17%), and 3) 12 low density lesions of extraesophageal wall in the mediastinum (5%). Chest pain, high fever and esophageal mucosal ulcerlation were seen in patients who had low density lesions of extra-esophageal wall. 2. Pleural effusion occurred after 20 of the 24 procedures (84%). Various pulmonary changes were recognized: Ten cases of atelectasis (42%), 16 dilatations of peripheral pulmonary vessels (66%), and 5 small nodular or irregular shadow (21%). Changes in the mediastinum and pleural space were ascribed to spreading of inflammation from the esophagus, but the changes in the lung field, especially dilatation of peripheral vessels, suggested the penetration of the sclerosant into the lung periphery on the blood stream of pulmonary vessels. 3. CT showed changes of the mediastinum after all 24 procedures (100%), but X-ray examination revealed dilatation of the mediastinum only after 2 procedures (8%). Changes in the pleural space and in the lung field on CT were recognized after 20 procedures (92%), but only after 12 procedures (50%) by X-ray examination. In particular, X-ray examination failed to show shadows on the lung field.(ABSTRACT TRUNCATED AT 250 WORDS)