Prospective randomized controlled study on bestatin in resectable gastric cancer —Third report—

The efficacy of Bestatin as adjuvant immunochemotherapy for patients with resectable gastric cancer was investigated. Ninety-six patients with similar background factors were randomized into two groups; a control group and an experimental group, the patients in the experimental group receiving a daily oral dose of 60 mg Bestatin over a long period. All 96 patients were treated with a bolus intravenous injection of mitomycin C (MMC) plus oral administration of tegafur (FT-207, FT). The survival rate of the patients in the MMC+FT+Bestatin group was more favorable than that of the patients in the MMC+FT group, but the difference was not statistically significant. The survival rates of the MMC+FT+Bestatin group patients intthe stratification of stage III+IV and positive histological serosal invasion, ps(+), were significantly superior to those of the MMC+FT group patients (Logrank test: p<0.05). Moreover, in patients with positive histological serosal invasion, the recurrence of peritoneal dissemination was significantly suppressed in the MMC+FT+Bestatin group.     

Postoperative adjuvant immunochemotherapy with mitomycin C,futraful and PSK for gastric cancer. An analysis of data on 579 patients followed for five years

In order to evaluate the combination of immunochemotherapy with mitomycin C (MMC), futraful (FT) and PSK, as an adjuvant to surgery for curatively resected gastric cancer, a randomized controlled study by the sealed envelope method was performed with the participation of 97 hospitals in the Kyushu and Chugoku districts of Japan. The MMC+FT+ PSK group showed a significant increase in 5 year survival from the other groups (p<0.05). Moreover the survival rate was significantly higher in the MMC+FT+PSK group than in the MMC+FT group (p<0.01). According to the analysis on stratification, the MMC+FT+PSK group showed the best survival rate in cases with positive lymph node metastases, positive serosal invasion and positive lymph node metastases plus serosal invasion, and in cases of undifferentiated carcinoma by histological type and in those with a preoperative positive PPD reaction (p<0.01 or p<0.05). Thus, the combination of MMC, FT and PSK was indicated to be useful as an adjuvant immunochemotherapy for those patients with gastric cancer submitted to curative resection. The Co-operative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer     

Postoperative adjuvant chemotherapy for gastric cancer, the second report. Analysis of data on 2873 patients followed for five years

The effectiveness of combination chemotherapy with mitomycin-C (MMC) plus futraful (N1-(2'-tetrahydrofuryl)-5-fluorouracil), as an adjunct to surgery for gastric cancer was investigated in a prospective randomized controlled study. Three thousand and thirty-three Japanese patients in 344 hospitals were entered and 2873 could be followed for 5 years. All patients had undergone gastrectomy from April 1977 to May 1979 and were assigned, at random, to either Groups A, B or C. In Group A, bolus MMC was administered with no further treatment. In Group C, oral futraful was given for one year, without MMC induction. In Group B, both a bolus MMC injection and oral futraful were prescribed. This randomized study showed no statistical difference in the 5 year survival rate among the three groups. However, in patients given MMC and put on oral futraful for one year, the 5 year survival rate for those with stage III gastric cancer or for those with positive lymphnode metastasis plus obvious serosal invasion seemed to be improved.     

Postoperative adjuvant chemotherapy for gastric cancer,the second report. Analysis of data on 2873 patients followed for five years

The effectiveness of combination chemotherapy with mitomycin-C (MMC) plus futraful (N₁-(2′-tetrahydrofuryl)-5-fluorouracil), as an adjunct to surgery for gastric cancer was investigated in a prospective randomized controlled study. Three thousand and thirty-three Japanese patients in 344 hospitals were entered and 2873 could be followed for 5 years. All patients had undergone gastrectomy from April 1977 to May 1979 and were assigned, at random, to either Groups A, B or C. In Group A, bolus MMC was administered with no further treatment. In Group C, oral futraful was given for one year, without MMC induction. In Group B, both a bolus MMC injection and oral futraful were prescribed. This randomized study showed no statistical difference in the 5 year survival rate among the three groups. However, in patients given MMC and put on oral futraful for one year, the 5 year survival rate for those with stage III gastric cancer or for those with positive lymphnode metastasis plus obvious serosal invasion seemed to be improved.     

Prolonged survival of gastric cancer patients on a specific adjuvant chemotherapy

Since 1970, there has been a remarkable improvement in Japan in the outcome of surgery for patients with gastric cancer. Not only the increased rate of detection of early gastric cancer but the standardization of the prophylactic extended lymphadenectomy (ELX) has brought about a remarkable rise in survival rate. In patients with regional lymph node metastasis, we obtained a 5 year survival rate of 39 percent in the ELX group, whereas the rate was only 18 percent in the simple gastrectomy group. The difference was statistically significant (P<0.001). As to adjuvant chemotherapy, the Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer found in data on 1,805 patients followed for 5 years that the protocol, intraoperative bolus intravenous injection of Mitomycin C (MMC) plus oral administration of Futraful (Tegafur) for 3 months, concomitantly applied with ELX, proved to be effective for improving the survival of patients with advanced cancer such as stage III and positive lymph node metastasis with obvious serosal invasion. The 5 year survival rate of Japanese patients with gastric cancer after resective surgery was an overall 56 percent, 48 percent when confined to those with stage III cancer.     

血管内皮生长因子-C和生存素在胃癌组织中的表达及其临床意义

目的 探讨胃癌组织中血管内皮生长因子（vascular endothelial growth factor，VEGF）-C和生存素（sunrivin）蛋白表达及其临床意义。方法 采用免疫组织化学SP法检测97例原发性胃癌组织、癌旁组织及20例正常胃黏膜组织中VEGF-C和survivin蛋白的表达，并分析其与临床病理特征和预后的关系。结果 胃癌组织VEGF-C和survivin蛋白表达阳性率分别为66．0％和57．2％，显著高于癌旁组织和正常胃组织（P〈0．05）；VEGF-C蛋白表达与肿瘤分化程度、肿瘤部位、肿瘤直径、静脉侵犯及远处转移等无关，但与淋巴结转移、淋巴管侵犯、浆膜面受累和肿瘤TNM分期等密切相关；survivin蛋白表达与肿瘤分化程度、肿瘤部位、肿瘤直径、静脉侵犯等无关，但与浆膜面受累、淋巴管侵犯、淋巴结转移、远处转移和肿瘤TNM分期等密切相关；VEGF-C和survivin阳性表达组术后生存率明显低于阴性组；VEGF-C和survivin在胃癌组织中阳性表达呈正相关。结论 VEGF-C及survivin蛋白的阳性表达可作为胃癌预后不良的参考指标。     

Combination chemoimmunotherapy for advanced gastric carcinoma

Eighty-nine patients with advanced gastric carcinoma were treated with a combination chemo-immunotherapy regimen that consisted of active immunotherapy with Vibrio cholerae neuraminidase (VCN) treated autologous tumor cells admixed with BCG and drugs including cyclophosphamide, mitomycin C (MMC) and 5-fluorouracil, followed by long term tegafur (FT) and immunomodulators. This treatment significantly improved survival rate of patients in Stages III, IV and unresectable or recurrent carcinoma, compared to that of historical controls. As compared to controls treated with MMC followed by long term FT and immunodulators concurrently, survival rate of those in Stage III tended to improve (p<0.1) and survival rate at 4.5 years in Stage III was significantly higher (p<0.01), although it was not improved in Stage IV. In patients with unresectable or recurrent tumor, survival time was not significantly lengthened with this therapy when compared with that in patients given BCG alone in the same treatment schedule (CCI-BCG group). However, none of 19 patients in CCI-BCG group survived more than 15 months, although 4 of 28 patients receiving this therapy survived. These results suggest that this combination chemo-immunotherapy is effective for a selected group of patients with advanced gastric carcinoma.     

Clinico-pathological study on recurrent gastric cancer after curative resection

Among 675 patients who had undergone curative resection of gastric cancer during last 13 years, 113 died of cancer recurrence. One hundred and forty-five patients who had survived longer than 5 years were used as controls. In the recurrence group, the primary lesion was larger and the lymph node metastasis more common as compared with the surviving controls. Moreover, these lesions were often located at the upper third of the stomach and exhibited Borrmann 3 or 4 type. Prognostic serosal invasion was positive in 75 per cent of the recurrence group and negative in 84 per cent of the surviving controls. The most frequent mode of recurrence was hematogenous metastasis in negative prognostic serosal invasion (54%) and peritoneal disseminated metastasis in positive prognostic serosal invasion (52%). There were no differences in the distribution of gross and histological types of cancer in the modes of recurrence. It was found that peritoneal dissemination and/or local recurrence dominated as the mode of recurrence (51%), followed by hematogenous metastasis (34%), but that lymph node recurrence was uncommon (15%). In peritoneal disseminated cases, long-term survival following reoperation should not be expected. It was suggested that in order to improve the prognosis in the case of hematogenous metastasis, postoperative immunochemotherapy should be applied.     

The clinical usefulness of preoperative CEA determination in gastric cancer

Between 1980 and 1984, preoperative serum carcinoembryonic antigen (CEA) was determined in 468 patients with gastric cancer to evaluate its clinical usefulness. The positive rate of preoperative CEA was 20.9 per cent in these 468 patients. A significantly higher CEA positive rate was obtained in those patients with liver metastasis (69.2 per cent), n3-4 (40.0 per cent), stage IV gastric cancer (37.0 per cent) and Pap, Tub1 histological type (26.3 per cent) (p less than 0.01). It is interesting that the positive rate of the 49 unresectable patients was 51.0 per cent, which was significantly higher than 17.4 per cent of the 419 resectable cases (p less than 0.01). CEA levels in 16 of the 39 patients with liver metastasis were more than 100 ng/ml. In contrast, serosal invasion and peritoneal metastasis were less correlated to the CEA positive rate. In the 419 resected cases, the 5 year survival rate in the higher CEA group of more than 50 ng/ml (35 cases) was 4.4 per cent, which was significantly lower than 64.0 per cent in the negative group (346 cases) (p less than 0.01). These results show that CEA determination in patients with gastric cancer is useful for the prediction of prognosis, as well as for a diagnostic tool to discover the presence of liver or lymph node metastasis.     

淋巴结转移对无浆膜浸润胃癌患者预后的影响

目的 探讨淋巴结转移对无浆膜浸润胃癌预后的影响.方法 回顾性分析1994年1月至2005年12月间大连医科大学附属第一医院普通外科行D2或D2以上胃癌根治术、且具有完整随访资料的616例无浆膜浸润胃癌患者的临床资料;并选取同期接受相同术式的有浆膜浸润的162例胃癌患者为对照组.结果 无浆膜浸润胃癌患者的5年生存率为77.9％,明显高于浆膜浸润组的37.3％（P＜0.01）.不同浸润深度患者5年生存率分别为T１a（M）95.6％,T1b（SM） 92.5％,T2（MP）73.5％,T3（SS） 62.7％,T4（SE、SI） 37.3％.按日本第13版《胃癌处理规约》,N0、N1（第1站）、N2（第2站）和N3（第3站）无浆膜浸润胃癌患者的5年生存率分别为91.5％、75.3％、54.8％和14.7％,差异有统计学意义（P＜0.01）;按第7版TNM分期,N0、N1（1～2枚）、N2（3～6枚）、N3a（7～15枚）和N3b（15枚以上）无浆膜浸润胃癌患者的5年生存率分别为91.5％、83.6％、59.8％、17.2％和11.8％,差异亦有统计学意义（P＜0.01）.淋巴结转移是无浆膜浸润胃癌患者预后的独立预后因素（P＜0.0l）.结论 无论是按转移淋巴结的范围还是数量进行评价,淋巴结转移均能对无浆膜浸润胃癌患者的预后作出较好的预测.     

The clinical usefulness of preoperative CEA determination in gastric cancer

Between 1980 and 1984, preoperative serum carcinoembryonic antigen (CEA) was determined in 468 patients with gastric cancer to evaluate its clinical usefulness. The positive rate of preoperative CEA was 20.9 per cent in these 468 patients. A significantly higher CEA positive rate was obtained in those patients with liver metastasis (69.2 per cent), n_3–4 (40.0 per cent), stage IV gastric cancer (37.0 per cent) and Pap, Tub₁ histological type (26.3 per cent) (p<0.01). It is interesting that the positive rate of the 49 unresectable patients was 51.0 per cent, which was significantly higher than 17.4 per cent of the 419 resectable cases (p<0.01). CEA levels in 16 of the 39 patients with liver metastasis were more than 100 ng/ml. In contrast, serosal invasion and peritoneal metastasis were less correlated to the CEA positive rate. In the 419 resected cases, the 5 year survival rate in the higher CEA group of more than 50 ng/ml (35 cases) was 4.4 per cent, which was significantly lower than 64.0 per cent in the negative group (346 cases) (p<0.01). These results show that CEA determination in patients with gastric cancer is useful for the prediction of prognosis, as well as for a diagnostic tool to discover the presence of liver or lymph node metastasis.     

Laparoscopic Cholecystectomy: Its Effect on the Prognosis of Patients with Gallbladder Cancer

Numerous reports suggest more recurrences and a worse prognosis after laparoscopic cholecystectomy (LC) than after open cholecystectomy (OC). The objective of this study was to compare the survival rate of patients undergoing a laparoscopic procedure versus those undergoing an open operation. A series of 24 patients with gallbladder cancer detected after LC were compared with 40 consecutive patients with gallbladder cancer detected after OC. Patients were matched by wall invasion, age, and whether they underwent a reoperation or only cholecystectomy. The series included 2 patients with in situ tumors, 2 with mucosal tumors, 1 with muscular invasion, 13 with subserosal invasion, and 6 with serosal invasion. Recurrences were observed in 4 of the 10 patients with subserosal compromise who underwent reoperation. In contrast, in the OC group of 26 patients with subserosal invasion, 20 of whom were reoperated, only 2 had a recurrence. Of the six patients with serosal infiltration, three in the LC underwent reoperation, all of whom had recurrences that precluded resection. Of the 12 patients in the OC group who presented with serosal invasion, 6 were reoperated and 4 had a recurrence. Overall survival curves did not show differences when patients were compared according to the type of procedure performed. Similarly, the analysis of patients according to the level of wall invasion indicated that there was no significant difference in survival. Although multiple reports have shown a worse prognosis for patients with gallbladder cancer undergoing LC, this study did not show a significant survival difference between the two methods. Although there is a higher but insignificant recurrence rate among the patients who underwent LC, this is not translated into survival.     

Proposal of a risk score for recurrence in patients with curatively resected gastric cancer

In this study, 168 patients who underwent curative resection for gastric cancer with prognostic serosal invasion [ps(+)] and 150 without prognostic serosal invasion [ps(–)] were analyzed separately to determine the prognostic importance of clinicopathological factors, and identify which patients were at high risk of recurrence. A multivariate analysis of survival time using Cox's proportional hazard model revealed the important prognostic factors to be: Lymph node involvement, the classification of gross appearance, macroscopic serosal invasion, and interstitial connective tissue in the ps(+) group; and lymph node involvement, macroscopic serosal invasion, and venous invasion in the ps(–) group. We proposed a risk score of recurrence based on the results of a further multivariate analysis called Hayashi's Quantification Analysis II, in which recurrence was chosen as an objective variable and the above prognostic factors were chosen as explanatory variables. Eighty-four percent of the patients with a score of 0 or higher in the ps(+) group and 83% of those with a score of +6 or higher in the ps(–) group showed recurrence. Thus, we believe that this score is useful for identifying those patients at high risk of recurrence, who should receive intensive chemotherapy even after curative resection.     

Serosal invasion in TNM staging of mass-forming intrahepatic cholangiocarcinoma

Background/Purpose The Liver Cancer Study Group of Japan established a tumor-nodule-metastasis (TNM) staging system for mass-forming intrahepatic cholangiocarcinoma, with T determined by tumor number and size and vascular or serosal invasion. Serosal invasion is not considered in the designation established by the International Union Against Cancer. Methods Sixty-three patients who underwent hepatic resection for mass-forming intrahepatic cholangiocarcinoma were investigated retrospectively, with the investigation including univariate and multivariate analyses of potential prognostic factors. Results By log-rank test, tumor size more than 3.0 cm, vascular invasion, lymph node metastasis, intrahepatic metastasis, and involved resection margin, but not serosal invasion, were associated significantly with poor prognosis. Even in patients with serosal invasion, the postoperative outcome was much better in those without than in those with vascular invasion. Multivariate analysis identified vascular invasion, lymph node metastasis, and an involved resection margin as independent prognostic factors. When serosal invasion was excluded from tumor staging, the 5-year survival rates became more clearly stratified: 100% in those with stage I disease, 62% in those with stage II, 25% in those with stage III, and 7% for patients with stage IV. Conclusions Serosal invasion showed no survival impact after hepatic resection for mass-forming intrahepatic cholangiocarcinoma. When serosal invasion was omitted from the TNM staging proposed by the Liver Cancer Study Group of Japan, stratification of postoperative survival between stages was more effective.     

进展期胃癌腹主动脉旁淋巴结转移规律及其清扫对临床结局的影响

目的 分析进展期胃癌腹主动脉旁淋巴结转移规律，评价该区域淋巴结清扫对临床结局的影响。方法 根据1994—2004年胃癌数据库资料，按1999年日本第13版胃癌规约的淋巴结清扫分类，行D3或D3^＋淋巴结清扫（D3组）共126例，分析其淋巴结转移的规律。从同一数据库中选择同一手术组施行D2手术的患者146例（D2组），对两组患者的临床结局进行比较。结果 16a2区及16b1区是No16淋巴结转移常见部位。腹主动脉周围淋巴结转移率T1为3、8％，T2为22、3％，T3为46．8％，T4为32．1％；腹膜播散阴性者其转移率为16、3％，腹膜播散阳性者则为69、5％；浆膜无侵犯者转移率为16．3％，浆膜侵出阳性者则为69．5％。D2和D3组患者手术死亡各2例，并分别有4例和6例出现并发症（P〉0、05）。D3组No16淋巴结转移3枚以下与4枚以上者与D2清扫组的平均生存期、中位生存及生存率比较，差异均有统计学意义（P〈0．01）；胃癌D3与D2手术后Ⅰ期、Ⅱ期、Ⅲ。期、Ⅲb期、Ⅳ期患者平均生存期、中位生存及生存率曲线比较，差异均有统计学意义（P〈0．01）。结论 胃癌淋巴结转移率与肿瘤侵犯深度和浆膜侵出程度密切相关。腹主动脉周围淋巴结清扫可以提高No16转移淋巴结在3枚以内和阴性患者的5年生存率。     

Oral fluoropyrimidines may not reduce the risk of postoperative recurrence in colorectal cancer associated with mesenteric lymph node metastasis

To clarify the efficacy and problems of postoperative adjuvant chemotherapy using oral fluoropyrimidines, the clinicopathological data of 307 colorectal cancer patients treated with or without postoperative chemotherapy were analyzed retrospectively. Patients in the chemotherapy group (n=188) who underwent curative resection were followed by administration of oral fluoropyrimidine. The other 119 patients underwent surgery alone. The disease-free survival rates were compared between the two groups. The disease-free survival rate in the chemotherapy group was significantly higher than that in the surgery alone. However, no significant difference in disease-free survival rate was found for those with tumors that were associated with mesenteric lymph node involvement and tumors with a high grade of lymphatic invasion or high grade of venous invasion. Postoperative adjuvant chemotherapy using oral fluoropyrimidines such as UFT (litegafur +4:uracil) and 5'-DFUR (doxifluridine) might not reduce the risk of recurrence in colorectal cancer with mesenteric lymph nodes involvement.     

Prognostic significance of serosal invasion and free intraperitoneal cancer cells in gastric cancer

Survival rates after curative gastrectomy for advanced gastric cancer among 238 patients in whom the cancer was invading the serosa were compared with 283 patients without serosal invasion. Generalized Wilcoxon estimates for 5-year survival rate were 47.1 per cent for patients exhibiting serosal invasion and 75.9 per cent for patients without serosal invasion. The frequency of lymph node metastasis increased proportionately with the extent of serosal invasion: 18.4 per cent in cases of S0; 53.8 per cent in cases of S1; 80.0 per cent in cases of S2; and 91.4 per cent in cases of S3. The higher the aggregate total of S (serosal invasion) and n (lymph node metastasis) factors, the lower the 5-year survival rate. In addition, patients with serosal invasion had a propensity for peritoneal dissemination of cancer cells; the percentage of cases with intraperitoneal free cancer cells increased with the extent of serosal invasion. It is worth noting that when cancer infiltration proceeded to the deeper layers and was accompanied by nodal metastasis, cancerous invasion of the perinodal fatty tissue was frequently evident. Therefore, unfavourable prognosis after curative resection in gastric cancer patients with serosal invasion may be largely dependent on whether or not the cancer has invaded the peritoneal cavity and the perinodal fatty tissue.     

Mitomycin C plus carmofur (HCFU) adjuvant chemotherapy for noncuratively resected cases of colorectal carcinoma (interim report)

In order to examine the efficacy of adjuvant chemotherapy employing Mitomycin C (MMC) and carmofur (HCFU) for patients with noncuratively resected colorectal carcinoma, a cooperative study was performed by 54 institutions in the Kyushu and Chugoku areas in Japan. The prospective randomized controlled study consisted of two groups, one receiving only MMC and the other receiving MMC as well as HCFU. Out of an original total of 200, 170 cases were evaluable. Concerning the 30-month survival rate, a better result was observed in the MMC + HCFU group than in the MMC only group (Z-test: p less than 0.05). Significantly better survival rates were obtained in those cases with disseminating peritoneal metastasis, hepatic metastasis and Stage V cancer in the MMC + HCFU group as when compared with the MMC only group (generalized Wilcoxon test: p less than 0.05). No significant side effects due to the combined administration of HCFU were recognized. The combined administration of MMC and HCFU were recognized. The combined administration of MMC and HCFU was suggested to be a safe and effective adjuvant chemotherapy in noncuratively resected cases of colorectal carcinoma.     

The Implications of Positive Peritoneal Lavage Cytology in Potentially Resectable Pancreatic Cancer

Background

The clinical implications of peritoneal lavage cytology (CY) status in patients with potentially resectable pancreatic cancer have not been established.

Method

We retrospectively reviewed clinical data from 254 consecutive patients who underwent macroscopically curative resection for pancreatic cancer from February 2003 to December 2010 in our institution. Correlations between CY status and survival and clinicopathological findings were investigated.

Results

Of the 254 patients, 20 were CY+ (7.9?%). There were no significant differences between CY+ and CY? patients in background data (age, sex, the level of preoperative tumor marker, and adjuvant chemotherapy). Patients with positive serosal invasion were more likely to be CY+ than those with negative serosal invasion (P?P?=?0.302). The median recurrence-free survival of CY+ and CY? patients was 8.1?months (95?% CI?=?0.0–17.9) and 13.5?months (95?% CI?=?11.5–15.5), respectively (P?=?0.089).

Conclusion

CY+ status without other distant metastasis does not necessarily preclude resection in patients with pancreatic cancer.     

Effect of intra-hepatoarterial infusion of MMC and CDDP for gastric cancer patients with liver metastases

The influence of operative treatment and chemotherapy on the prognosis in 93 gastric cancer patients with liver metastasis was studied. Chemotherapy included the systemic administration of mitomycin C (MMC) (39 patients), an intra-hepatoarterial infusion of MMC (MMC IAC group) (19 patients) and an intra-hepatoarterial infusion of MMC and cisplatin (CDDP) (MMC + CDDP IAC group) (24 patients). Either MMC or MMC and CDDP were given in 1–4 courses every 3–4 weeks from the first one to two post operative weeks. The response rate was 4 per cent (1/23), 29 per cent (5/17) and 73 per cent (17/23) for MMC systemic administration, MMC IAC and MMC + CDDP IAC, respectively, with a significantly high rate of effectiveness for the MMC + CDDP IAC. In addition, regarding the median survival period, the MMC + CDDP IAC group showed 11.8 months, as compared with 2.9 months for other chemotherapeutic treatments, indicating a good prognosis regardless of any possible resection of the primary lesion. A Cox proportional hazard model revealed the treatment by MMC + CDDP IAC alone to be a significant independent factor. These results indicated that MMC + CDDP intra-arterial chemotherapy is an effective approach to gastric cancer with liver metastasis.