Fluorouracil and leucovorin with or without interferon alfa-2a as adjuvant treatment, in patients with high-risk colon cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-alpha and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. PURPOSE: To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. PATIENTS AND METHODS: From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). RESULTS: A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received > or =80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. CONCLUSIONS: The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer.

Postoperative radiation and concomitant bolus fluorouracil with or without additional chemotherapy with fluorouracil and high-dose leucovorin in patients with high-risk rectal cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group.

BACKGROUND: Randomized studies have shown that postoperative chemotherapy with or without radiation therapy (RT) improved local control and survival of patients with stages II or III rectal cancer. However, the optimal sequence of treatments and the optimal chemotherapeutic regimen have not been defined. Modulation of fluorouracil (FU) by leucovorin (LV) has yielded a highly significant difference in response rate from that of FU monotherapy, as suggested by an overview of randomized trials in patients with advanced colorectal cancer. However, this difference in response rate did not translate into a survival benefit. PURPOSE: To evaluate the impact on the disease-free survival (DFS) and overall survival (OS) of patients with stages II or III rectal cancer of postoperative RT and concomitant bolus FU administration alone or with additional chemotherapy using FU and high-dose LV. PATIENTS AND METHODS: From October 1989 until February 1997, 220 patients were randomized postoperatively to receive either one cycle of chemotherapy with FU (600 mg/m2/week x 6 followed by a two-week rest) and leucovorin (LV, 500 mg/m2/week x 6 as a two-hour infusion) followed by pelvic RT with concomitant FU (400 mg/m2) as a rapid intravenous injection during the first three and last three days of RT, and three more cycles of the same chemotherapy with FU and LV (standard, group A, 111 patients) or pelvic RT with concomitant FU only (experimental, group B, 109 patients). RESULTS: As of August 1998, after a median follow-up of 4.9 years, there was no significant difference in either three-year DFS (Group A, 70.3%; group B, 68.2%, P = 0.53) or OS (group A, 77%; group B, 73.3%. P = 0.75). Cox multivariate analysis revealed stage of disease, number of infiltrated nodes, tumor grade, presence of regional implants and perforation to be significant prognostic factors. The incidence of severe side effects was significantly higher in the patients in group A than in those in group B (32.4% vs. 4.6%, P < 0.0001). CONCLUSIONS: The incorporation of additional chemotherapy with FU and LV into postoperative concomitant RT and bolus infusion of FU does not offer a > or = 10% three-year survival benefit over that of concomitant RT and bolus infusion of FU, and significantly increases toxicity in patients with stages II or III rectal cancer.

Myoelectric assessment of large bowel viability: an experiment in dogs.

OBJECTIVE: To design a device for myoelectric assessment of intestinal ischaemia and compare it with every day surgical experience and Doppler signals recorded on the bowel wall. DESIGN: Experimental study. SETTING: Thessaloniki university hospital, Greece. MATERIAL: 12 adult mongrel dogs. INTERVENTIONS: On the first day the large intestine was devascularised for a length of 20 cm, 5 cm away from the ileocaecal valve, and the threshold of the electric stimulus (mA) required to produce a contraction of the normal large bowel was recorded. On the second day, measurements were made on the ischaemic segment of the large bowel at 0.5 cm intervals. Bowel resection and anastomoses were done at the stimulus level of 40 mA. RESULTS: The mean (SD) stimulus threshold of the normal large intestine was 12.2 mA. The necrotic intestine demanded current stimulus of 100 mA or failed to contract. On the eighth postoperative day the animals were killed to assess anastomotic healing. Of the 12 anastomoses made at the 40 mA stimulus point, only one ruptured. The 40 mA limit of the stimulus level seems to be of value in assessments of bowel viability in vivo. CONCLUSION: The use of a personal computer as a read out device makes myoelectric analysis easier and more reliable in the assessment of intestinal viability. This method may have a clinical application.

Management of large rectal wall defects with open pedicle grafts of small intestine. An experimental study.

The aim of this study was to evaluate the possible repair of large rectal wall defects using an open pedicle ileal graft as a mucosal patch. This experiment was carried out in 14 adult mongrel dogs. By excision of a portion of the antimesenteric wall comprising 50-70% of the circumference and measuring 5-6 cm in length, a suitable full thickness defect was created in the lower part of the rectum. A segment of the distal ileum was then isolated on a mesenteric pedicle and opened from its antimesenteric border. This was sutured over the defect in two layers. The animals were observed for a period of 15 days to 12 months. All the animals survived the operation apart from 1 dog that died of fecal peritonitis. Function of the rectum generally remained normal. Barium X-ray did not show any obstruction, shrinkage of the patch, lumen dilatation or extravasation. At the time of autopsy pedicles of ileal grafts appeared intact and pulsating. On gross examination there was no evidence of focal hemorrhage, ulceration or any cicatricial thickening of the grafts. Healing was good and the ileal mucosa retained its villi and general characteristics without any major inflammatory reactions. There was an increase in the number of goblet cells which returned to normal in 6 months.

Prognostic variable in patients with advanced colorectal cancer treated with fluorouracil and leucovorin-based chemotherapy.

Possible prognostic variables for tumor response, time to progression (TTP), and survival in 141 patients with advanced colorectal cancer treated with fluorouracil and leucovorin-based chemotherapy were analyzed. None of the variables examined for their possible influence on tumor response attained significance in the stepwise logistic regression. In the univariate analysis, variables found to be strongly associated with TTP were performance status (PS) (P = 0.0301), liver involvement (P = 0.030), and the initial values of WBC (P = 0.0319), lactic dehydrogenase (LDH; P = 0.0053), gamma-glutamyl-transpeptidase (gamma-GT; P = 0.0013), alkaline phosphatase (ALP; P = 0.0186), albumin (P = 0.0004), and carcinoembryonic antigen (CEA; P = 0.0014). In the Cox analysis, liver involvement (P = 0.0553), albumin (P = 0.0181), PS (P = 0.484), and ALP (P = 0.0553) were retained as independently significant variables. When only patients with liver metastases were included in the analysis, then only albumin (P < 0.001) demonstrated a prognostic significance. Also, in the univariate analysis, variables predicting survival were PS (P = 0.0230), grade (P = 0.00600), liver involvement (P = 0.0002), LDH (P = 0.0001), gamma-GT (P < 0.001), ALP (P = 0.0006), albumin (P = 0.0309), and CEA (P = 0.005). With the multivariate analysis, gamma-GT (P = 0.0004), albumin (P = 0.0634), and CEA (P = 0.0804) were selected as significant. In those patients who presented with liver involvement, variables predicted survival were gamma-GT (P = 0.0041), albumin (P = 0.0442), and the percentage of involved liver parenchyma (P = 0.0690). These results could be helpful for the stratification of future trials in advanced colorectal cancer.

A comparative study with two administration schedules of leucovorin and 5-fluorouracil in advanced colorectal cancer.

One hundred and seven previously untreated patients with measurable metastatic colorectal cancer who were treated with 5-fluorouracil (5FU) and leucovorin (LV) in two different maximum doses and schedules were retrospectively analyzed. Group A, 52 pts, was treated with LV 200 mg/m2/D i.v. push, followed by 5FU 700 mg/m2/D i.v. 1 h infusion for 5 D. Cycle was repeated every 21 D. Group B, 55 pts, was treated with LV 500 mg/m2/D in a 2 h infusion and 5FU 600 mg/m2/D i.v. bolus at mid-time of LV infusion, repeated every week for 6 wk followed by 2-wk rest period. There was no difference in response (A 8%, B 11%). Median survival for A was 37 (2-131) wk, B was 59 (1-112) wk (P = 0.021), time to progression for A was 20 (0-131) wk, B 30 (0-102) wk (P = 0.021). Administered mean dose intensity of LV was 350.8 mg/m2/wk in group A and 405.0 mg/m2/wk in group B without any significant difference; that of 5FU was significantly higher in group A as compared to group B (1205.3 vs 468.9 mg/m2/wk, respectively) (p < 0.0001). This difference was a consequence of the planned dose intensity for this drug in the two treatment regimens. Toxicity was more frequent and intense in group A for mucositis (P < 0.001), fatigue (P < 0.01), and neurotoxicity (P < 0.05), and in group B for neutropenia (P < 0.001) and nausea-vomiting (P < 0.001). There were one and four iatrogenic deaths in group A and B patients, respectively (NS).(ABSTRACT TRUNCATED AT 250 WORDS)

The significance of dysplasia in colorectal adenomatous polyps associated with carcinoma.

The relation of colorectal carcinoma and adenomatous polyps was studied retrospectively in 72 patients. Severe dysplasia was found in 47.8% and malignant transformation in 18.2% of the patients with adenomatous polyps and coincidental colorectal carcinoma. The incidence decreased to 21.4% and 7.1%, respectively, in patients with adenomatous polyps only. This difference between the two groups constitutes indirect evidence of malignant potential of adenomatous polyps associated with colorectal carcinoma. Moreover, when severe dysplasia of an adenomatous polyp is found, the patient should be carefully examined for synchronous colorectal carcinoma.

High-dose leucovorin, fluorouracil and oral dipyridamole in the treatment of advanced colorectal cancer.

Fifty-five patients with advanced colorectal cancer were treated with the combination of leucovorin (LV), fluorouracil (FU) and dipyridamole (DP). Two (4%) patients achieved a clinical complete remission, 4 (7%) a partial remission, 24 (44%) had stable disease while 25 (45%) patients progressed during the chemotherapy period. Median survival was 47 weeks and median time to progression 19.5 weeks. Major toxicities included diarrhea (66%), leukopenia (45%), anemia (50%) and nausea/vomiting (44%). In conclusion, the addition of oral DP does not appear to improve the efficacy of the standard LV/FU regimen in patients with advanced colorectal cancer.