Lemuel Herrera

The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.

A total of 343 patients with previously untreated metastatic measurable colorectal carcinoma were studied to evaluate the impact on toxicity, response, and survival of leucovorin-modulated fluorouracil (5-FU). A maximally tolerated intravenous bolus loading course regimen of 5-FU alone (500 mg/m2 x 5 days every 4 weeks with 25 mg/m2 escalation) was compared with a high-dose leucovorin regimen (600 mg/m2 of 5-FU with 500 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest) and with a similar low-dose leucovorin regimen (600 mg/m2 of 5-FU with 25 mg/m2 of leucovorin weekly for 6 weeks with a 2-week rest). The dose-limiting toxicity for the two 5-FU and leucovorin regimens was gastrointestinal, specifically diarrhea; severe diarrhea was seen frequently, and treatment-related toxicity was implicated in the demise of 11 of the patients (5%). Significant improvements in response rates were observed with a response rate of 33 of 109 (30.3%) on the high-dose leucovorin regimen (P less than .01 v control); 13 of 107 (12.1%) on the 5-FU control; and 21 of 112 (18.8%) on the low-dose leucovorin regimen. A trend toward longer survival in the 5-FU plus high-dose leucovorin regimen was observed. In this study, leucovorin was shown to significantly enhance the therapeutic effect of 5-FU in metastatic colorectal carcinoma.

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.

Resection of the liver for colorectal carcinoma metastases. A multi-institutional study of long-term survivors.

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized.

Surgical resection of pulmonary metastases from colorectal adenocarcinoma

From 1962 to 1982, 27 patients with pulmonary metastases as the only site of recurrent colorectal carcinoma underwent pulmonary resection at Roswell Park Memorial Institute. Only five of these patients had symptomatic pulmonary lesions. No postoperative mortality occurred. The median survival after pulmonary resection was 27 months. Five patients are alive presently without recurrent colorectal cancer and two patients are alive with recurrent pulmonary metastases. Patients with solitary lesions had a better survival than patients with multiple lesions. The major sites of recurrence following thoracotomy were the lungs and liver.

Morbidity and mortality after pelvic exenteration for colorectal adenocarcinoma.

A retrospective analysis was made of the complications from pelvic exenterations performed over the past 30 years for colorectal adenocarcinoma at the Roswell Park Cancer Institute. Seventy-five patients underwent exenteration, 51 for primary disease (PD) and 24 for recurrent disease (RD). Both total and posterior exenterations were included. Twenty of the fifty-one patients (39%) undergoing exenteration for PD developed severe complications, with an operative mortality rate of 6%. The most common complications were injuries to the ureter or bladder, intra-abdominal abscesses, and anastomotic leaks from the urinary diversion. After exenteration for RD, 12 of 24 patients (50%) developed severe complications, with an operative mortality rate of 4%. The most common major complication was an anastomotic leak from the urinary diversion; this occurred in 33% of all patients with RD (8/24). The authors conclude that, although exenteration for colorectal adenocarcinoma may be performed with a low operative mortality rate, patients must be carefully selected because the associated morbidity rate remains high.

Plasma and tumor tissue pharmacology of high-dose intravenous leucovorin calcium in combination with fluorouracil in patients with advanced colorectal carcinoma

Plasma pharmacokinetics of high-dose (500 mg/m2) leucovorin calcium (dl-5-formyltetrahydrofolic acid [dl-CF]) and fluorouracil (FUra) have been evaluated in patients with advanced colorectal cancer treated with the combination of FUra and dl-CF by two different intravenous (IV) schedules: (A) In patients with no prior chemotherapy, dl-CF was administered by a two-hour IV infusion and FUra by rapid IV injection one hour after the start of the dl-CF infusion and (B) in previously treated patients, dl-CF and FUra were administered by five-day continuous IV infusion (CI). Following the two-hour infusion of dl-CF, mean peak plasma concentration and elimination half-life of I-5-formyltetrahydrofolic acid (I-CF) were 24 +/- 6 mumol/L and 0.8 +/- 0.1 hour, respectively. CI of dl-CF over five days yielded a mean steady-state plasma level of I-CF of only 1.2 +/- 0.5 mumol/L. Peak and steady-state plasma concentrations of the metabolite 5-methyl tetrahydrofolic acid were comparable in the two schedules (17 +/- 8 mumol/L for the two-hour infusion and 12 +/- 5 mumol/L for the CI). Areas under the concentration v time curve (AUC) of total reduced folates were significantly greater under conditions of CI: 89.0 v 16.7 mmol/L/min for the two-hour infusion. In tumor tissue, 5,10-methylenetetrahydrofolate increased eight-fold two to four hours following the two-hour infusion and two-fold during the CI of dl-CF and FUra. Inhibition of thymidylate synthase (dTMP-S) by the two-hour and CI infusion schedules were 66% v 39%, respectively. The observed differences in the intracellular dTMP-S folate cofactor pools and the degree of inhibition of dTMP-S achieved in patients treated by two different schedules may be due to differences in the biochemical properties and/or to differences in the modulation of FUra metabolism by folate of tumor tissues obtained from newly diagnosed and previously treated patients.

Squamous-cell carcinoma of the colon and rectum

Six cases of squamous-cell carcinoma of the colon or rectum (one of the colon and five of the rectum) treated at Roswell Park Memorial Institute during the last 20 years are reported in this paper, and the literature on the subject is reviewed. The pathogenetic theories proposed for explanation of the origin of this rare malignancy are discussed. The clinical features of the disease are presented and the role of endoscopy in diagnosis is stressed. The importance of surgery as the primary treatment modality is emphasized. The role of other modalities in the treatment of this disease is discussed.

Morbidity and survival of liver resection for colorectal adenocarcinoma

Sixty-two patients underwent hepatic resection for isolated colorectal metastases from 1963 to 1988. The numbers of hepatic resections were: lobectomy, 24 (39 percent); wedge resection, 23 (37 percent); and segmentectomy, 15 (24 percent). The median number of intraoperative blood transfusions was 3 0 units (range, 0–16 units). The median number of days in the hospital following hepatic resection was 13 (range, 4–51 days). There were 19 patients (30 percent), who developed a total of 23 complications. Surgery was required for complications in nine patients. Surgical mortality occurred in 5 of 62 (8 percent) patients. The estimated median survival in 56 patients with one to three metastases was 26 months, with a 28 percent estimated 5-year survival. The median size of the metastases was 4.0 cm (range, 0.7–13 cm). The estimated median survival in 27 patients with metastases less than 4 cm in diameter was 26 months, with a 24 percent estimated 5-year survival. The estimated median overall survival from the time of hepatic resection was 25 months.

Treatment of bowel obstruction after operation for colorectalcarcinoma

Operative therapy is beneficial in patients with bowel obstruction after operation for colorectal carcinoma. The cause of the bowel obstruction is more likely to be benign following colorectal carcinoma than following other malignancies. Also, the period of preoperative nasogastric suction can safely be extended to 3 to 4 days in these patients, since a resolution rate of 28 percent can be achieved with minimal risk of strangulation.

Intraoperative small bowel enteroscopy in familial adenomatous and familial juvenile polyposis

BACKGROUND In familial adenomatous polyposis and juvenile polyposis, polyps can occur throughout the gastrointestinal tract. METHODS We report seven patients with familial adenomatous polyposis and two patients with juvenile polyposis who underwent small bowel enteroscopy at the time of exploratory celiotomy either for colectomy or other pathology. RESULTS Polyps in the jejunum and/or ileum were noted in five of nine (56%) patients at enteroscopy. In three of nine (33%) patients these polys were adenomatous. Two of these patients had polyps in the jejunum and in the ileum, whereas one patient had jejunal adenomas alone. These polyps were from 3 mm to 30 mm in size. The remaining two patients with polyps had lymphoid hyperplasia in the ileum. All three patients who had adenomas at intraoperative small bowel enteroscopy had duodenal adenomas at esophagogastroduodenoscopy. At the age of 14 years, one patient had an intramucosal carcinoma in a small bowel juvenile polyp. CONCLUSION Baseline small bowel enteroscopy should be considered at the time of surgical exploration in patients with asymptomatic familial adenomatous polyposis and juvenile polyposis. In patients with duodenal polyps, enteroscopy should be performed at the time of surgery. Biopsy and/or excision of larger polyps should be performed because these polyps may harbor a carcinoma.