Toxicity and effects of adjuvant therapy in colon cancer: results of the german prospective, controlled randomized multicenter trial fogt-1

In this adjuvant three-arm multicenter trial, we studied whether modulating the standard 5-fluorouracil (S-FU) treatment with either folinic acid (FA) or interferon-alpha-2_a (IFN-α) was superior to the recommended standard of adjuvant treatment in RO resected colon cancer, 5-FU plus levamisole (LEV) for 12 months, in terms of toxicity and outcome. From July 1992 to October 1999, a total of 813 patients with resected colon cancer in stage II (T4N0M0; n = 63) or stage III (TxNl-3M0; n = 750) were randomized into three treatment groups and stratified according to N stage and participating centers (64 hospitals). The patients received a postoperative loading dose of S-FU (450 mg/m² on days 1 to 5 [arms A and C]) or S-FU (450 mg/m²) plus FA (Rescuvolin, Medac, Hamburg, Germany, 200 mg/m² on days 1 to 5 [arm BJ). After completion of the first chemotherapy cycle, LEV was administered orally at a dosage of 1.50 mg per day on days 1 to 3, once every 2 weeks. After a 4-week chemotherapy-free interval, the treatment was continued weekly for 52 weeks. Treatment in one arm A ("standard") (n = 279) consisted of 5-FU intravenously (450 mg/m² on day 1, once a week) plus LEV 5-FU plus LEV was modulated in arm B (n = 283) with FA (200 mg/m² on day 1, once a week) and in arm C (n = 251) with IFN-α at 6 million units three times a week repeated weekly. Treatment dosages were adjusted if toxic events above WHO grade 2 occurred. Patients were closely followed to determine recurrence and survival; the latter was calculated according to Kaplan-Meier analysis. Toxic events above WHO grade 2, mainly leukopenia, diarrhea, and nausea, occurred in 113 (14%) of 649 patients who had completed treatment in arms A (8.4%), B (13.5%), and C (31.7%). Discontinuance rates were as follows: 28% for all patients, 29% in arm A, 21% in arm B, and 34% in arm C. Overall relapse rates were 27% for all patients, 30% in arm A, 24% in arm B, and 28% in arm C. Relapses were local (8%) distant (78%), or combined (12%). Fouryear overall survival rates in arms A, B, and C were 66.1%, 77.5%, and 66.2%, respectively. The 4-year survival rate in arm B was significantly higher compared to arm A (P <0.02, log-rank test) with arm A being equal to arm C. Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV for 12 months). IFN-α modulation of 5-FU (plus LEV) adds to the toxicity with no therapeutic benefit.     

亚叶酸与5－FU联合化疗防治结直肠癌复发（附87例分析）

自１９８８年以来采用亚叶酸和５－ＦＵ联合化疗结直肠癌２６２例，经随访生存逾５年者８７例。６６例为术后辅助化疗组，属ＤｕｋｅｓＡ期１４例，Ｂ期１５例，Ｃ期３７例。２１例为治疗组，均系Ｄ期病例。化疗采用亚叶酸１５０～３００ｍｇ／ｄ和５－ＦＵ１０００ｍｇ／ｄ静脉滴注，连续５天为１疗程，每月１次，共６～９疗程。结果显示，辅助化疗组总的５年生存率为６６．６７％。治疗组总有效率５２．３８％。本研究表明，亚叶酸和５－ＦＵ联合化疗不论作为辅助或治疗均是安全和有效的选择。     

An anticancer drug sensitivity test to determine the effectiveness of UFT as postoperative adjuvant chemotherapy for patients with stage III colorectal cancer

BACKGROUND: Tissue samples from patients with pathologic ((p)) stage III colorectal cancer were tested for sensitivity to 5-fluorouracil (5-FU). On the basis of the results, patients were divided into 5-FU-sensitive and 5-FU-resistant groups, and both groups were treated with fluoropyrimidine (UFT) as postoperative adjuvant chemotherapy. Recurrence, 5-year survival rates, and 5-year recurrence-free survival rates were compared. METHODS: The anticancer sensitivity test described in this study was carried out using tumor samples obtained surgically from 34 patients with curatively resectable colorectal cancer that had been diagnosed definitively as (p)stage III (IIIa, 23 patients; IIIb, 11 patients). Regardless of tumor sensitivity or resistance to 5-FU, all 34 patients were subsequently treated daily with UFT at 300 mg/day as postoperative adjuvant chemotherapy. Treatment was initiated 3 weeks after surgery and continued for 2 years. RESULTS: Of the 34 patients with (p)stage III colorectal cancer, the tumors of 16 (47%) were 5-FU-sensitive (S group) and 18 (53%) were 5-FU-resistant (R group). The recurrence rates in the S and R groups following postadjuvant therapy with UFT were 25% and 61%, respectively, which is a significantly lower response in the S group (P = .045). The odds ratio of recurrence in the R group vs. the S group was 4.71. The 5-year survival rate was 85.7% in the S group and 46.7% in the R group, but the difference was not significant (P = .066). The 5-year recurrence-free survival rate was significantly higher in the S group than in the R groups (71% vs. 32%, P = .010). According to Cox's multivariate analysis of recurrence-free survival, the sensitivity test was significantly predictive. CONCLUSION: Administration of UFT as postoperative adjuvant therapy to 5-FU-resistant patients had no significant effect on outcome.     

Randomized trial of the efficacy of adjuvant chemotherapy for colon cancer with combination therapy incorporating the oral pyrimidine 1-hexylcarbamoyl-5-fluorouracil

BACKGROUND AND AIMS: The purpose of the present trial was to clarify the efficacy of postoperative adjuvant chemotherapy including an oral fluoropyrimidine anticancer drug, the 1-hexylcarbamoyl-5-fluorouracil (HCFU), for the treatment of colon cancer. METHOD: Patients with clinical stage Dukes' B and C colon cancer, who had been treated surgically, were assigned to a chemotherapy group treated with mitomycin C, 5-fluorouracil (5-FU), and HCFU and to a control group that received no postoperative adjuvant chemotherapy. RESULTS: Of the 1,001 patients registered for the study, 17 (1.7%) were ineligible. The incidence of toxicity was significantly higher in the chemotherapy group than in the control group. However, there were few severe side effects and no deaths related to the treatment. Overall survival showed no significant difference between the groups. The disease-free survival or the recurrence-free intervals was significantly higher in the chemotherapy group than in the control group. The incidence of hepatic recurrence was significantly (P=0.003) lower in the chemotherapy group than in the control group. CONCLUSION: The results of this study demonstrated the efficacy of adjuvant chemotherapy for colon cancer, i.e., combined chemotherapy that included the 5-FU oral anticancer drug HCFU.     

Efficacy of a continuous venous infusion of fluorouracil and daily divided dose cisplatin as adjuvant therapy in resectable colorectal cancer: A prospective randomized trial

PURPOSE: Daily divided dose cisplatin (DDD-P) is used as an efficient modulator of fluorouracil (5-FU), as is leucovorin (LV). We performed a randomized trial to compare the efficacy 5-FU plus DDD-P (DDD-FP) therapy with 5-FU alone in resected colorectal cancer as the adjuvant therapy. METHODS: One hundred and eighty-eight stage II or III colorectal cancer patients were enrolled. Patients were randomly assigned to receive DDD-FP (5-FU, 320 mg/ m(2), daily for 21 days; CDDP, 3.5 mg/m(2) daily for 21 days) followed by oral 5-FU (200 mg/body daily for 2 years) (DDD-FP arm) or oral 5-FU therapy (200 mg/ body daily for 2 years) exclusively (oral 5-FU arm). RESULTS: The 5-year disease-free survival (DFS) rates and the overall survival (OS) rates indicated no significant difference between the two arms. By stratified analysis, in the colon cancer patients, the DFS and the OS for the DDD-FP arm were significantly increased: 93.5% and 95.7% in the DDD-FP arm as compared with 76.9% and 82.2% in the oral 5-FU arm (P = 0.024 and P = 0.038). Regarding adverse effects, grade 3-4 toxicities were not significant in two arms. CONCLUSIONS: DDD-FP followed by oral 5-FU therapy suggested a feasible regimen for patients with resected colon cancer as the adjuvant therapy.     

Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method

Background Thymidylate synthase (TS) is regarded as a parameter of 5-fluorouracil (5-FU) chemosensitivity for colorectal carcinoma. Recent researchers indicate that the chemosensitivity of 5-FU for colorectal carcinoma with low expression of TS is better than tumors with high expression of TS. But the relation between TS expression and overall survival of curatively resected colorectal cancer patients has been less studied. Methods Specimens of curatively resected colon carcinoma from 148 patients were included in this study. TS expression in the tumor was assessed by immunohistochemical staining technique, and the patients were categorized into TS-(+) and TS-(−) groups. First, the relation between TS expression and survival of patients was examined. Next, for each group, we compared survival between the chemotherapy-(+) and the chemotherapy-(−) subgroup. Results Overall survival was significantly better in the TS-(−) group (n=107) than in the TS-(+) group (n=41) (P=.0003). In the TS-(−) group, there was little difference between the chemotherapy-(+) and the chemotherapy-(−) subgroup. In the TS-(+) group, the survival of the chemotherapy-(+) subgroup was significantly better than the chemotherapy-(−) subgroup (P=.0439). Conclusions TS, itself, may be a prognostic factor for colon carcinoma; and 5-FU adjuvant chemotherapy may be appropriate for colon carcinoma with high expression of TS.     

Bisherige entwicklungen und aktueller stand der adjuvanten chemo- und radiotherapie beim kolon- und rektumkarzinom

Zusammenfassung In der Arbeit werden bisherige und aktuelle Konzepte der adjuvanten Chemo- und Radiotherapie in einer Übersicht dargestellt. Nach frühen Chemotherapiestudien mit systemischem Einsatz verschiedener Einzelsubstanzen folgten Versuche, die therapeutische Effizienz durch Wirkstoffkombinationen zu steigern. 5-FU erwies sich als relativ wirkungsvollste Einzelsubstanz, 5-FU/MeCCNU/Vincristin als wirksamste Kombination. Verbesserungen der Fünfjahresüberlebensraten konnten nur vereinzelt erzielt werden. Einen deuthchen Fortschritt erbrachte die Modulation der 5-FU-Wirkung durch Levamisol (LEV). Hierdurch wurde fur Kolonkarzinome im Stadium Dukes C eine Verbesserung der Fünfjahres-überlebensrate um 33% erzielt. Basierend auf diesen Daten wird empfohlen, alle Kolonkarzinompatienten im Stadium III mit 5-FU/LEV zu behandeln, soweit sie nicht einer aktuellen Adjuvansstudie zugeführt werden können. Der Empfehlung kann his heute noch keine weitere allgemeine Richtlinie hinzugefügt werden. Beim Rektumkarzinom kann durch prdoperative Radiotherapie ein Down-Staging nach Dosen von 35-45 Gy erzielt werden. Eine signifikant positive Beeinflussung der Überlebens-prognose ist jedoch weder durch eine alleinige prä- noch postoperative adjuvante Bestrahlung überzeugend dokumentiert. Demgegenüber konnten durch kombinierte postoperative Radio-Chemo-Therapien (5-FU/MeCCNU) sowohl verbesserte Überlebensraten als auch eine verbesserte lokale Tumorkontrolle im Vergleich mit der alleinigen Resektion aufgezeigt werden. Es besteht die Empfehlung, alle Rektumkarzinompatienten im Stadium II und III einer kombinierten Radio-Chemo-Therapie unter Studienbedingungen zuzuführen. Als effektivste Chemotherapie in Verbindung mit Radiatio gilt 5-FU/MeCCNU. Interimsergebnisse deuten jedoch darauf hin, daß MeCCNU verzichtbar ist. Die intraoperative Radiatio (IORT) erlaubt eine Dosiseskalation zur Optimierung der lokalen Tumorkontrolle bei maximaler Schonung strahlensensibler Strukturen. Bisher liegen noch wenig Ergebnisse vor. Eine generelle Wertung der IORT im Rahmen adjuvanter Konzepte ist noch nicht möglich. Die bisherigen Daten sind jedoch erfolgversprechend.

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Developments and current status of adjuvant chemo-and radiotherapy for colorectal cancer

A review is given of the historical and current concepts of adjuvant chemo- and radiotherapy of colorectal cancer. Early studies analyzing the use of single drug regimens were followed by a second study generation investigating adjuvant chemotherapeutic combinations. 5-FU proved to be the most efficient single drug investigated and 5-FU/MeCCNU/vincristin the most efficient chemotherapeutic combination, but no significant improvement in 5-year survival rates was achieved. Clear progress was noted with the introduction of levamisol (LEV) for modulation of 5-FU. A 33% improval in the 5-year survival rate in patients with stage III colon carcinoma was documented. It was therefore recommended (NIH consensus conference 1990) that all patients with stage III colon carcinoma be treated with this regimen unless admitted to other trials of adjuvant therapy. Preoperative radiotherapy with a dosage of 35–45 Gy can lead to downstaging of rectal cancer. Nevertheless, significant improvement in patient survival has not been proved convincingly using either isolated pre- or postoperative adjuvant radiotherapy. However, combined radiochemotherapy has been shown to improve both patient survival and local tumor control compared to surgical resection alone. It is therefore recommended that all stage II and III rectal cancer patients be treated with adjuvant combined radiochemotherapy. 5-FU/MeCCNU is currently expected to be the most efficient chemotherapy in combination with radiotherapy. Early data point out that MeCCNU could possibly be omitted. Intraoperative radiotherapy (IORT) allows further dosage escalation in order to improve local tumor control without affecting radiosensitive structures. Available data are still sparse and mostly based on the treatment of advanced carcinoma. A general validation of IORT is not yet possible, but current data are promising.

     

Evaluation of the relevance of lymph node density in a contemporary series of patients undergoing radical cystectomy

PURPOSE: Lymph node density, that is the ratio of positive nodes to the total number of nodes excised, has been suggested to better stratify patients with bladder cancer who have nodal metastasis. We evaluated its relevance in a contemporary series of patients treated with radical cystectomy and in the context of adjuvant chemotherapy. MATERIALS AND METHODS: From 1993 to 2003, 150 patients had pN+M0 disease at cystectomy, of whom 108 who did not receive neoadjuvant chemotherapy form the basis of this report. Statistical analyses were performed using standard methodology. RESULTS: Five-year overall, disease specific and recurrence-free survival rates were 30.9%, 45.5% and 29.7%, respectively. The median number of lymph nodes removed was 12 and the median number of positive nodes was 2. Of the patients 70% received adjuvant chemotherapy. Patients with a lymph node density of 25% or less had 5-year overall and recurrence-free survival rates of 37.3% and 38.1% compared with 18.7% and 10.6%, respectively in those with a lymph node density of greater than 25% (p = 0.02). In the context of adjuvant chemotherapy, which was associated with prolonged overall, disease specific and recurrence-free survival (p < or =0.01), lymph node density still remained prognostic for recurrence-free survival (HR 1.69, p = 0.047). The total number of nodes removed and the number of positive nodes were not prognostic. CONCLUSIONS: Our results support the relevance of lymph node density in a contemporary series of patients with bladder cancer treated with radical cystectomy. Lymph node density remains a significant prognostic factor for recurrence-free survival even when adjuvant chemotherapy is used.     

Intraarterial Adjuvant Chemotherapy after Pancreaticoduodenectomy for Pancreatic Cancer: Significant Reduction in Occurrence of Liver Metastasis

The clinical benefit of adjuvant chemotherapy in pancreatic cancer patients is still questionable. Phase II studies using radiochemotherapy based on 5-fluorouracil (5-FU) provided evidence of an increase in median survival times. Because palliative chemotherapy by celiac artery infusion (CAI) led to an increase in survival in pancreatic cancer, we treated 24 patients with adjuvant CAI following resection of the head of the pancreas for pancreatic cancer (21 patients with Union Internationale contre le Cancer (UICC) stage III, 2 with UICC stage II, 1 with UICC stage I). Catheters were placed angiographically into the celiac artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-FU, folinic acid, and cisplatinum. This treatment was repeated five times at monthly intervals. CAI was well tolerated, and World Health Organization (WHO) grade III toxicities were observed in 8%; WHO grade IV was seen in none of the treatment cycles. Furthermore, we observed pain reduction in nearly all patients under CAI. Median survival times in patients who received CAI were 23 months for all patients, whereas in patients who did not receive adjuvant treatment the median survival was 10.5 months. With Kaplan-Meier regression analysis of the patients who were curatively resected (R0 resection) and received CAI, the overall 4-year survival was 54%, whereas in patients without CAI the 4-year survival was 9.5%. The occurrence of liver metastases in the CAI group went down to 17%. These results demonstrate that CAI is well tolerated, reduces the risk of liver metastasis, and increases the survival time of pancreatic cancer patients.     

Chemotherapy for colorectal cancer

Colorectal cancer is the most commonly diagnosed cancer in the EU. Various randomised studies have shown a survival benefit with chemotherapy in the adjuvant setting. Adjuvant chemotherapy with 5-fluorouracil/folinic acid (5FU/FA) for 6 months after curatively resected node-positive colon cancer has become the standard practice. However, controversy still exists regarding the optimal regimen and whether to treat node-negative patients. The latest QUASAR trial results seem to strengthen the argument in favour of adjuvant treatment of Dukes B cancer. Patients with Dukes B tumours and any adverse prognostic indicator should be given the benefit of adjuvant therapy. A number of novel agents (oxaliplatin, irinotecan) showing activity in advanced disease are currently being evaluated in the adjuvant setting. A patient with metastatic colorectal cancer should today be expected to have a median survival of 18-20 months compared to that of 11-14 months only a few years ago. 5FU/FA has been the mainstay of therapy for metastatic colorectal cancer for over 40 years and confers a survival benefit over supportive care. The response rate of 5FU is improved by modulation with FA or by continuous infusional regimens (currently the best expected response rate is around 20-25%). As per the recent National Institute for Clinical Excellence guidelines, the oral agents capecitabine or tegafur with uracil (in combination with FA) can be used as first-line treatment in metastatic colorectal cancer and, although their response rate has not been directly compared to infusional 5FU, survival is unlikely to be inferior. Newer chemotherapeutic agents like irinotecan and oxaliplatin are now entering regular usage due to improved response rates (around 50% in 5FU/FA-containing doublets) and survival. Irinotecan monotherapy is second-line treatment approved by the National Institute for Clinical Excellence, although sequential infusional 5FU/FA irinotecan to infusional 5FU/FA oxaliplatin may convey the best survival with the least side effects. The position of combination chemotherapy before (to downstage) or after metastasectomy (usually from the liver) is still a topic of heated debate. Other routes (intrahepatic, intraperitoneal) are still to be proven and not recommendable outside the trial setting. The latest results of chemotherapy combinations with biological treatments (bevacuzimab and cetuximab) have been very promising indeed. Further improvements in survival, response and quality of life are expected. .     

Clinical study of clonogenic assays--with reference to adjuvant cancer chemotherapy after operation

One hundred surgical specimens were used for the clonogenic assay to determine the chemosensitivity in vitro and the results were compared with the antitumor effect of the adjuvant cancer chemotherapy after operation. The clonogenic assay was performed according to the method of Salmon et al. The dissociated tumor cells were contacted with drugs in a concentration of 1 microgram/ml for 1 hr. (mitomycin C; MMC) or 2-3 wks. (5-fluorouracil; 5-FU). Fifty percent or more inhibitory rate of the colonies were evaluated as positive. The clinical antitumor effects were assessed by the tumor reduction in non-curatively operated cases and by the survival period after the operation in curatively operated cases. Overall evaluable cases were 52 of 100 cases with a median cloning efficiency rate of 0.1%. The efficacy rates of the drugs in vitro were found to be 21.3% for MMC and 31.8% for 5-FU. The histological differentiations, Stages, pretreatments and cloning efficiency rates were observed to have few influence on the chemosensitivity. Nineteen non-curatively operated cases were eligible for the comparison between in vitro and in vivo, showing 40% true positive, 100% true negative and 84.2% predictable rates. In curatively operated cases, whereas 2 of 14 cases have died of cancer in not adapted adjuvant cancer chemotherapy group, no cancer deaths were encountered in 7 cases whose adjuvant cancer chemotherapy was evaluated as effective in the clonogenic assay. From these findings, it was concluded that in vitro clonogenic assay might be useful to select a suitable adjuvant cancer chemotherapy in curatively operated cases as well as cases with advanced carcinomas.     

Adjuvant intraperitoneal 5-fluorouracil in high-risk colon cancer: A multicenter phase III trial

OBJECTIVE: To evaluate the results of a prospective multicenter randomized study of adjuvant intraperitoneal 5-fluorouracil (5-FU) administered during 6 days shortly after resection of stages II and III colon cancers. SUMMARY BACKGROUND DATA: Systemic adjuvant chemotherapy improves the survival of patients with stage III colon cancer receiving treatment for 6 months. Intraperitoneal chemotherapy theoretically combines peritoneal and hepatic effects. METHODS: After resection, 267 patients were randomized into two groups. Patients in group 1 (n = 133) underwent resection followed by intraperitoneal administration of 5-FU (0.6 g/m2/day) for 6 days (day 4 to day 10). These patients also received intravenous 5-FU (1 g) during surgery. Patients in group 2 underwent resection alone (n = 134). RESULTS: In group 1, 103 patients received the total dose, 18 received a partial dose as a result of technical or tolerance problems, and 12 did not receive the chemotherapy. Rates of surgical death and complications were similar in both groups. Tolerance to treatment was excellent or fair in 97% of the patients and poor in 3%. After a median follow-up of 58 months, 5-year overall survival rates were 74% in group 1 and 69% in group 2; disease-free survival rates were 68% and 62%, respectively. Survival curves were superimposed until 3 years after treatment and began diverging thereafter. Among patients receiving the full treatment, the 5-year disease-free survival rate was improved in the treatment group in patients with stage II cancers but was unchanged in patients with stage III cancers. CONCLUSIONS: Chemotherapy with intraperitoneal 5-FU administered during a short period after surgery was well tolerated but was not sufficient to reduce the risk of death significantly. However, it reduced the risk of recurrence in stage II cancers. These results suggest that it should be associated with systemic chemotherapy to reduce both local and distant recurrences.     

Adjuvant therapy of colorectal cancer: an overview

The substantial recurrence rate of colorectal cancer following potentially curative resection has fuelled the search for effective adjuvant therapy. Previous trials using 5-fluorouracil (5-FU) as a single agent or in combination chemotherapy regimens have not demonstrated meaningful benefits, an impression reflected in the results of a meta-analysis encompassing large patient numbers. Newer developments utilizing intraportal chemotherapy and the combination of 5-FU and levamisole have resulted in lower recurrence rates and improved survival in patients with colon cancer. In advanced disease, the biochemical modulation of 5-FU by Leucovorin has been shown to prolong survival in some studies. Combined chemotherapy and radiotherapy or chemotherapy alone have showed promising results in rectal cancer. These developments have now been incorporated into ongoing trials.     

Antitumor effects of 5-fluorouracil on human colon cancer cell lines: antagonism by levamisole

BACKGROUND: The addition of levamisole (Lev) to 5-fluorouracil (5-FU) for the adjuvant treatment of stage III colon cancer has been shown to improve 5-year survival in patients. The mechanism of action of Lev remains unknown. Because we showed little in vitro immunological effect of Lev, we asked whether Lev, alone or in combination with 5-FU, had antitumor activity in vitro. METHODS: Proliferation of COLO-205 and HT-29 colon cancer cells incubated for 2 to 3 days in Lev and 5-FU was measured in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium colorimetric assays. Cell cycle analysis was performed by treating tumor cells for 6, 24, and 48 h with Lev and 5-FU, staining cells with propidium iodide, and measuring DNA content by flow cytometry. RESULTS: The addition of Lev to 5-FU did not reduce proliferation below that of 5-FU alone. The inhibitory concentration 50% (IC(50)) for 5-FU was 3.2 x 10(-6) M for COLO-205 and 1.3 x 10(-5) M for HT-29. An IC(50) was not reached for Lev, even at millimolar doses. DNA analysis of cells treated for 48 h revealed significant S-phase accumulation of both HT-29 (from 17% in control cells to 36% in treated cells) and COLO-205 (from 35% in control cells to 59% in treated cells) cell lines at micromolar 5-FU concentrations. In contrast, Lev alone did not affect cell cycle distribution for either cell line. The addition of Lev to 5-FU not only did not augment, but inhibited, the effects of 5-FU. CONCLUSIONS: Levamisole has no direct cytotoxic effect and no additive or synergistic cytotoxic effect when combined with 5-FU on two colon cancer cell lines. Either the observed clinical effects of Lev treatment occur through an as yet unknown mechanism, require longer treatment periods in vitro to become evident, or the results of clinical trials showing its effectiveness should be carefully reexamined.     

Protracted oral chemotherapy with fluorinated pyrimidines as an adjuvant to surgical treatment for stomach cancer.

Studies of oral chemotherapy of 5-fluroruracil (5-FU) combined with FT-207, a furanyl analog of 5-FU, as an adjuvant to surgical treatment of stomach cancer have been performed since 1970 in the first department of surgery of Chiba University, Japan. These studies were performed on 107 patients with curative stomach cancer and 22 patients with non-curative stomach cancer. These patients received consecutively 3.5mg/kg/day of 5-FU and 8mg/kg/day of FT-207 for 24 to 36 months and were compared with control patients who had undergone only surgical treatment. A significant higher survival was observed in the curatively resected patients receiving oral 5-FU and FT-207, as compared to the control group. Studies on non-curative stomach cancer patients treated with the same dose schedule gave encouraging results. Because of the limited number of patients treated in this study, the drawing of reliable conclusions must wait the results of further studies.     

Recent advances in chemotherapy for advanced gastric cancer in Japan

In the early 1990s, a combination of 5-fluorouracil (5-FU) and cisplatin was widely adopted to treat advanced gastric cancer; however, no survival advantage over single-agent 5-FU was confirmed by the results of randomized trials conducted over a long period. Recently developed agents such as irinotecan, taxanes (docetaxel), and new oral fluorouracil (S-1) have yielded more promising results, with a response rate of over 50% and a median survival time of over 10 months in combination studies. These newer combination regimens were investigated in various randomized phase III studies to clarify if the newer-generation regimens provided a survival advantage over the oldergeneration regimens. Based on the findings of a large randomized study, S-1 has become standard in the adjuvant setting after D2 dissection curatively resected stage II and III gastric cancer. This article reviews the recent advances in gastric cancer chemotherapy, especially in Japan.     

Systemic treatment of colorectal cancers--factual standards and perspectives

Adjuvant therapy has been shown to reduce recurrence and improve survival in patients with stage III colo-rectal cancer (CRC). However, the use of adjuvant therapy is still much debated in stage II disease. Fluorouracil (5-FU) and folinic acid (FA) are currently the standard adjuvant drug combination. The treatment of patients with metastatic colorectal cance has changed dramatically over the years. The more optimal use of 5-FU in association with FA, the new drugs such as irinotecan and oxaliplatin, and the oral fluoropyrimidines capecitabine and uracil/tegafur(UFT) have contributed to the increased therapeutic option and to improved outcome of patients with metastatic CRC. It has been shown that combination therapy with 5-FU/FA and irinotecan or oxaliplatin is more active than 5-FU/FA in the first line of advanced CRC. The oral fluoropyrimidines capecitabine and UFT/FA seem to have a comparable activity to intravenous bolus 5-FU/FA in the first line treatment of metastatic CRC. New agents acting on novel targets are under development. Epidermal growth factors inhibitors, vascular endothelial growth inhibitors, and cyclo-oxygenase 2 inhibitors might play a role in the future in the treatment of CRC.     

A Phase II Prospective Multi-institutional Trial of Adjuvant Active Specific Immunotherapy Following Curative Resection of Colorectal Cancer Hepatic Metastases: Cancer and Leukemia Group B Study 89903

Background Patients with curatively resected colorectal cancer hepatic metastases often harbor occult metastatic disease and are at high risk of experiencing recurrence. This patient cohort is ideally suited to test novel therapies such as immunotherapy. We treated patients—post-hepatic resection—with anti-idiotype monoclonal antibody vaccines to the tumor-associated antigens carcinoembryonic antigen (CeaVac) and human milk fat globule (TriAb), both of which are co-expressed in more than 90% of colorectal cancer patients. Methods Vaccinations commenced 6–12 weeks post-hepatic resection and consisted of four biweekly treatments of 2 mg CeaVac and TriAb, then monthly treatments for 2 years, then on every other month for 3 years. The primary endpoint was to investigate the proportion of patients recurrence-free at 2 years, and the objective of the study was to demonstrate that at least 58% would be recurrence-free at this time to consider the regimen worthy of further study. Results Between July 2001 and October 2004, 56 patients were accrued; 52 patients with margin-negative resection were eligible for analysis. Hepatic lobectomy was performed in 56% of patients with a median of one metastasis (range 1–3). Of the 52 eligible patients, 49 were evaluable for the primary end point. Median follow-up was 3.1 years. The proportion of patients recurrence-free at 2 years was 39%, with a lower confidence bound (LCB) of 0.29. Median recurrence-free survival was 16 months. The 2-year overall survival was 94% (95% CI, 0.81, 0.98). Only 10% of patients had documented grade-3 adverse events. Conclusions Anti-idiotype monoclonal antibody vaccine therapy with CeaVac and TriAb as an adjuvant to curative resection of colorectal cancer hepatic metastases is well tolerated but did not improve 2-year recurrence-free survival when compared with the expected value of 40% reported for hepatic resection alone. Presented in part at the 60th Annual Cancer Symposium of the Society of Surgical Oncology, March 15-18, 2007, Washington, DC     

Adjuvant arterial infusion chemotherapy after resection of hepatocellular carcinoma with portal thrombosis: a pilot study

Background/Purpose The prognosis of hepatocellular carcinoma (HCC) with tumor thrombosis of the main trunk or major branches of the portal vein (mPVTT) is extremely poor, even if it is curatively resected. Uncontrollable multiple metastases to the residual liver are often observed within several months after the operation. We report here the results of a pilot study, showing the efficacy of adjuvant arterial infusion chemotherapy after the resection of HCC with mPVTT.Methods Twelve patients had curative resection of HCC with mPVTT. Six of the patients were treated by the arterial infusion of a chemotherapeutic agent via a subcutaneously implanted injection port after curative resection of HCC with mPVTT. The initial course consisted of the daily administration of cisplatin (CDDP) and continuous infusion of 5-fluorouracil (5-FU). This was followed by the weekly or biweekly administration of CDDP and subsequent infusion of 5-FU until the cumulative dose of 5-FU reached 15 g.Results The median overall survival time was 58.0 months with adjuvant chemotherapy and 8.0 months without adjuvant chemotherapy. The median disease-free interval was 15.0 months with adjuvant chemotherapy and 4.0 months without adjuvant chemotherapy. Adverse reactions were tolerable nausea and loss of appetite.Conclusions This chemotherapeutic regimen achieved favorable results and may be useful as adjuvant chemotherapy in treating patients after curative resection of HCC with mPVTT.