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.

Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2-positive gastric cancer (HERBIS-1).

BACKGROUND: S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC. METHODS: Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1-14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84-99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%). CONCLUSIONS: Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC.

Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer.

BACKGROUND: Perioperative enteral immunonutrition is thought to reduce postoperative morbidity in patients undergoing major gastrointestinal surgery. This study assessed the clinical effects of preoperative enteral immunonutrition in well nourished patients with gastric cancer undergoing total gastrectomy. METHODS: Well nourished patients with primary gastric cancer, fit for total gastrectomy, were randomized to either a control group with regular diet, or an immunonutrition group that received regular diet supplemented with 1000 ml/day of immunonutrients for 5 consecutive days before surgery. The primary endpoint was the incidence of surgical-site infection (SSI). Secondary endpoints were rates of infectious complications, overall postoperative morbidity and C-reactive protein (CRP) levels on 3-4 days after surgery. RESULTS: Of 244 randomized patients, 117 were allocated to the control group and 127 received immunonutrition. SSIs occurred in 27 patients in the immunonutrition group and 23 patients in the control group (risk ratio (RR) 1.09, 95 per cent confidence interval 0.66 to 1.78). Infectious complications were observed in 30 patients in the immunonutrition group and 27 in the control group (RR 1.11, 0.59 to 2.08). The overall postoperative morbidity rate was 30.8 and 26.1 per cent respectively (RR 1.18, 0.78 to 1.78). The median CRP value was 11.8 mg/dl in the immunonutrition group and 9.2 mg/dl in the control group (P = 0.113). CONCLUSION: Five-day preoperative enteral immunonutrition failed to demonstrate any clear advantage in terms of early clinical outcomes or modification of the systemic acute-phase response in well nourished patients with gastric cancer undergoing elective total gastrectomy. REGISTRATION NUMBER: ID 000000648 (University Hospital Medical Information Network (UMIN) database).

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer.

BACKGROUND: The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced gastric cancer. METHODS: We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m(2) divided in two daily doses for 21 days and cisplatin at 60 mg/m(2) intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy. RESULTS: Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes. CONCLUSIONS: Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.

Influence of preoperative chemotherapy for advanced thoracic oesophageal squamous cell carcinoma on perioperative complications.

BACKGROUND: The Japan Clinical Oncology Group (JCOG) 9907 trial has changed the standard of care for advanced thoracic oesophageal cancer in Japan from postoperative chemotherapy to preoperative chemotherapy. The impact of preoperative chemotherapy on the risk of developing postoperative complications remains controversial. This article reports the safety analysis of JCOG9907, focusing on risk factors for postoperative complications. METHODS: Patients with potentially resectable advanced thoracic oesophageal squamous cell carcinoma were randomized to either postoperative or preoperative chemotherapy followed by transthoracic oesophagectomy with D2-3 lymphadenectomy. Chemotherapy consisted of two cycles of cisplatin and 5-fluorouracil. Clinical baseline data, intraoperative complications, postoperative complications and in-hospital mortality, collected on the case report forms in a predetermined format, were analysed. Univariable and multivariable analyses were used to explore the risk of postoperative complications in relation to treatment group, age, sex, tumour depth, nodal metastasis, stage and location. RESULTS: Of 330 patients randomized, 166 were assigned to receive postoperative chemotherapy and 164 preoperative chemotherapy; 162 and 154 patients respectively underwent surgery. The incidence of intraoperative complications, postoperative complications and in-hospital mortality was similarly low in both groups. Multivariable analysis showed that age, sex and tumour location were independently associated with an increase in postoperative complications, but preoperative chemotherapy was not. CONCLUSION: Preoperative chemotherapy does not increase the risk of complications or hospital mortality after surgery for advanced thoracic oesophageal cancer.

The significance of gastrectomy in advanced gastric cancer patients with non-curative factors.

BACKGROUND: The role of gastrectomy in the treatment of advanced gastric cancer patients with non-curative factors remains controversial. We investigated prognostic factors and evaluated the role of gastrectomy in such patients. PATIENTS AND METHODS: Eighty-eight advanced gastric cancer patients with non-curative factors were prospectively studied. The patients were categorized into the following two groups: Group A: 52 patients who underwent gastrectomy and subsequently received chemotherapy, Group B: 36 patients who received chemotherapy alone. RESULTS: The median survival times of group A and B patients were 351 and 182 days, respectively (p=0.008). Multivariate analysis showed that gastrectomy was the only positive independent prognostic factor, with no effect on the results of chemotherapy. There was no significant difference in the duration of hospital stay between patients of the two groups, while significantly longer maintenance of oral intake was observed for group A. CONCLUSION: In advanced gastric cancer patients with non-curative factors, gastrectomy was beneficial for survival with longer maintenance of oral intake.

Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.

Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.

Stage migration caused by D2 dissection with para-aortic lymphadenectomy for gastric cancer from the results of a prospective randomized controlled trial.

BACKGROUND: Extended lymphadenectomy (D2) provides accurate nodal staging of gastric cancer. The aim of this study was to clarify the degree of stage migration seen with D2 combined with para-aortic lymph node dissection for gastric cancer invading the subserosa, the serosa and adjacent structures (T2ss-4) in patients considered not to have distant metastases (M0). METHODS: Between July 1995 and April 2001, 523 patients were recruited and randomized in a prospective phase III trial comparing D2 with D2 and para-aortic nodal dissection for T2ss-4 gastric cancer without macroscopic para-aortic nodal metastases. Stage migration was evaluated by Japanese Gastric Cancer Association staging in 260 patients who underwent D2 with para-aortic dissection by analysing pathological information from the dissected lymph nodes. RESULTS: Node (N)-stage migration was observed in 1 per cent (1 of 82) of patients with N1 disease, 20 per cent (12 of 59) with N2, 43 per cent (10 of 23) with N3 and 8.8 per cent (23 of 260) of all patients. Final stage migration occurred in 9 per cent (5 of 58) of patients with stage IIIa, 19 per cent (8 of 42) with stage IIIb, 56 per cent (9 of 16) with stage IVa and 8.5 per cent (22 of 260) of all patients. Metastasis to N4 nodes was found in 4 per cent (four of 95) of tumours invading the subserosa and 17.4 per cent (19 of 109) of tumours penetrating the serosa. The overall incidence of N4 involvement was 8.8 per cent (23 of 260). CONCLUSION: Extended para-aortic lymphadenectomy for gastric cancer provides accurate nodal staging and results in stage migration, which may improve stage-specific survival regardless of overall survival benefit.

Phase I study of the combination of nedaplatin, adriamycin and 5-fluorouracil for treatment of advanced esophageal cancer.

This trial was conducted to determine the maximum-tolerated dose, principal toxicity, and recommended dose (RD) for the phase II study of the combination of nedaplatin (NED), adriamycin (ADM), and 5-fluorouracil (5-FU) in patients with advanced esophageal cancer. Patients with previously untreated esophageal cancer were eligible if they had performance status 0-1, were 75 years or younger and had adequate organ function. The dose of NED, the key anticancer platinum complex drug, was increased from 60 to 70, and 80 mg/m(2) on day 1. ADM and 5-FU were administered at fixed doses (30 mg/m(2) on day 1, and 700 mg/m(2) on days 1-5). The dose-limiting toxicities of NED were neutropenia and severe diarrhea, and its maximum-tolerated dose and RD were 70 mg/m(2) and 60 mg/m(2), respectively. There were four responders among the six patients administered the RD. The present study thus revealed combination chemotherapy with NED, ADM, and 5-FU to be active and well-tolerated and to warrant phase II study.

[A case of hepatocellular carcinoma responding to hepatic arterial infusion chemotherapy with low-dose cisplatin and 5-fluorouracil].

A 74-year-old man had multiple liver recurrence of hepatocellular carcinoma (HCC) after extended left hepatectomy. He was treated by continuous hepatic arterial infusion (HAI) chemotherapy with low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) via an implanted reservoir. A catheter was inserted percutaneously into the hepatic artery using the Seldinger technique. The patient was administered 10 mg of CDDP on day 1 and 500 mg/day of 5-FU for 4 days as one course. Four courses were administered and the PIVKA-II level decreased from 427 to 216 mAU/ml. However, infusion port problems led to interruption of chemotherapy and PIVKA-II increased to 798 mAU/ml. His chemotherapy was changed to 10 mg of CDDP on day 1 and 750 mg/day of 5-FU for 2 days. After five courses were administered, PIVKA-II decreased to 540 mAU/ml. This patient is still alive 15 months after the start of therapy. This case suggests that HAI with low-dose CDDP and 5-FU might be useful for prolonging the survival of HCC patients with a good quality of life.

[Efficacy of continuous hepatic arterial infusion of high-dose 5-FU for liver metastases of gastric cancer].

We studied the efficacy of continuous hepatic arterial infusion of high-dose 5-FU (high-dose CHAI) in two patients with multiple (five or more) bilobar liver metastases of gastric cancer. 5-FU was given continuously via the hepatic artery at 1 g/day for 3 days, followed by one day off therapy and repetition of the initial treatment as one course. Case 1 was a 67-year-old man with Borrmann type 2 gastric cancer who had undergone total gastrectomy. Metachronous multiple liver metastases (maximum diameter: 3.5 cm) were detected at 11 months after surgery. One month later, we started high-dose CHAI and gave two courses with a 4-day interval between them. After that, 5-FU was given twice by hepatic arterial infusion (HAI) at dose of 1.5 g/week. The tumor diameter had decreased by 50% at 3 months after high-dose CHAI. Case 2 was a 64-year-old man with Borrmann type 3 gastric cancer who had synchronous multiple liver metastases (maximum diameter: 9 cm) and liver dysfunction. One month after distal gastrectomy, we started high-dose CHAI and finished one course. After that, liver function returned to normal and 5-FU was given by HAI at dose of 1 g/week on an outpatient basis. The tumor diameter decreased to 1/3 of the initial size at four months after high-dose CHAI. High-dose CHAI using 5-FU may be safe and effective for liver metastases from gastric cancer.

New technique of laparoscopic-assisted excision of a cholecystocolic fistula: report of a case.

Cholecystocolic fistula is a rare complication of gallstone disease that is most commonly diagnosed at the time of surgery. It is generally considered to be a contraindication to laparoscopic cholecystectomy because of the difficulties involved in its management intraoperatively. Laparoscopic stapling or suturing techniques have been reported as feasible and safe methods for repairing such fistulas; however, these procedures are not always able to be performed due to technical difficulties. We exteriorized a cholecystocolic fistula through an umbilical incision, whereby it was repaired safely and easily. This report describes our new technique for managing a cholecystocolic fistula found incidentally during a laparoscopic cholecystectomy.

[Clinical results of concurrent chemoradiation therapy for primary highly advanced esophageal cancer].

Clinical results after non-curative resection of highly advanced esophageal cancer are extremely poor. We administered concurrent chemoradiation therapy (CRT) as a multidisciplinary therapy in cases of highly advanced esophageal cancer for which non-curative resection is expected. The efficacy rate of the therapy was 59.4%, and the 3-year-survival rate 10.2%. A life-prolonging effect (the 3-year survival being 17.9%) was observed in the effective cases. Our future aim is to establish a safer, more reliable and cost-effective therapy by estimating the degree of efficacy before administration of CRT and then selecting cases suitable for CRT.

Detection of peritoneal micrometastases of gastric carcinoma with green fluorescent protein and carcinoembryonic antigen promoter.

The aim of this study was to specifically visualize micrometastases in the peritoneal cavity, which cannot be detected by conventional methods, by using enhanced Green Fluorescent Protein (EGFP) containing carcinoembryonic antigen (CEA) promoter in an upstream position. In in vitro experiments, two cell lines from human gastric cancer, MKN45 and MKN1, and a cell line from human fibrosarcoma, HT1080, were transduced with pCEA-EGFP, which contains the CEA promoter region. MKN45 and MKN1, which expressed CEA mRNA, showed positive fluorescence after transduction of pCEA-EGFP, whereas HT1080 did not. In in vivo experiments, 7 days after 10(7) MKN45 had been injected into the peritoneal cavity of BALB/c nude mice, pCEA-EGFP was transduced in the peritoneal cavity using a fusogenic liposome with the envelope protein of Hemagglutinating Virus of Japan on the surface. On the peritoneum of the abdominal wall, fluorescent nodules were detected by fluorescence stereomicroscopy. These nodules had a minimal size of approximately 0.15 mm and could not be detected by conventional stereomicroscopy or macroscopy. They were histologically confirmed to be cancer cells by H&E staining. The results suggest that visualization of peritoneal micrometastasis of gastric cancer using CEA promoter and EGFP can offer a new strategy for diagnosis of micrometastasis.

Carcinoma of the head of the pancreas after excision of a choledochal cyst.

We here report a 53-year-old woman who had undergone resection of a choledochal cyst and hepaticojejunostomy three years before. She was readmitted because of intermittent fever, and abdominal computed tomography revealed a 4-cm tumor in the head of the pancreas. We performed pancreatoduodenectomy, and examination of the resected specimen showed well-differentiated papillary adenocarcinoma. Only 5 cases of carcinoma occurring after the resection of a choledochal cyst have been reported, and to our knowledge, this is the second case of carcinoma of the head of the pancreas.

Prognostic factors for recurrence in stage II and III gastric cancer patients receiving a curative resection and postoperative adjuvant chemotherapy.

Prognostic value of clinicopathologic factors and biologic markers was analyzed in 185 patients who received a curative resection and adjuvant chemotherapy of pathologically confirmed stage II or III gastric cancer. No difference was found between the chemotherapeutic regimens according to the frequency of recurrence, but tumor type, histology, depth of invasion, nodal metastasis, and lymphatic and venous invasion were significantly different between recurrent (n=62) and non-recurrent (n=123) patients. However, the degree of lymphatic dissection and the patterns of biological markers (DNA ploidy, p53 staining and PCNA labeling) were not different. Hepatic metastasis and venous invasion were more frequent on patients recurring within one year, compared to those who recurred later. Multivariate analyses showed that depth of invasion, level 2 lymph node metastasis and tumor histology were risk factors for recurrence. Pathologic factors were more important for predicting recurrence than biological markers.

Synchronous rectal and esophageal cancer associated with prurigo chronica multiformis: report of a case.

The skin lesions that appear in association with internal malignancies are called dermadromes or paraneoplastic cutaneous disorders. These skin changes characteristically develop with progression of the internal malignancy. A 75-year-old Japanese man who had been diagnosed as having prurigo chronica multiformis, a form of dermadrome, 5 years previously was referred to our hospital for further investigation. On admission, numerous itchy red papules were present on the right side of the abdomen and the inner aspect of both thighs. Intensive screening for internal malignancies revealed advanced rectal cancer and early esophageal cancer. After surgical resection, the skin lesions improved without any treatment. To the best of our knowledge, this is the first case of synchronous double cancers associated with prurigo chronica multiformis.

Lymph node metastasis along the recurrent nerve chain is an indication for cervical lymph node dissection in thoracic esophageal cancer.

This study examined whether recurrent nerve chain node metastasis serves as an indicative factor for cervical lymph node dissection in thoracic esophageal cancer. The association of recurrent nerve chain lymph node metastasis and cervical node metastasis was analyzed for 91 patients with thoracic esophageal cancer who had undergone three-field lymph node dissection. In patients with upper thoracic esophageal cancer, the incidence of cervical lymph node metastasis was similar regardless of recurrent nerve chain node metastasis. On the other hand, in patients with middle or lower esophageal cancer, the incidence was significantly higher in recurrent nerve-positive (16/31, 51.6%) than in recurrent nerve-negative (5/43, 11.6%) patients. The prognosis of patients with recurrent nerve chain node metastasis was significantly better in the three-field dissection group than in the two-field dissection group, while in patients with no recurrent nerve chain node metastasis, survival was similar between the two groups. In conclusion, cervical lymphadenectomy can be omitted for recurrent nerve chain node-negative patients with middle and lower thoracic esophageal cancer.

Squamous cell carcinoma of the esophagus infiltrating the respiratory tract is less sensitive to preoperative concurrent radiation and chemotherapy.

BACKGROUND: The prognosis of upper thoracic esophageal cancer is poor when compared with middle and lower thoracic esophageal cancer because the tumor easily infiltrates the respiratory tract and surgical en-bloc resection is difficult. Recently, preoperative chemoradiation therapy has been shown to lead to down-staging of the disease and improve prognosis. But the benefit of this therapy for tumors infiltrating the respiratory tract remains unknown. STUDY DESIGN: Fifty-six patients with thoracic esophageal cancer infiltrating neighboring organs, but with no hematogeneous metastasis, were given preoperative concurrent chemotherapy (5-fluorouracil and cisplatin) and radiation (40 Gy) therapy. When a clinical response was observed, making a curative resection potentially possible, patients were scheduled for esophagectomy with extended lymphadenectomy. Patient prognosis with respect to the organs infiltrated by the tumors was estimated by calculating survival curves using the Kaplan-Meier method and comparing the curves by the log-rank test. RESULTS: The prognosis was significantly poorer for patients with tumors infiltrating the respiratory tract (T) or aorta plus respiratory tract (A + T) than for patients with tumors infiltrating the aorta alone (A) or other organs (Oth) (p < 0.05 for Oth versus T; p < 0.05 for Oth versus A + T; p < 0.0001 for A versus T; p < 0.0001 for A versus A + T by log-rank test). Patients positive for respiratory tract invasion (T, T + A), compared with those negative for respiratory tract invasion (A, Oth), showed a poorer clinical response to chemoradiation (3.0%, 45.5%, 39.4%, and 9.1% versus 4.3%, 82.6%, 4.3%, and 8.7% in complete response (CR), partial response (PR), nonresponse (NC) and progressive disease (PD), respectively, p = 0.0156) and surgical resectability (36.4% vs. 87.0%, p = 0.0003). Histologic effectiveness (8.3%, 50.0%, and 41.7% versus 25.0%, 70.0%, and 5.0% in grade 3, grade 2, and grade 1, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0189) and histologic stages (8.3%, 8.3%, 8.3%, 8.3%, 25.0%, and 41.7% versus 20.0%, 0%, 15.0%, 25.0%, 40.0%, and 0% in pathologic CR, stage I, stage IIA, stage IIB, stage III, and stage IV, respectively, for patients with respiratory tract invasion versus those without it, p = 0.0496) were significantly better in patients negative for respiratory tract invasion; the percentages of patients with lymph node metastasis did not differ significantly between the two groups. Comparison of the recurrence patterns showed that local failure was most common in patients with respiratory tract invasion, and distant failure was the leading cause of recurrence in patients without it. CONCLUSIONS: Because the prognosis of patients with thoracic esophageal cancer infiltrating the respiratory tract is extremely poor, partially because of the low local effectiveness of preoperative concurrent chemotherapy and radiation therapy, caution is needed when deciding on salvage surgery.