Clinical T2N0 Rectal Cancer Treated with Neoadjuvant Chemoradiotherapy plus Local Excision.

INTRODUCTION: Total mesorectal excision is the standard treatment for clinical T2 (cT2) rectal cancer; however, this procedure can result in postoperative dysfunction, decreased quality of life, and stoma creation in some patients. We investigated neoadjuvant chemoradiotherapy (nCRT) plus local excision (LE) as an alternative treatment strategy for patients with cT2N0 rectal cancer. METHOD: Fifty-six patients with cT2N0M0 rectal cancer who exhibited the following characteristics (an anal verge of ≤8 cm, tumor size of <30 mm, well- or moderately differentiated adenocarcinoma on biopsy) underwent LE following nCRT. Chemoradiotherapy was administered at 40 or 45 Gy in 20-25 fractions with concurrent oral UFT (tegafur/uracil; 400 mg/m2) or S-1 (tegafur/gimeracil/oteracil; 80 mg/m2). RESULTS: Fifty-five patients (98%) completed nCRT as planned. Histologically, the excision margin was negative in all patients, and four patients with ypT3 disease underwent total mesorectal excision. Recurrence was observed in 15 patients (27%), local recurrence in 7 (13%), and distant recurrence in 10 (18%). The salvage surgery was possible for the local recurrence group. The 5-year disease-free and overall survival rates were 68.4% and 84.9%, respectively. Multivariate analysis showed that only the tumor regression grade (TRG) was an independent risk factor for recurrence (p = 0.025). Although 7 (26%) out of 27 patients with a TRG of 3 or 4 developed local recurrence and 6 (22%) had distant metastasis, 25 patients with a TRG of 1 or 2 did not exhibit local recurrence, and only 1 (4%) experienced distant metastasis. CONCLUSION: nCRT plus LE may be an alternative treatment for patients with cT2N0 rectal cancer who achieved a TRG of 1 or 2. However, additional treatment was required in patients who achieved a TRG of 3 or 4.

Prospective observational study of the efficacy of oral uracil and tegafur plus leucovorin for stage II colon cancer with risk factors for recurrence using propensity score matching (JFMC46-1201).

BACKGROUND: The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. METHODS: We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. Patients chose to be non-randomized or randomized to undergo surgery alone (NR-Group S or R-Group S) or surgery followed by 6 months of UFT/LV (NR-Group U or R-Group U). The primary endpoint was disease-free survival (DFS) after adjusting for previously reported risk factors using propensity score matching (1:2) and inverse probability of treatment weighting (IPTW) in the non-randomized arm. RESULTS: Overall, 1,902 (98%) and 36 (2%) patients were enrolled in the non-randomized and randomized arms, respectively. There were too few patients in the randomized arm and these were therefore excluded from the analysis. Of the 1,902 patients, 402 in NR-Group S and 804 in NR-Group U were propensity score-matched. The 3-year DFS rate (95% confidence interval) was significantly higher in NR-Group U (80.9% [77.9%-83.4%]) than in NR-Group S (74.0% [69.3%-78.0%]) (hazard ratio, 0.64 [0.50-0.83]; P = 0.0006). The 3-year overall survival rate was not significantly different between NR-Group S and NR-Group U. Significantly higher 3-year DFS (P = 0.0013) and overall survival (P = 0.0315) rates were observed in NR-Group U compared with NR-Group S using IPTW. CONCLUSIONS: Adjuvant chemotherapy with UFT/LV showed a significant survival benefit over surgery alone in patients with high-risk stage II CC characterized by at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or < 12 dissected lymph nodes. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180155 (date of registration: 25/02/2019) (UMIN Clinical Trials Registry: UMIN000007783 , date of registration: 18/04/2012).

Outcomes of Local Excision plus Chemoradiotherapy in Patients with T1 Rectal Cancer.

OBJECTIVE: The National Comprehensive Cancer Network (NCCN) guidelines recommend local excision and observation as standard treatment for selected patients with clinical T1N0M0 rectal cancer. In patients with pathological T1 (pT1) rectal cancer who received local excision, the local recurrence rate is at least 10%. We studied oncological outcomes in patients with pT1 rectal cancer who received chemoradiotherapy (CRT) after local excision. METHODS: Local excision was performed in 65 patients with clinical T1N0M0 rectal cancer (≤8 cm from the anal verge, tumor size < 30 mm, well or moderately differentiated adenocarcinoma). The patients received CRT (40 or 45 Gy in 1.8-2.0 fractions with concurrent oral UFT [tegafur/uracil] or S-1 [tegafur/gimeracil/ote-racil]) after confirmation of pT1 and negative margins. RESULTS: Patients who had pT2 cancer or who did not provide informed consent were excluded. The remaining 50 patients additionally received CRT. The CRT was completed in 48 patients (96%). The median follow-up period was 71 months. Local recurrence occurred in 1 patient (2%). Distant metastases occurred in 3 patients (6%). The 5-year disease-free survival rate was 86%, and the 5-year overall survival rate was 92%. CONCLUSIONS: Our study suggested that multidisciplinary treatment with local excision plus CRT can be used as a treatment option in selected patients with clinical T1N0M0 rectal cancer.

Risk Factors for Peritoneal Recurrence in Stage II to III Colon Cancer.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil-based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

Expandable Metallic Stent for Endobronchial Metastasis from Colorectal Cancer: Reports of 2 Cases.

In recent years, there have been many reports about the efficacy of stenting for central bronchial stenosis. When central bronchial stenosis is due to metastasis of a malignant tumor to the trachea and/or bronchi (endobronchial metastasis: EM), it is classified as "narrow EM" and "broad EM." [1] We managed two patients in whom bilateral stent placement was required for narrow and broad EM arising from colorectal cancer. Case 1: In September 2011, a 66-year-old man underwent low anterior resection for advanced colorectal cancer associated with unresectable liver metastasis. The liver metastasis became resectable after chemotherapy, with two resection procedures and radiofrequency ablation (RFA) being performed. Thereafter, lung metastasis occurred and a tumor in the left lung was resected. In May 2015, he developed respiratory distress. CT identified multiple lesions protruding into the lumen of the trachea and the left and right main bronchi. There was no evidence of mediastinal relapse or local relapse at the resection margin, and tumors were only detected in the tracheobronchial walls. Accordingly, narrow EM was diagnosed. An expandable metallic stent (EMS) was placed on the right side where stenosis was more severe, and radiation therapy was conducted for the non-stented tumors. The patient died 8 months later. Case 2: A 69-year-old woman had undergone laparoscopic right hemicolectomy and adjuvant chemotherapy for Stage lllb cancer of the ascending colon. Due to subsequent elevation of tumor markers, PET-CT was conducted and abnormal uptake was seen in the apex of the right lung and right upper abdomen. Both lesions were resected, and omental and lung metastases were diagnosed. She received treatment with UFT / calcium folinate, but relapse occurred at the resection margin in the right lung. At 7 years and 5 months after initial surgery, she complained of respiratory distress at an outpatient visit. CT demonstrated displacement of the trachea and right main bronchus due to enlargement of upper mediastinal lymph nodes. There was also severe stenosis of the right main bronchus due to tumor infiltration. Because there was both infiltration from local recurrence after resection and upper mediastinal lymph node enlargement, broad EM was diagnosed. An EMS was placed at the site of severe stenosis in the right main bronchus. Similar to Case 1, radiation therapy was also conducted, but respiratory distress occurred after 3 months due to tumor re-growth at the stent margin. Accordingly, stent-in-stent placement was performed and her respiratory symptoms improved. However, superior vena cava syndrome occurred 1 month later and the patient died. We consider that placing an EMS is effective in patients with tracheal stenosis due to EM that is judged to be an oncological emergency.

A comparison of the localization of rectal carcinomas according to the general rules of the Japanese classification of colorectal carcinoma (JCCRC) and Western guidelines.

PURPOSE: The aim of this study was to compare the localization of rectal cancers as classified according to the general rules of the Japanese classification of colorectal carcinoma (JCCRC) and also according to the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines, which are based on rigid endoscopic measurements. METHODS: The medical records of patients scheduled to receive curative surgery for histologically proven rectal adenocarcinoma during 2009-2015 were investigated (n = 230). Rigid proctoscopy was performed in patients with rectal cancer located in the upper (Ra) or lower (Rb) division using double-contrast barium enema. RESULTS: The median values of height from the anal verge were 7.5 cm (range 2-12) and 3 cm (0-9.5) on rigid proctoscopy for cancers assigned as Ra and Rb, respectively. All 159 cancers at Ra or Rb were located within 12 cm from the anal verge by rigid proctoscopy, while only 79.7% of Ra or 82.1% of Rb cancers were located in the mid (5.1-10 cm) or low (≤5 cm) rectum, respectively. CONCLUSION: Ra and Rb cancers are deemed to be rectal cancers according to NCCN guidelines, but these classifications are not interchangeable with mid- and low-rectal cancers, respectively, according to the ESMO guidelines.

[Postoperative Adjuvant Chemotherapy for Stage III Colon Cancer--Drug Selection, Tolerability, and Safety in Clinical Practice].

In the National Comprehensive Cancer Network (NCCN) guidelines, oxaliplatin (L-OHP)-based chemotherapeutic regimens, including 5-fluorouracil, Leucovorin (LV), and L-OHP (FOLFOX); capecitabine and L-OHP (CapeOX); and 5-fluorouracil, folinic acid, and L-OHP (FLOX) are designated as category 1 recommendations for postoperative adjuvant chemotherapy in Stage III colon cancer, followed by capecitabine and 5-fluorouracil plus LV as category 2A recommendations. We studied the selection of drugs for adjuvant chemotherapy and assessed the tolerability and safety of CapeOX and tegafur-uracil (UFT) plus LV (UFT/LV) in patients with Stage III colon cancer. The study group included 104 consecutive patients with Stage III colon cancer who underwent curative surgery. One patient changed hospitals immediately after surgery. Among the remaining 103 patients, 82 (80%) received adjuvant chemotherapy and 21 (20%) did not. CapeOX was administered to 32 patients (31%), UFT/LV to 49 patients (48%), and capecitabine to 1 patient (1%). In 59 patients, the treatment choice was determined according to the patient's preference; 32 patients (54%) selected CapeOX, 26 (44%) selected UFT/LV, and 1 (2%) selected no chemotherapy. The treatment completion rate was 80% for CapeOX and 84% for UFT/LV. Among patients who completed chemotherapy, dose reduction and drug withdrawal were not required in 22% of patients who received CapeOX and 80% of those who received UFT/LV. Neither CapeOX nor UFT/LV was associated with any serious adverse events. The tolerability and safety of CapeOX and UFT/LV were acceptable. However, CapeOX dose had to be carefully adjusted according to each patient's condition.

Treatment Rationale and Study Design for Clinical Trial on the Efficacy of UFT/LV for Stage II Colorectal Cancer With Risk Factors for Recurrence (JFMC46-1201).

BACKGROUND: The usefulness of adjuvant chemotherapy for stage II colon cancer has not been established. Meanwhile, the presence of stage II colon cancer with high-risk factors for recurrence has been reported. To our knowledge, no prospective study of adjuvant chemotherapy for stage II colon cancer with high-risk factors has been implemented to date. PATIENTS AND METHODS: This study is a prospective nonrandomized controlled study based on patients' selection of treatment option, including randomized therapeutic decision-making, to evaluate the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) with leucovorin (LV) for stage II colon cancer with high-risk factors for recurrence, compared with surgery alone. Five courses of UFT/LV therapy will be given as follows: UFT (300 mg/m(2)/d) with LV (75 mg/d) will be orally administered in 3 doses per day. Treatment will be received daily for 28 days, followed by a 7-day rest or will be received daily for 5 days, followed by a 2-day rest. For both regimens, 1 course will last 5 weeks, and 5 courses will be given. The primary end point is disease-free survival. A propensity score matching will be conducted based on 7 variables that represent risk factors to minimize selection bias in a comparison between the nonrandomized arms. For this nonrandomized comparison, a target sample size is set at 1200 (400 and 800 patients for the surgery alone and UFT/LV groups, respectively) and 1720 patients will be enrolled. In this study we aim to evaluate the therapeutic usefulness of adjuvant chemotherapy with UFT/LV for stage II colorectal cancer with risk factors for recurrence.

Safety analysis of two different regimens of uracil-tegafur plus leucovorin as adjuvant chemotherapy for high-risk stage II and III colon cancer in a phase III trial comparing 6 with 18 months of treatment: JFMC33-0502 trial.

PURPOSE: The JFMC33-0502 trial is a phase III clinical study designed to determine the most appropriate duration of postoperative adjuvant chemotherapy with uracil-tegafur (UFT) plus leucovorin in patients with stage IIB or III colon cancer. We report the interim results of preplanned safety analyses. METHODS: Patients with stage IIB or III colon cancer who had undergone curative resection were randomly assigned to receive UFT (300 mg/m(2)) plus leucovorin (75 mg/day) for 6 months (control group, 4 weeks of treatment followed by a 1-week rest, five courses) or for 18 months (study group, 5 days of treatment followed by a 2-day rest, 15 courses). Treatment status and safety were evaluated. RESULTS: A total of 1,071 patients were enrolled, and 1,063 were included in safety analyses. Treatment completion rate at 6 months was 74.0 % in the control group and 76.7 % in the study group. Treatment completion rate in the study group at 18 months was 56.0 %. The overall incidence of adverse events (AEs) was 75.3 % in the control group and 77.6 % in the study group. The incidences of grade 3 or higher AEs were low in both groups. During the first 6 months, the incidences of the subjective AEs were significantly lower in the study group. CONCLUSIONS: Oral UFT plus leucovorin given by either dosage schedule is a very safe regimen for adjuvant chemotherapy. In particular, 5 days of treatment followed by a 2-day rest was a useful treatment option from the viewpoint of toxicity even when given for longer than 6 months.

Relationship between histologic response and the degree of tumor shrinkage after chemoradiotherapy in patients with locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) significantly decreases local recurrence in advanced rectal cancer. We studied whether the degree of tumor shrinkage can be used as a predictor of histologic response. METHODS: The subjects were 114 patients with locally advanced rectal cancer who underwent total mesorectal excision after receiving radiotherapy combined with uracil/tegafur (UFT) or S-1. The degree of tumor shrinkage based on barium enema examination and magnetic resonance imaging (MRI) were assessed before CRT and immediately before surgery. RESULTS: A histologic complete response (ypCR), histologic marked regression, T and N downstaging were associated with significantly higher tumor-shrinkage rates on barium enema (P < 0.01, P < 0.01, P < 0.01, and P < 0.01, respectively) as well as on MRI (P < 0.01, P < 0.01, P < 0.01, and P = 0.01, respectively). On multivariate analysis, ypCR and histologic marked regression were significantly related only to tumor-shrinkage rates on barium enema (P < 0.01 and P < 0.01, respectively), and were not related to tumor-shrinkage rates on MRI. CONCLUSIONS: The degree of tumor shrinkage is closely related to the final histologic response. Two-dimensionally evaluated tumor-shrinkage rates based on barium enema are adequate for the prediction of histologic response.

Clinical significance of and future perspectives for hepatic arterial infusion chemotherapy in patients with liver metastases from colorectal cancer.

The most common site of metastases in patients with colorectal cancer is the liver. Hepatic resection is considered to be the treatment of choice for liver metastasis from colorectal cancer; however, hepatic resection can be performed in only 20 or 25% of all patients. Recurrence develops in the remnant liver or other organs after hepatic resection in over half of all patients with liver-only metastasis. Hepatic arterial infusion (HAI) chemotherapy can provide relatively high concentrations of drugs to microscopic or macroscopic metastases in the liver, with less toxicity than systemic administration. Meta-analyses have shown HAI chemotherapy to have a significantly higher response rate than systemic chemotherapy and its effect on extrahepatic metastases is negligible. HAI chemotherapy provides much better local control of liver metastases from colorectal cancer than systemic chemotherapy. However, well-controlled studies are needed to elucidate the optimal treatment strategies for neoadjuvant and postoperative adjuvant chemotherapy that optimally combine HAI chemotherapy, molecular targeted agents, and systemic chemotherapy such as FOLFOX or FOLFIRI.

Biopsy specimens obtained 7 days after starting chemoradiotherapy (CRT) provide reliable predictors of response to CRT for rectal cancer.

PURPOSE: Preoperative chemoradiation therapy (CRT) significantly decreases local recurrence in locally advanced rectal cancer. Various biomarkers in biopsy specimens obtained before CRT have been proposed as predictors of response. However, reliable biomarkers remain to be established. METHODS AND MATERIALS: The study group comprised 101 consecutive patients with locally advanced rectal cancer who received preoperative CRT with oral uracil/tegafur (UFT) or S-1. We evaluated histologic findings on hematoxylin and eosin (H&E) staining and immunohistochemical expressions of Ki67, p53, p21, and apoptosis in biopsy specimens obtained before CRT and 7 days after starting CRT. These findings were contrasted with the histologic response and the degree of tumor shrinkage. RESULTS: In biopsy specimens obtained before CRT, histologic marked regression according to the Japanese Classification of Colorectal Carcinoma (JCCC) criteria and the degree of tumor shrinkage on barium enema examination (BE) were significantly greater in patients with p21-positive tumors than in those with p21-negative tumors (P=.04 and P<.01, respectively). In biopsy specimens obtained 7 days after starting CRT, pathologic complete response, histologic marked regression according to both the tumor regression criteria and JCCC criteria, and T downstaging were significantly greater in patients with apoptosis-positive and p21-positive tumors than in those with apoptosis-negative (P<.01, P=.02, P=.01, and P<.01, respectively) or p21-negative tumors (P=.03, P<.01, P<.01, and P=.02, respectively). The degree of tumor shrinkage on both BE as well as MRI was significantly greater in patients with apoptosis-positive and with p21-positive tumors than in those with apoptosis-negative or p21-negative tumors, respectively. Histologic changes in H&E-stained biopsy specimens 7 days after starting CRT significantly correlated with pathologic complete response and marked regression on both JCCC and tumor regression criteria, as well as with tumor shrinkage on BE and MRI (P<.01, P<.01, P<.01, P<.01, and P=.03, respectively). CONCLUSIONS: Immunohistochemical expressions of p21 and apoptosis together with histologic changes on H&E-stained biopsy specimens obtained 7 days after starting CRT are strong predictors of the response to CRT.

Does 1 year adjuvant chemotherapy with oral 5-FUs in colon cancer reduce the peak of recurrence in 1 year and provide long-term OS benefit?

The objective of our study was to clarify the characteristics of survival and hazard function in patients who received adjuvant chemotherapy after surgery for colon cancer. The data of 2848 patients with curatively resected colon cancer were analyzed; we used the patient data provided by the Japanese Foundation for Multidisciplinary Treatment for Cancer in three trials, namely, JFMC7-1 (n = 869), JFMC7-2 (n = 978) and JFMC15 (n = 1001). The total number of events were 605 (overall survival) and 724 (disease-free survival). The disease-free survival events consisted of 117 cases of death and 607 cases of disease recurrences. Logrank test showed a borderline significant difference in both overall survival (P = 0.0452) and disease-free survival (P = 0.0462). The 5 year overall survival proportion was 0.769 (control) and 0.802 (treated), and the absolute drug effect was 3.3%. The difference between the 5 year disease-free survival proportion (0.728 [control] and 0.760 [drug]) was 3.2%, which is almost similar to the result of overall survival. The disease-free survival curve of the treated group differed from that of the control group after 1 year, whereas the overall survival curve of the treated group became distinct from that of the control group after 2 years. The hazard rate plots indicated the possibility that 1 year adjuvant chemotherapy with oral 5-fluorouracils may translate the short-term reduction in the risk of recurrence in patients with resected colon cancer into a delayed advantage in overall survival.

Endoscopic balloon dilation for obstructive colorectal cancer: a basic study on morphologic and pathologic features associated with perforation.

BACKGROUND: The use of endoscopic dilation and a self-expandable stent for colorectal cancer (CRC) presenting with a stricture or obstruction, either prior to surgery or as a palliative measure (an alternative to colostomy), causes perforation with relative high incidence (1%-17%). OBJECTIVE: To experimentally investigate risk factors associated with perforation in excised CRC specimens. DESIGN: Experimental study. SETTING: Ex vivo experiment on freshly excised human colon cancer specimens at an academic hospital. PATIENTS: This study involved 47 patients with strictured CRCs of <15 mm in internal diameter as assessed by a preoperative contrast enema. INTERVENTION: Immediately after surgical resection, a balloon with a diameter of 18 mm was placed in the stricture. The balloon was inflated slowly with hydrostatic pressure over 1 minute and kept at the maximum diameter for 1 minute. MAIN OUTCOME MEASUREMENTS: Correlations between macroscopic perforation and 20 items, including morphological and histopathological characteristics. RESULTS: Perforation occurred in 8 of 47 (17.0%) CRC specimens. Four items showed statistically significant (P < .05) correlations with perforation: peritumoral proliferation of collagen fibers (relative area > or =23.9% in the visual field), annularity of the tumor, severe stricture (<7.9 mm), and fewer residual smooth muscle cells in the muscularis propria, reflecting tumor encroachment. The best predictor of perforation was a combination of severe stricture and pronounced peritumoral proliferation of collagen fibers. LIMITATIONS: An uncontrolled study with a small number of patients. CONCLUSION: Histopathological and morphological items associated with a decrease in elastic compliance were more important as predictors of perforation than dilation procedure parameters, such as balloon pressure.

Long-term postoperative adjuvant chemotherapy of UFT/LV improves survival in a primary tumor resection-pulmonary metastasis model.

BACKGROUND: The optimum regimen and optimum duration of administration of postoperative chemotherapy would vary with the postoperative residual tumor volume. Whether or not prolonged administration of oral uracil/tegafur (UFT) with leucovorin (LV) would prolong the survival period was assessed experimentally. MATERIALS AND METHODS: Murine models of pulmonary metastasis with different volumes of residual tumor after primary tumor resection were prepared, and the efficacy of 12-week and 4-week oral administration of UFT/LV as postoperative adjuvant chemotherapy was compared. RESULTS: In the model with only a small volume of occult residual tumor after early resection of the primary tumor, the survival period in the 12-week UFT/LV group was significantly increased as compared with that in the untreated group, whereas no significant difference was noted between the 4-week UFT/LV group and the untreated group. CONCLUSION: Long-term administration of UFT/LV as postoperative adjuvant chemotherapy may be potentially beneficial.

Predictors of tumor downsizing and regression with preoperative radiotherapy alone and with concomitant tegafur/uracil (UFT) for resectable advanced rectal adenocarcinoma.

BACKGROUND/AIMS: Predictors of sensitivity to preoperative radiotherapy (RT) may differ from those of chemo-radiotherapy (CRT). This study attempts to evaluate retrospectively the significance of apoptosis-related and proliferative indexes in biopsy specimens obtained before treatment as predictors of sensitivity to RT or to CRT for locally advanced rectal adenocarcinoma. METHODOLOGY: The subjects were 96 patients with clinical T3-4/Nx/M0 adenocarcinoma of the middle third or lower third of the rectum. Sixty-one patients were treated with preoperative RT alone (20 Gy in 10 fractions) [RT group] during 1991-1998, and 35 patients received concurrent oral tegafur/uracil (UFT) [CRT group] since 1999. Radical surgery including TME and pelvic nerve preservation with 15 Gy of intraoperative RT was performed two weeks after completion of the preoperative radiation. We evaluated apoptotic index (AI) and p53, p21 and Ki-67 protein expression in the biopsy specimens, and histological differentiation, pathologic regression in the resected specimens and the degree of tumor shrinkage based on the double contrast barium enema images. RESULTS: AI-positivity, p53-negativity, p21-positivity and well differentiated adenocarcinoma were predictors of high sensitivity in RT group, whereas AI-positivity alone was the predictor in CRT group. The addition of UFT to RT increased sensitivity in patients with p53-positivity, p21-negativity and moderately differentiated adenocarcinoma. CONCLUSIONS: Predictors of sensitivity are different between RT and CRT.

[Feasibility of weekday-on/weekend-off oral UFT/Leucovorin schedule as postoperative adjuvant chemotherapy for colorectal cancer].

Two phase III studies revealed an oral UFT/Leucovorin (LV) regimen, in which the drugs are taken for 28 consecutive days every 35 days, which proved to be equivalent to an infusional 5-fluorouracil/LV regimen for metastatic colorectal cancer (CRC). The weekday-on/weekend-off schedule for UFT, which is taken for 5 consecutive days followed by 2 drug-free days,has been reported to be safe and to have good feasibility. In the present study, we investigated the weekday-on/weekend-off schedule for UFT/LV in 54 patients with CRC. The median administration period was 8 months. Ten patients (19%) showed grade 2 or more severe adverse reactions. One of them had grade 3 diarrhea and anorexia. Grade 2 anemia was observed in 9 cases (19%) and grade 2 leucopenia was in 2 cases (4%). Myelotoxicity was mild. These results suggested that the adverse reactions in the weekday-on/weekend-off schedule for UFT/LV are less severe than the conventional UFT/LV schedule reported previously. Antitumor effects and survival benefits of the two schedules should be evaluated by a phase III study.

[Multicenter comparative study of the recurrence-inhibitory effect of oral fluoropyrimidine drugs in patients with colorectal cancer following curative resection].

HCFU and UFT were reported effective in adjuvant chemotherapy for colorectal cancer. This investigation was planned as a randomized study to compare the usefulness of combination therapies with mitomycin C (MMC)+HCFU and MMC+UFT as postoperative adjuvant chemotherapy in patients with colorectal cancer following curative resection, in terms of survival rate, recurrence rate, and adverse drug reactions. A total of 501 patients consisting of 252 patients with stage III/IV colon cancer (Colorectal Cancer Handling Rules, 4th Ed.) for which macroscopic curative resection was possible and 249 patients with stage II/III/IV rectal cancer (ibid, 4th Ed.) were registered from 40 participating institutions. The patients were randomly allocated to two groups with colon cancer and rectal cancer employed as stratification factors. Beginning on Day 14 after surgery, HCFU at 300 mg/day was administered to one group and UFT at 300 mg/day or 400 mg/day to another group, both orally and daily for one year. MMC 6 mg/m2 was administered intravenously to both groups on the day of surgery and the day following. Among the 501 patients, 496 patients (99%) were eligible. The 5-year survival rates were 77.1% for the MMC+ HCFU group and 79.2% for the MMC+UFT group, with the 5-year recurrence-free survival rates were 76.1% and 72.9%, respectively, neither showing a significant difference between the groups. Adverse drug reactions appeared in 23% of patients in the MMC+HCFU group and in 19% in the MMC+UFT group, with no serious reactions. One year after surgery the administration completion rates were good, at 82% for the MMC+HCFU group and 83% for the MMC+UFT group. No clear difference in effectiveness was noted between MMC+HCFU therapy and MMC+UFT therapy as postoperative adjuvant chemotherapy for colorectal cancer. The administration completion rates were good, and no serious adverse drug reactions were observed for either therapy. It was thus considered that both therapies could be administered safely, and both were useful as postoperative adjuvant chemotherapies for colorectal cancer. It is considered necessary to compare them with standard therapies in Western countries in the future.

Prophylactic hepatic arterial infusion chemotherapy for the prevention of liver metastasis in patients with colon carcinoma: a randomized control trial.

BACKGROUND: The liver is the most frequent site of recurrence after curative resection in patients with colon carcinoma. For liver metastasis, a high response rate can be achieved with hepatic arterial infusion (HAI) chemotherapy. In the current study, the authors administered 5-fluorouracil (5-FU) as adjuvant chemotherapy by HAI to patients with colon carcinoma without liver metastases and studied its effects on recurrence in the liver and survival. METHODS: A total of 316 patients with preoperative Stage II or Stage III colon carcinoma (according to the 1997 revision of the International Union Against Cancer TNM staging system) were randomly assigned to receive surgery plus 3-week continuous HAI of 5-FU or surgery alone. There were 305 eligible patients, of whom the 119 patients assigned to the HAI arm actually received 5-FU. The primary endpoint was disease-free survival, whereas the secondary endpoints were overall survival and liver metastasis-free survival. Analysis was by intent to treat. RESULTS: There were no significant differences noted in morbidity between the two treatment arms. During the follow-up period (median, 59.0 months), the incidence of liver metastasis was significantly decreased in the HAI arm whereas there were no significant differences reported between the 2 arms with regard to the frequency of metastasis at other sites. In the HAI arm, the risk ratio for recurrence was 0.40 (95% confidence interval [95% CI], 0.24-0.64; P=0.0002), the risk ratio for death was 0.37 (95% CI, 0.21-0.67; P=0.0009), and the risk ratio for liver metastasis was 0.38 (95% CI, 0.22-0.66; P=0.0005). These differences were found to be significant only for patients with Stage III disease. Toxicities were mild. CONCLUSIONS: A schedule of 3-week HAI of 5-FU given as adjuvant chemotherapy to patients with Stage III colon carcinoma appeared to contribute to a significant decrease in the frequency of liver metastases and was associated with an improved survival rate.

Pharmacokinetics of 5-fluorouracil following hepatic intra-arterial infusion in a VX2 hepatic metastasis model.

BACKGROUND: Hepatic intra-arterial infusion chemotherapy of 5-fluorouracil (5-FU) or fluorodeoxyuridine (FUDR) has been a treatment option for liver metastasis from colorectal cancer. However, an optimal administration schedule of 5-FU is still controversial. This study was conducted to evaluate a suitable schedule from the viewpoint of 5-FU metabolites and related enzymes. METHODS: 5-FU was infused into the hepatic artery of rabbits having hepatic deposits of VX2 tumor cells in a daily dose of 1, 4, or 8 mg/kg using various schedules. 5-FU, Thymidylate synthase (TS), TS inhibition rate (TSIR), and the amount of fluoro-RNA (F-RNA) were measured. RESULTS: A high concentration of 5-FU was detected in the tumors of the group that was administered a dose of 8 mg/kg. TSIR in the tumor was about two-fold higher in the rabbits that were administered a total dose of 8 mg/kg than in those that were administered doses of 4 mg/kg or less. F-RNA, ranging from 27 to 36 ng/mg RNA, was detected in the tumor of the rabbits that were administered a total dose of 8 mg/kg. No difference was observed between the short period and the continuous administration schedules of rabbits that were administered a dose of 8 mg/kg of 5-FU. However, DNA synthesis inhibition in normal hepatic tissue was more dependent on the administration schedule than on the total dose of 5-FU because TSIR was significantly higher with shorter periods of drug administration. CONCLUSION: Intermittent bolus administration of large doses of 5-FU might cause more severe hepatic impairment than continuous administration. These results suggest that hepatic intra-arterial infusion of 5-FU should be administered continuously for liver metastasis, although further experiments including a longer administration period of 5-FU are required.