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.     

Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha

BACKGROUND: The benefit of adjuvant therapy in curatively resected lymph node-positive colon cancer was established using 5-fluorouracil (5-FU) and levamisole (LEV) for 12 months. 5-FU cytotoxicity can be modulated by folinic acid (FA) or interferon-alpha (INF-alpha). The aim of this study was to investigate the efficacy of modulating 5-FU+ LEV by either FA or IFN-alpha in the adjuvant treatment of high-risk colon cancer. METHODS: Patients with curatively resected colon cancer (stages UICC IIb and III) were stratified according to T, N, and participating center and randomized to receive a 12-month treatment using 5-FU + LEV alone or in combination with FA or IFN-alpha. RESULTS: A total of 855 of 904 entered patients (94.6%) were eligible. The median follow-up of all eligible patients was 4.6 years. Addition of FA to 5-FU + LEV improved recurrence-free and overall survival in comparison with 5-FU + LEV alone (P = 0.007 and P = 0.004, respectively, 1-sided). The 5-year overall survival rates were 60.5% (95% confidence interval, 54.3-66.7) and 72.0% (95% confidence interval, 66.5-77.5) for 5-FU + LEV and 5-FU + LEV + FA, respectively. Addition of INF-alpha showed a tendency to improve recurrence-free survival, however, without altering overall survival. Toxicities (WHO III + IV) were generally tolerable except one toxic death in the control arm and were observed in 9.9% of the patients receiving 5-FU + LEV alone and in 13.3% and in 30.7% of patients receiving additional FA and IFN-alpha, respectively. CONCLUSIONS: Addition of IFN-alpha was associated with increased toxicity without markedly influencing the outcome and should therefore not be recommended for adjuvant treatment. Addition of FA increased the 5-year recurrence-free and overall survival rate by 9.3 and 11.5 percentage points, respectively. 5-FU + LEV + FA for 12 months may be an effective adjuvant treatment option for locally advanced high-risk colon cancer.     

A Prospective Randomized Trial Comparing Intravenous 5- Fluorouracil and Oral Doxifluridine As Postoperative Adjuvant Treatment for Advanced Rectal Cancer

Background: Postoperative adjuvant chemoradiation treatment after curative resection for rectal cancer was needed to reduce recurrence and improve a survival rate. Intravenous 5-fluorouracil (5-FU) and leucovorin has been a mainstay of chemotherapy, but oral 5-FU derivatives have been shown a comparable antitumor activity. Intravenous 5-FU and oral doxifluridine were compared with respect to therapeutic efficacy, drug toxicity, and quality of life.Methods: A total of 166 patients were randomized to receive intravenous 5-FU (450 mg/m²/day) or oral doxifluridine (900 mg/m²/day) in combination with leucovorin (20 mg/m²/day) for depth of invasion, nodal status, metastasis (TNM) stage II and III patients between October 1997 and February 1999. Consecutive daily intravenous infusion for 5 days per every month for a total of 12 cycles (IV arm, n = 74) and oral doxifluridine daily for 3 weeks and 1 week rest for a total of 12 cycles (oral arm, n = 92). Drug toxicity and quality of life were observed. Quality of life was scored according to 22 daily activity items (good, 71; fair, < 70; poor, < 52).Results: There was no difference of sex between two groups (IV arm: male/female = 45/29, oral arm: male/female = 59/33). The mean age was 52.3 vs. 59.5, respectively. There was also no difference of TNM stage distribution and type of operation between groups (P = .05). Mean numbers of chemotherapy cycles were 6.5 ± 3.7 (IV arm) vs. 7.2 ± 4.3 (oral arm), respectively. The rate of recurrence was 9/74 (12.1%) in the IV arm and 6/92 (6.5%) in the oral arm, respectively (P = .937). Local recurrence was 2/74 (stage III; 2.7%) in the IV arm and 1/92 (stage II;1.1%) in the oral arm, respectively. Systemic recurrence was 7/74 (stage III; 9.4%) in the IV arm and 5/92 (stage III; 5.4%) in the oral arm, respectively. The most common site of systemic recurrence was the liver. Toxicity profile was as follows: leukopenia (30/74 vs. 17/92) and alopecia (21/74 vs. 13/92) were statistically more common in the IV arm. Diarrhea was more common in the oral arm. Poor quality of life score between two groups was observed at 1 month (23.9% vs. 13%) and 2 months (15.8% vs. 3.7%) after chemotherapy. Good quality of life score was observed at 1 month (19.5% vs. 49%) and 2 months (47% vs. 72%), respectively (P < .05).Conclusions: Oral doxifluridine with leucovorin shows a comparable therapeutic efficacy to intravenous 5-FU regimen with high quality of life as postoperative adjuvant therapy. The oral regimen also can be safely given with appropriate toxicity and tolerability.Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, March 16–19, 2000, New Orleans.     

Fluorouracil, doxorubicin, and cyclophosphamide followed by tamoxifen as adjuvant treatment for patients with stage IV breast cancer with no evidence of disease

We conducted a single-institution study to determine whether local therapy plus six cycles of chemotherapy with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) followed by 5 years of tamoxifen is superior to local treatment alone in terms of disease-free survival (DFS) and overall survival (OS) in patients with stage IV breast cancer with no evidence of disease (stage IV-NED breast cancer). Patients with breast cancer were eligible if they had histologic proof of a locoregional or distant recurrence that had been curatively resected, irradiated, or both and had no other evidence of disease. Patients who had received prior anthracycline therapy were not eligible. All patients received six cycles of intravenous FAC, with cycles repeated every 3 weeks. After completion of chemotherapy, patients whose tumors had not previously demonstrated resistance to tamoxifen and had positive or unknown estrogen receptor status received tamoxifen 20 mg by mouth daily for 5 years. Patients in this study were compared with a historical control population (patients with stage IV-NED breast cancer who never received systemic therapy) as well as with the patients in two previously reported trials of chemotherapy for stage IV-NED disease. Forty-seven patients were registered, but only 45 were evaluable. There was a highly statistically significant difference ( p < 0.001) in OS and DFS among the four groups, with patients in our most recent study having the best OS and DFS at 3 years compared with the control group (84% vs. 55% and 66% vs. 11%, respectively). When patients in all four groups were analyzed together in search of prognostic factors, we found that patients whose primary tumors had negative axillary lymph nodes had a statistically significant improvement in OS and DFS ( p < 0.01) compared with patients with positive axillary lymph nodes. No survival differences were found between patients with positive and those with negative hormone receptor status. This study demonstrates a benefit in terms of OS and DFS for patients with stage IV-NED breast cancer who receive doxorubicin-based adjuvant chemotherapy. The benefit was greater on patients with node-negative primary tumors. In patients with stage IV-NED disease, doxorubicin-based chemotherapy should be considered standard treatment after adequate local control is achieved.     

HER2/neu表达对乳腺癌术后应用CMF化疗病人预后的影响

目的：研究HER2/neu癌基因在乳腺癌组织中的表达，探讨其对接受手术及CMF（环磷酰胺、氨甲碟呤和氟脲嘧啶）辅助化疗病人预后的影响。方法：选择1995年至2001年间112例接受手术和术后行CMF化疗的乳腺癌病人的组织标本，用免疫组织化学方法检测原发肿瘤HER2/neu蛋白及雌孕激素受体的表达，结合临床病理资料并分析其与5年生存率的关系。结果：本组乳腺癌组织中HER2/neu的过度表达率为21．4％（n=24）。经随访13～104月，整体病人的5年无病生存率为85．3％，5年总体生存率为91．1％。HER2／neu过度表达者的5年无病生存率为43．2％，而HER2/neu表达缺失者为71％（P=0．01）。HER2/neu过度表达者的5年总体生存率为49．2％，而HER2/neu表达缺失者为83.3％（P=0．02）。同时，生存率亦与肿瘤大小和孕激素受体密切相关。结论：乳腺癌组织中HER2/neu蛋白的过度表达与接受手术及术后CMF化疗病人的预后密切相关，可以作为预测其复发及转移的重要指标。     

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.     

Long-Term Survival Results of Surgery Alone Versus Surgery plus UFT (Uracil and Tegafur)-Based Adjuvant Therapy in Patients with Stage II Colon Cancer

Background  

It is well established that adjuvant chemotherapy with 5-fluouracil and leucovorin (5-FU/LV) improves survival for patients with resected colon cancer; however, the benefits of oral uracil and tegafur (UFT) chemotherapy in these patients are still uncertain.     

Fluorouracil-based Chemoradiation with Either Gemcitabine or Fluorouracil Chemotherapy after Resection of Pancreatic Adenocarcinoma: 5-Year Analysis of the U.S. Intergroup/RTOG 9704 Phase III Trial

Background

The impact of the addition of gemcitabine to 5-fluorouracil (5-FU) chemoradiation (CRT) on 5-year overall survival (OS) in resected pancreatic adenocarcinoma are presented with updated results of a phase III trial.

Methods

After resection of pancreatic adenocarcinoma, patients were randomized to pre- and post-CRT 5-FU versus pre- and post-CRT gemcitabine. 5-FU was provided continuously at 250 mg/m²/day, and gemcitabine was provided at 1000 mg/m² weekly. Both were provided over 3 weeks before and 12 weeks after CRT. CRT was provided at 50.4 Gy with continuously provided 5-FU. The primary end point was survival for all patients and for patients with tumor of the pancreatic head.

Results

Four hundred fifty-one patients were eligible. Univariate analysis showed no difference in OS. Pancreatic head tumor patients (n = 388) had a median survival and 5-year OS of 20.5 months and 22% with gemcitabine versus 17.1 months and 18% with 5-FU. On multivariate analysis, patients on the gemcitabine arm with pancreatic head tumors experienced a trend toward improved OS (P = 0.08). First site of relapse local recurrence in 28% of patients versus distant relapse in 73%.

Conclusions

The sequencing of 5-FU CRT with gemcitabine as done in this trial is not associated with a statistically significant improvement in OS. Despite local recurrence being approximately half of that reported in previous adjuvant trials, distant disease relapse still occurs in ≥70% of patients. These findings serve as the basis for the recently activated EORTC/U.S. Intergroup RTOG 0848 phase III adjuvant trial evaluating the impact of CRT after completion of a full course of gemcitabine.     

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.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Metastatic lymph node size and colorectal cancer prognosis

BACKGROUND: Colorectal cancer patients with lymph node metastasis constitute a heterogeneous population with variable prognoses. In this study, my colleagues and I propose a simpler lymph node (LN) staging system for colorectal cancer. STUDY DESIGN: Four-hundred and twenty-three consecutive colorectal cancer patients were studied. Of these, 36 were excluded because another carcinoma was present. The remaining 387 patients entered the TNM staging analysis. In the survival analysis, 76 patients with distant metastasis were excluded and the remaining 311 patients (LN(-) = 204 and LN(+) = 107) were studied. The diameter of the largest metastatic LN (MLN) was measured on histopathological slides. After examination of various cutpoints and survival outcomes, patients with MLNs were classified into n1 (< or = 9 mm) and n2 (> or = 10 mm) groups, according to size of MLNs (n-stage). RESULTS: Using disease-free survival (DFS) and overall survival (OS) as outcomes, patients were separated into significant prognostic groups by MLN size (univariate, p < 0.0001) (5-year survival, DFS: n0 = 91.5%, n1 = 62.2%, and n2 = 34.4%; OS: n0 = 85.1%, n1 = 63.5%, and n2 = 42.5%) and International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) (N-stage) (univariate, p < 0.0001) (5-year survival, DFS: N0 = 91.5%, N1 = 60.5%, and N2 = 36.8%; OS: N0 = 85.1%, N1 = 65.3%, and N2 = 38.0%). But in patients with fewer than 15 LNs examined (n = 31), only the new nodal stage stratified patients into significant groups (OS: p = 0.003 and DFS: p = 0.001). Only the UICC/AJCC N-stage subcategories were further split into significant prognostic groups by MLN size (UICC/AJCC N1: DFS, p = 0.048 and OS, p = 0.11; N2: DFS, p = 0.04 and OS, p = 0.04). n-stage was an independent important factor both in the DFS and OS in multivariable analysis. CONCLUSIONS: MLN size is a strong prognostic variable in colorectal carcinoma. This new metric may help clinicians treating colorectal cancer patients, but additional studies are required before clinical application.     

Clinicopathological Characteristics and Survival Analysis of 87 Male Breast Cancer Cases

BACKGROUND: The aim of this study was to investigate the clinicopathologic characteristics, therapy methods, and prognosis of male breast cancer. PATIENTS AND METHODS: We retrospectively analyzed the clinicopathological characteristics, recurrence or metastasis, and survival information of 87 male breast cancer patients. Statistical analysis included the Kaplan-Meier method to analyze survivals, log-rank to compare curves between groups, and Cox regression for multivariate prognostic analysis. A p value of <0.05 was considered statistically significant. RESULTS: 5-year disease free survival (DFS) and 5-year overall survival (OS) were 66.3 and 77.0%, respectively. Monofactorial analysis showed tumor size, stage, lymph node involvement, and adjuvant chemotherapy to be prognostic factors with regard to 5-year DFS and 5-year OS. Multivariate Cox regression analysis showed tumor size, stage, and adjuvant chemotherapy to be independent prognostic factors with regard to 5-year DFS and 5-year OS. CONCLUSION: Male breast cancer has a lower incidence rate and poor prognosis. Invasive ductal carcinoma is the main pathologic type. Operation-based combined therapy is the standard care for these patients. Tumor size, stage, and adjuvant chemotherapy are independent prognostic factors. More emphasis should be placed on early diagnosis and early therapy, and adjuvant chemotherapy may improve survival.     

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.     

Clinical node-negative thick melanoma

BACKGROUND: Patients with T4 N0 M0 melanoma are considered at high risk for having occult metastases, and adjuvant therapy is usually recommended. HYPOTHESIS: Long-term survival in patients with thick melanoma is not universally poor. DESIGN: A retrospective study. SETTING: University teaching hospital. PATIENTS: We evaluated clinical node-negative thick (> or = l4.0 mm) melanoma in 151 patients who received their primary definitive surgical treatment in our department. None of these patients received any adjuvant therapy. RESULTS: Median follow-up was 44 months; median thickness, 5.5 mm. Median overall (OS) and disease-free survivals (DFS) were 70 (5-year survival, 52%) and 51 months (5-year survival, 47%), respectively. Patients with node-positive disease faired significantly worse than did those with node-negative disease. Median OS and DFS for patients with node-positive disease were 49 and 32 months (5-year survival, 35%), respectively, compared with 209 (5-year survival, 61%) and 165 months (5-year survival, 56%), respectively, for patients with node-negative disease. Similarly, OS and DFS were significantly lower when the primary tumor had at least 5 mitoses/mm(2) or was located in the head and neck region. After multivariate analysis, status of the lymph nodes was the most predictive variable for OS and DFS. CONCLUSIONS: The thickness of melanoma, by itself, should not be used as a criterion for adjuvant therapy. Other prognostic factors should be considered.     

Phase III trial comparing UFT + PSK to UFT + LV in stage IIB,III colorectal cancer (MCSGO-CCTG)

Purpose

Oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) is not inferior to standard weekly fluorouracil and folinate for stage II/III colon cancer. However, protein-bound polysaccharide K (PSK) has been evaluated as postoperative adjuvant therapy for colorectal cancer. This report is the first of MCSGO-CCTG, which compared UFT/LV to UFT/PSK as adjuvant chemotherapy for stage IIB or III colorectal cancer in patients who had undergone Japanese D2/D3 lymph node dissection.

Methods

The primary endpoint was the 3-year disease-free survival (DFS). A randomized non-inferiority study compared UFT/LV to UFT/PSK. The overall survival, adverse events, compliance, and quality of life were also investigated as the secondary endpoints.

Results

Between March 2006 and December 2010, 357 patients were randomized to UFT/PSK (n = 178) or UFT/LV (n = 179) (median age 65 years, colon/rectum 67.4/32.6%, stage IIB/IIIA/IIIB/IIIC 11.1/15.7/55.0/18.2%). The 3-year DFS rate was 82.3% in those receiving UFT/LV and 72.1% in those receiving UFT/PSK. The non-inferiority of UFT/PSK adjuvant therapy to UFT/LV therapy was not verified (?9.06%, 90% confidence interval ?17.06 to ?1.06%). The 3-year overall survival rate was 95.4% in those receiving UFT/LV and 90.7% in those receiving UFT/PSK.

Conclusions

As adjuvant chemotherapy for stage IIB and III colorectal cancer patients, UFT/PSK adjuvant therapy was not non-inferior to UFT/LV therapy with respect to the DFS.

     

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。     

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.     

Adjuvant continuous metronomic adriamycin + cyclophosphamide followed by weekly nab‐paclitaxel for high‐risk early‐stage breast cancer

Many studies have sought to optimize the dosing schedule of adjuvant chemotherapy in early‐stage breast cancer. Here, we assessed the use of continuous metronomic weekly doxorubicin plus daily oral cyclophosphamide (AC) with continuous G‐CSF growth factor support for 12 weeks followed by weekly nab‐paclitaxel (nP) for 12 weeks. A nonrandomized phase II clinical trial was designed to assess (1) DFS at 2 years, (2) dose delivered, (3) use of nP in the adjuvant setting, and (4) toxicities. The dosing of A was 24 mg/m2 IV weekly and C was 60 mg/m2 oral daily (with scheduled filgrastim 5mcg/kg 6 days/week); nP, 100 mg/m2 IV weekly. For patients with HER2 + disease, trastuzumab was started during the nP portion of therapy and continued for 12 months. Sixty patients enrolled with a median follow‐up of 6 years. Node‐positive disease was present in 58% of patients. Receptor categories included hormone receptor positive/HER2 negative (n = 25; 42%); triple negative (n = 19; 32%); or HER2 positive (n = 16; 27%). DFS at 2 years was 93%. Mean dose delivered was greater than 90% for metronomic AC and 88% for nP. Treatment was well tolerated with a 2% incidence of febrile neutropenia. Continuous metronomic AC followed by nP was well tolerated in our patients with comparable DFS to historical controls.     

Adjuvant Hepatic Arterial Infusion Chemotherapy after Hepatic Resection of Hepatocellular Carcinoma With Macroscopic Vascular Invasion

Background

The prognosis of hepatocellular carcinoma (HCC) with macroscopic vascular invasion is extremely poor even after hepatic resection. We aimed to clarify the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) for HCC with vascular invasion.

Methods

A total of 73 HCC patients with macroscopic vascular invasion were divided into two groups: 38 with hepatectomy with HAI (HAI group) and 35 with hepatectomy alone (non-HAI group). From 1997 to 2007, HAI was performed via an implanted injection port. The treatment comprised three courses of weekly infusion of HAI, which comprised cisplatin (10 mg daily on days 1–5) followed by 5-fluorouracil (5-FU; 250 mg daily on days 1–5) infusion. From 2007, cisplatin (60 mg/m²), 5-FU (600 mg/m²), and a mixture of mitomycin C (3 mg/m²) and degradable starch microspheres were administered for two courses.

Results

Overall, 92 % of patients completed adjuvant HAI. In the HAI and non-HAI groups, the 5-year disease-free survival (DFS) rates were 33.1 % and 11.8 %, respectively (p = 0.029), and the 5-year overall survival (OS) rates were 46.7 % and 32.7 %, respectively (p = 0.318). Among the patients with Vp3/4 or Vv3 (n = 32) in the HAI group, the 3-year DFS and OS rates were 33.7 % and 56.8 %, respectively (p = 0.049). Those in the non-HAI group were 8.3 % and 12.0 %, respectively (p = 0.023). Cox proportional multivariate analysis for DFS revealed that HAI was an independent favorable prognostic factor in all 73 patients (hazard ratio 0.536; p = 0.029).

Conclusions

Adjuvant HAI for HCC patients with vascular invasion might reduce the risk of recurrence.     

Intra-arterial 5-fluorouracil and intravenous folinic acid in the treatment of liver metastases from colorectal cancer.

OBJECTIVE: To compare two regimens of intra-arterial chemotherapy for the treatment of hepatic metastases from colorectal cancer. DESIGN: Open study. SETTING: Teaching hospital, UK SUBJECT: 57 patients with unresectable metastases confined to the liver, and an indwelling catheter in the hepatic artery. INTERVENTIONS: The first 33 patients had a 24-hour intra-arterial infusion of 5-fluorouracil (5-FU) 1500 mg/m2, together with folinic acid 200 mg/m2 intravenously for the first and last two hours of the 5-FU infusion. This was repeated at weekly intervals for six weeks followed by a two-week gap before the next cycle. The remaining 24 patients had a two-weekly regimen in which folinic acid 200 mg/m2 was infused intravenously over 2 hours followed by an intra-arterial loading dose of 5-FU 400 mg/m2 over 15 minutes; 5-FU 1600 mg/m2 was then given by intra-arterial infusion over 22 hours. This was repeated on day 2 and then at two-weekly intervals. MAIN OUTCOME MEASURES: Response rate and toxicity. RESULTS: Median follow-up was 21 months, and estimated median survival 19 months. 29 patients (51%) have responded, 5 completely. There are no significant differences between the groups. Sites of progression were liver alone 26 (53%), lung alone 9 (18%), liver and lung 3 (6%), and the remainder in local or regional nodes (n = 7) or bone (n = 4). Six patients experienced WHO grade 3 or 4 toxicity. CONCLUSION: The two regimens have high response rates and cause little systemic toxicity. Intra-arterial chemotherapy for hepatic metastases from colorectal cancer is currently being compared with conventional systemic chemotherapy in a randomised controlled trial.