Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch gastric cancer group trial.

PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still under debate. We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2) lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of relapse. We have reviewed the results of our trial after follow-up of more than 10 years. PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were collected prospectively, and patients were followed for more than 10 years. RESULTS: A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with curative intent. Morbidity (25% v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P =.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection. The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections, splenectomy, pancreatectomy, and age older than 70 years. CONCLUSION: Overall, extended lymph node dissection as defined in this study generated no long-term survival benefit. The associated higher postoperative mortality offsets its long-term effect in survival. For patients with N2 disease an extended lymph node dissection may offer cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.

Prospective evaluation of anorectal function after total mesorectal excision for rectal carcinoma with or without preoperative radiotherapy.

OBJECTIVE: Anorectal function is greatly disturbed after rectal surgery with or without radiotherapy (RT). To clarify the underlying mechanisms, we designed a prospective study to evaluate the effect of RT and surgery on anorectal function and clinical outcome of patients with a rectal carcinoma. METHODS: Thirty-four patients with a rectal carcinoma participated in this study. They filled out a symptom questionnaire and underwent anal manometry, anal and rectal mucosal electrosensitivity testing, and a rectal barostat, before surgery, 4 and 12 months postoperatively. Thirteen patients were lost to follow-up, 14 underwent surgery alone (total mesorectal excision [TME]), and seven also received RT (RT + TME). RESULTS: Functional outcome was disappointing in both groups, with at 4 months a significantly higher defecation frequency after RT + TME as compared with TME. Anal sphincter function and rectal sensitivity to pressure-controlled distention were not affected by either treatment. Rectal compliance, however, was significantly reduced after RT + TME at 4 and 1 2 months, resulting in lower rectal volumes at the thresholds for first sensation and desire to defecate. Rectal but not anal mucosal electrosensitivity was higher after TME + RT. CONCLUSIONS: Anorectal function after rectal surgery with or without RT is greatly hampered because of a decreased rectal compliance. After 12 months, partial improvement is shown, especially in the absence of RT.

What is the benefit of preoperative sperm preservation for patients who undergo restorative proctocolectomy for benign diseases?

PURPOSE: In patients with benign colorectal diseases undergoing a restorative proctocolectomy with an ileal pouch-anal anastomosis, semen cryopreservation seems rational to enable the possibility of procreation in case surgery leads to sexual disorders or impotence. The aim of this study was to determine the preoperative and postoperative semen quality in patients undergoing ileal pouch-anal anastomosis. In addition, the study sought to determine the incidence of surgery-induced sexual dysfunction to evaluate the economic efficiency of semen cryopreservation as compared with alternatives such as microsurgical epididymal sperm aspiration. METHODS: Preoperative and postoperative semen analyses were offered to 97 patients with ileal pouch-anal anastomosis with benign colorectal diseases since 1989. The direct costs of the semen cryopreservation program were determined and compared with those of alternatives. RESULTS: In 34 of 40 consecutive patients with ileal pouch-anal anastomosis who made use of preoperative semen preservation, normal sperm concentrations, motility, and morphology were found. Mean semen characteristics of all 23 patients who returned for postoperative analysis were not different from preoperative values, but they were for total sperm number. Two patients developed temporary retrograde ejaculation postoperatively. None of the preserved semen samples was used, thus semen cryopreservation benefited none of these patients. The total costs of semen cryopreservation are between 2.2 and 5 times higher than the costs for one microsurgical epididymal sperm aspiration procedure. CONCLUSIONS: Preoperative semen cryopreservation in patients undergoing ileal pouch-anal anastomosis because of benign colorectal diseases is quite feasible. However, most likely because of improved surgical techniques and the increasing number of effective alternatives, preoperative semen cryopreservation in patients with ileal pouch-anal anastomosis is no longer cost effective.

Quality of life after total colectomy with ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis for familial adenomatous polyposis.

BACKGROUND: Knowledge of postoperative health status is important in decision-making about the type of operation necessary in patients with familial adenomatous polyposis (FAP). This study compared the quality of life (QoL) between patients with an ileorectal anastomosis (group 1) and those with an ileal pouch-anal anastomosis (group 2). METHODS: QoL was assessed with both a generic questionnaire (Short Form-36 Health Survey; SF-36) and a disease-specific questionnaire (European Organization for Research and Treatment of Cancer Colorectal QoL Questionnaire; EORTC QLQ-CR38). The SF-36 consists of 36 items representing eight generic health domains, and the EORTC QLQ-CR38 comprises 38 items representing disease-specific health domains. Both questionnaires were distributed among 323 patients with FAP known at the Dutch Polyposis Registry who had previously undergone either operation. The results of the SF-36 were compared with the scores of age- and sex-matched respondents from the general population. RESULTS: Some 279 patients (86 per cent), 161 in group 1 and 118 in group 2, completed the questionnaire. Generic and disease-specific QoL was the same for groups 1 and 2. The SF-36 scores of both groups were significantly lower than those of the general population. CONCLUSION: There were no differences with respect to health status between patients in groups 1 and 2, and preference for either procedure cannot be based on QoL.

[Proctocolectomy with an ileal pouch-anal anastomosis; results from 100 consecutive patients in the Academic Medical Center at Amsterdam, 1994-1999]. / Proctocolectomie met een ileum-'pouch'-anale anastomose; resultaten bij 100 opeenvolgende patiënten in het Academisch Medisch Centrum te Amsterdam, 1994/'99.

OBJECTIVE: To evaluate the results of proctocolectomy with creation of an ileac pouch anal anastomosis (IPAA). DESIGN: Retrospective. METHOD: Of the 100 patients in whom an IPAA procedure was performed in the period 1994/'99 in the Department of Surgery of the Academic Medical Centre, Amsterdam, the Netherlands, data were collected on the complications: in the patients with a follow-up of over 12 months the functional results were studied. RESULTS: The group comprised 48 males and 52 females with a mean age of 36.3 years (range: 15-62). Preoperative diagnoses were ulcerative colitis (n = 84), familial polyposis coli (12), slow transit obstipation (2), Hirschsprung's disease (1) and Muir-Torre syndrome (1). Median operating time was 2.3 h, peroperative blood and fluid loss 500 ml and median hospital stay 15 days. There was no mortality. Ten patients had a loop ileostomy formation, in 6 because of postoperative complications. A total of 30 patients developed postoperative complications, peroperatively or during follow-up 10 of those patients needed a relaparotomy. After 12 months 1 pouch had to be excised and 2 patients still had a loop ileostomy due to postoperative complications. In 56 patients with at least 12 months follow-up, median 24-hour stool frequency was 6. Eighty-nine per cent of these patients were satisfied or highly satisfied with the overall outcome. CONCLUSION: A proctocolectomy with IPAA formation is a safe procedure with good functional results.

Functional outcome after colectomy and ileorectal anastomosis compared with proctocolectomy and ileal pouch-anal anastomosis in familial adenomatous polyposis.

OBJECTIVE: To compare the long-term functional results of ileorectal anastomosis (IRA) with those of ileal pouch-anal anastomosis (IPAA) in patients with familial adenomatous polyposis (FAP). SUMMARY BACKGROUND DATA: In patients with FAP, hundreds of colorectal adenomas develop, and the patient will die of colorectal cancer if left untreated. The surgeon must choose between colectomy with IRA and restorative proctocolectomy with IPAA. One factor crucial to decision making is the functional outcome after either procedure. To date, studies on this issue have reported conflicting results and have been based on small series of patients. METHODS: To assess various functional variables, a questionnaire was sent to 323 patients with FAP who underwent either IRA or IPAA and who were registered at the Netherlands Foundation for the Detection of Hereditary Tumors. The overall response rate was 86%; the responders comprised 161 patients who underwent IRA and 118 patients who underwent IPAA. RESULTS: Patients who underwent IRA scored significantly better for daytime and nighttime stool frequency, soiling, occasional passive incontinence, flatus and feces discrimination, stool consistency, and need for antidiarrheal medication. There was no difference with regard to perianal irritation, episodes of bowel discomfort, or dietary restrictions. The functional results according to the aggregate score of the Gastro-Intestinal Functional Outcome Scale, where the items specified above were integrated (0 indicating a poor and 100 a good overall function), were significantly better in patients with an IRA (74.5) than in patients with an IPAA (66.0) (p < 0.01). CONCLUSION: The functional outcome after IRA is significantly better than after IPAA. On the basis of these results, IRA might still be considered in patients with a mild phenotypic expression of the disease in the rectum.

Cumulative risk of developing polyps or malignancy at the ileal pouch-anal anastomosis in patients with familial adenomatous polyposis.

Restorative proctocolectomy with an ileal pouch-anal anastomosis is performed in an increasing number of patients with familial adenomatous polyposis (FAP). Two techniques are currently used to construct an ileal pouch-anal anastomosis: (1) a double-stapled anastomosis between the pouch and the anal canal and (2) mucosectomy with a hand-sewn ileoanal anastomosis at the dentate line. Although this procedure is thought to abolish the risk of colorectal adenoma, an increasing number of case reports have been published concerning the development of adenoma at the anastomotic site. The purpose of this study was to evaluate the overall cumulative risk of developing adenomatous polyps after ileal pouch-anal anastomosis and to compare the cumulative risk after either anastomotic technique. A total of 126 consecutive FAP patients undergoing a restorative proctocolectomy were identified from polyposis registries in The Netherlands, Denmark, Italy, Germany, and New York. Life-table analysis was used to calculate the cumulative risk of developing polyps in 97 patients with at least 1 year of endoscopic follow-up (median 66 months, range 12 to 188 months). A double-stapled anastomosis was used in 35 patients, whereas in 62 patients a hand-sewn anastomosis with a mucosectomy was performed. In 13 patients polyps developed at the anastomotic site, four with severe and four with moderate dysplasia. None of the patients developed a carcinoma at the anastomotic site. The cumulative risk of developing a polyp at the anastomotic site was 8% (95% confidence interval 2% to 14%) at 3.5 years and 18% (95% confidence interval 8% to 28%) at 7 years, respectively. The risk of developing a polyp at the anastomotic site within 7 years was 31% for patients with a double-stapled vs. 10% for patients with a hand-sewn anastomosis with mucosectomy (P = 0.03 [log-rank test]). Because FAP patients undergoing a restorative proctocolectomy with either a double-stapled or hand-sewn anastomosis have a substantial risk of developing adenomatous polyps at the anastomotic site, lifelong endoscopic surveillance is mandatory in both groups.

Total mesorectal excision (TME) with or without preoperative radiotherapy in the treatment of primary rectal cancer. Prospective randomised trial with standard operative and histopathological techniques. Dutch ColoRectal Cancer Group.

OBJECTIVE: To document local recurrence in primary rectal cancer when standardised techniques of surgery, radiotherapy, and pathology are used, and to investigate whether the local recurrence rate after total mesorectal excision permits the omission of adjuvant short term preoperative radiotherapy. DESIGN: Prospective randomised study. SETTING: Dutch (n = 80), English (n = 1), German (n = 1), Swedish (n = 9), and Swiss (n = 1) hospitals. SUBJECTS: The first 500 randomised Dutch patients with primary rectal cancer. MAIN OUTCOME MEASURES: Local recurrence, survival, operation-related factors, specific pathological tumour characteristics, short and long term morbidity, and quality of life. RESULTS: Between January 1996 and April 1998, 871 Dutch and 94 other patients were randomised. Our feasibility analysis shows that cooperation between and within the participating disciplines goes well. With regard to the surgical part, this can be confirmed by the large number of operations attended by consultant surgeons (58%). The number of abdominoperineal resections appeared to be low (30%), as did the percentage of lateral margins involved (13%). The rate of adverse effects of radiotherapy was acceptable. Apart from a larger operative blood loss and a higher infective complication rate in the irradiated group, no significant differences were found with regard to morbidity and mortality between the randomised groups. CONCLUSIONS: The accrual of our trial is going well and it is feasible; short term preoperative radiotherapy is safe even in combination with TME.

Extended lymph-node dissection for gastric cancer.

BACKGROUND: Curative resection is the treatment of choice for gastric cancer, but it is unclear whether this operation should include an extended (D2) lymph-node dissection, as recommended by the Japanese medical community, or a limited (D1) dissection. We conducted a randomized trial in 80 Dutch hospitals in which we compared D1 with D2 lymph-node dissection for gastric cancer in terms of morbidity, postoperative mortality, long-term survival, and cumulative risk of relapse after surgery. METHODS: Between August 1989 and July 1993, a total of 996 patients entered the study. Of these patients, 711 (380 in the D1 group and 331 in the D2 group) underwent the randomly assigned treatment with curative intent, and 285 received palliative treatment. The procedures for quality control included instruction and supervision in the operating room and monitoring of the pathological results. RESULTS: Patients in the D2 group had a significantly higher rate of complications than did those in the D1 group (43 percent vs. 25 percent, P<0.001), more postoperative deaths (10 percent vs. 4 percent, P= 0.004), and longer hospital stays (median, 16 vs. 14 days; P<0.001). Five-year survival rates were similar in the two groups: 45 percent for the D1 group and 47 percent for the D2 group (95 percent confidence interval for the difference, -9.6 percent to +5.6 percent). The patients who had R0 resections (i.e., who had no microscopical evidence of remaining disease), excluding those who died postoperatively, had cumulative risks of relapse at five years of 43 percent with D1 dissection and 37 percent with D2 dissection (95 percent confidence interval for the difference, -2.4 percent to +14.4 percent). CONCLUSIONS: Our results in Dutch patients do not support the routine use of D2 lymph-node dissection in patients with gastric cancer.

Carney's triad.

The purpose of this study is to provide an overview of cases of Carney's triad and to discuss the clinical implications of this diagnosis. A search was made of the English-language literature for original articles, reviews and abstracts addressing Carney's triad. A new patient was described and added to the number of known patients. In literature 40 patients were found with a complete or incomplete triad. There exists no agreement on the pathology and possible common origin of these tumours. Directions are given for diagnostics and therapy. The diagnosis of Carney's triad has specific clinical implications that make a good knowledge of this syndrome mandatory.

Imaging of estrogen receptors in primary and metastatic breast cancer patients with iodine-123-labeled Z-MIVE.

PURPOSE: To evaluate the feasibility of noninvasive imaging of estrogen receptors (ERs) in primary and metastatic breast cancer with the iodine-123-labeled ER-specific ligand cis-11beta-methoxy-17alpha-iodovinylestradiol-17beta (Z-[123I]MIVE) using conventional nuclear medicine techniques. PATIENTS AND METHODS: Z-[123I]MIVE planar scintigraphy and single-photon emission computed tomography (SPECT) were performed in 12 patients with proven primary breast cancer and 13 patients with proven or from other imaging modalities evident bone, liver, lung, pleura and/or lymph node metastases. The results were compared with those of ER immunohistochemistry (IHC). Blocking studies with the antiestrogen tamoxifen were performed to test whether Z-[123I]MIVE tumor uptake was ER-mediated. RESULTS: Planar imaging showed uptake in 11 of 12 primary carcinomas. ER IHC performed for nine of these was positive. For the planar scintigraphy-negative patient, SPECT was faintly positive, but ER IHC negative (agreement, 90%). In nine of 13 metastatic patients, planar scintigraphy was positive. The agreement between the results of ER IHC on the original primary tumor and of Z-[123I]MIVE scintigraphy was 82%. Specificity of tumor Z-[123I]MIVE uptake was established by complete blockade of uptake by tamoxifen, except in two patients who showed progressive disease. Z-[123I]MIVE scintigraphy also enabled discriminating metastases from confounding nonmalignant abnormalities of the bone scan. CONCLUSION: Z-[123I]MIVE scintigraphy shows high sensitivity and specificity for the detection of ER-positive breast cancer. This may have impact on diagnostic possibilities and therapeutic management. Since ER imaging shows the functional status, addressing known intratumoral and intertumoral ER heterogeneity, it may improve the characterization of disease and the selection of patients who may benefit from hormonal therapy.

Complications of an implantable venous access device (Port-a-Cath) during intermittent continuous infusion of chemotherapy.

In 149 patients, treated with intermittent continuous infusion of different chemotherapeutic agents, 169 Port-a-Caths were implanted by qualified surgeons and residents in training. The peri- and postoperative complications of implantation of the Port-a-Cath system and the complications during treatment were retrospectively analysed. The Port-a-Cath was in situ for a total of 36247 days (median 181, range 1-1332). Of the 169 catheters, major complications occurred during treatment, with infection in 4 patients (2.4%), occlusion in 3 (1.8%), thrombosis in 8 (4.7%), extravasation in 8 (4.7%) and migration in 3 (1.8%). The peri- and postoperative complication rate was low, although pneumothorax occurred in 6 patients (3.6%). In 25 patients (14.8%) the Port-a-Cath had to be explanted due to complications. It can be concluded that continuous infusion of chemotherapy via a Port-a-Cath system is a relatively safe procedure, although major complications do occur. The experience of the surgeon could not be related to the complications.

Intermittent continuous infusion of 5-fluorouracil in combination with epirubicin and cisplatin in advanced gastric cancer: the importance of dose intensity.

BACKGROUND: Recently, high response rates have been reported in patients with advanced gastric cancer with a schedule of epirubicin, cisplatin, and protracted infusion of 5-fluorouracil (5-FU). We modified this schedule based on the assumption that shorter treatment intervals are more convenient for patients and that cytokinetically based data showed that most gastric cancers have a relatively short potential doubling time of of less than 14 days. PATIENTS AND METHODS: Fourteen patients with advanced gastric adenocarcinoma with progressive, measurable disease entered the study. Patients were treated from days 1 to 14 with 5-FU 200 mg/m2 per day as a continuous infusion using a portable infusion pump. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1. Courses were repeated every 4 weeks. RESULTS: No responses were observed (response rate 0% [95% CI 0-23%]). Toxicity was mild. Grade 3 toxicity occurred in only 2 patients (14%). The median progression free survival was 3.5 months (range 2 to 17). The median survival was 6.5 months (range 2 to 31+). CONCLUSIONS: The unexpected results of this study are most likely due to a diminished dose intensity. When comparing the results of several schedules with epirubicin, cisplatin, and 5-FU, it seems that the dose intensity for all three drugs may be important, but especially for 5-FU.

Intermittent continuous infusion of ifosfamide and 5-fluorouracil in patients with advanced adenocarcinoma of the pancreas.

BACKGROUND: In advanced adenocarcinoma of the pancreas treatment with 5-fluorouracil (5-FU) or ifosfamide results in response rates of approximately 20%. Continuous infusion of these drugs is on many grounds theoretically attractive and may therefore offer advantages over bolus or short-term infusion. PATIENTS AND METHODS: Sixteen patients with advanced adenocarcinoma of the pancreas with progressive measurable disease and no previous chemotherapy entered the study. After implantation of a subcutaneous infusion chamber patients were treated on days 1-12 with ifosfamide (1.0 g/m2/day) and 5-FU (300 mg/m2/day) as a continuous intravenous infusion using a portable infusion pump. Mesna (1.0 g/m2/day) was added as uroprotective agent from day 1-14. Courses were repeated every 4 weeks. RESULTS: Fifteen of the 16 patients were evaluable for response. One partial response was observed (response rate 7% [95% CI: 0%-32%]). Toxicity occurred in 64% of the courses. Dose limiting toxic effects were grade 3 nausea/vomiting (WHO) in 3 patients, grade 2 mucositis in 1 patient and grade 4 leukopenia in 1 patient. CONCLUSION: Intermittent continuous infusion with ifosfamide, mesna and 5-FU is feasible on an outpatient basis. Although continuous infusion of ifosfamide may have a more favorable toxicity profile, the combination of 5-FU and ifosfamide in this schedule is no more effective than bolus or short-term infusion.

Delayed postoperative emptying after esophageal resection is dependent on the size of the gastric substitute.

BACKGROUND: Delayed emptying of the gastric substitute is a common problem after resection and reconstruction of the esophagus. The occurrence of postoperative delayed gastric emptying in patients undergoing resection and reconstruction of the esophagus was studied with regard to the type and size of gastric substitute and the execution of a pyloroplasty. STUDY DESIGN: From 1983 to 1994, one hundred fifty-five patients underwent resection of the esophagus, with a hospital mortality rate of 7 percent. The inability to resume a diet of solid food within one week after a normal esophagography was defined as delayed gastric emptying. One hundred forty patients were studied; group 1, substitution with whole stomach with (1a, n = 9) and without (1b, n = 31) pyloroplasty; group 2, substitution with distal two-thirds stomach with (2a, n = 20) or without (2b, n = 45) pyloroplasty; and group 3, tubulized stomach without pyloroplasty (n = 35). RESULTS: Delayed gastric emptying was seen in 38 percent (15 of 40) of patients in group 1 (1a, 44 percent; 1b, 37 percent), in 14 percent (nine of 65) of patients in group 2 (1a, 10 percent; 2b, 15 percent), and in 3 percent (one of 35) of patients in group 3. The differences between patients in group 1 and group 2, and between patients in group 1 and group 3 were significantly different (p < 0.05). CONCLUSIONS: The type of gastric remnant used for reconstruction is an important determinant of postoperative gastric emptying. Pyloroplasty does not prevent delayed gastric emptying after esophageal substitution.

Randomised comparison of morbidity after D1 and D2 dissection for gastric cancer in 996 Dutch patients.

For patients with gastric cancer deemed curable the only treatment option is surgery, but there is disagreement about whether accompanying lymph-node dissection should be limited to the perigastric nodes (D1) or should extend to regional lymph nodes outside the perigastric area (D2). We carried out a multicentre randomised comparison of D1 and D2 dissection. 1078 patients were randomised (539 to each group). 26 allocated D1 and 56 allocated D2 were found not to satisfy eligibility criteria (histologically confirmed adenocarcinoma of the stomach without clinical evidence of distant metastasis). Each of the remainder was attended by one of eleven supervising surgeons who decided whether curative resection was possible and, if so, assisted with the allocated procedure. Among the 711 patients (380 D1, 331 D2) judged to have curable lesions, D2 patients had a higher operative mortality rate than D1 patients (10 vs 4%, p = 0.004) and experienced more complications (43 vs 25%, p < 0.001). They also needed longer postoperative hospital stays (median 25 [range 7-277] vs 18 [7-143] days, p < 0.001). Morbidity and mortality differences persisted in almost all subgroup analyses. While we await survival results, D2 dissection should not be used as standard treatment for western patients.

Risk of residual rectal mucosa after proctocolectomy and ileal pouch-anal reconstruction with the double-stapling technique. Postoperative endoscopic follow-up study.

PURPOSE: This study was designed to assess the risk of retained rectal mucosa after proctocolectomy and ileal pouch-anal anastomosis with the double-stapling technique. METHODS: A total of 113 patients underwent proctocolectomy with an ileal pouch-anal reconstruction. In 57 patients the anastomosis between pouch and proximal anal canal was performed using the double-stapling technique. In 26 patients the procedure was carried out without a protecting ileostomy. Of the remaining 31 patients with a proximal ileostomy, 15 underwent endoscopy six weeks postoperatively. Circular biopsies were taken just distal from the pouch-anal anastomosis. RESULTS: Histologic examination revealed rectal mucosa in at least one biopsy in 7 of 15 patients. At follow-up (mean 18 months) no (distal) pouchitis was clinically noticed. In one patient with familial polyposis, a few polyps, distal of the anastomosis, had to be endoscopically removed. CONCLUSIONS: Double-stapled ileal pouch-anal anastomosis has a considerable risk of residual rectal mucosa, because of combined linear transection and circular stapling with bilateral dog-ear formation of rectal mucosa. Residual rectal mucosa did not seem to influence clinical results at follow-up.

Intermittent continuous infusion of 5-fluorouracil and low dose oral leucovorin in patients with gastrointestinal cancer: relationship between plasma concentrations and clinical parameters.

Modulation of 5-fluorouracil (5-FU) by leucovorin and continuous infusion of 5-FU can both result in enhanced therapeutic efficacy. The main objective of this study was to determine the maximum tolerated dose (MTD) of oral leucovorin in combination with continuous infusion of 5-FU for 14 days every 4 weeks at a dose of 300 mg/m2/day in 30 patients with gastrointestinal cancer. The MTD of oral leucovorin was established at 10 mg/day. Dose-limiting toxicities were mucositis, diarrhoea and hand-foot syndrome. Plasma leucovorin concentrations were below the detection limit of the assay (< 0.5 microM). Plasma 5-FU concentrations varied considerably from 0.06 to 11.3 microM. A relation between toxicity, response and plasma concentration of 5-FU could not be established. Our data may indicate that even very low plasma concentrations of leucovorin are able to modulate 5-FU. In 17 patients with colorectal cancer the response rate was 24% (95% CI: 7-50%), which is comparable to other treatment schedules with leucovorin or to continuous infusion of 5-FU alone.

Role of extended lymph node dissection in the treatment of gastrointestinal tumours: a review of the literature.

UNLABELLED: Over recent decades the long-term survival of patients operated on for gastrointestinal cancer has shown little if any improvement, despite sometimes aggressive surgical procedures and a significant fall in postoperative mortality. BACKGROUND: We went through the literature to see if there were any eventual effects of extended lymph node dissection or survival. METHODOLOGY: We reviewed recent literature on the different types of gastrointestinal cancer. RESULTS: Japanese centres report excellent results when wide local excision is combined ith systematic extended lymph node dissection, especially in gastric and oseophageal cancer. The overall 5-year survival of over 50% for the large number of patients undergoing gastric resection for cancer seems to demonstrate convincingly the value of the extended lymphadenectomy. All oriental studies are uncontrolled, as are most reports from Western countries. The role of extended lymphadenectomy is therefore far from certain. The results from two randomized studies (British Medical Research Council and Dutch Gastric Cancer Trial) are awaited. It is evident from these prospective studies that the procedure adds a considerable operative risk. From non-randomized studies there is evidence that extended lymph node dissection in the treatment of pancreatic cancer might be of benefit to patients with small stage I and II tumours. In the treatment of proximal bile duct cancer the main goal of surgery is optimal relief of biliary obstruction. Whether there will ever be a role for extensive lymphadenectomy is doubtful. The extent of the surgical procedure in the treatment of gallbladder cancer is related to the depth of tumour infiltration. Extended resections are only recommended for patients with stage II to IV tumours. Extended lateral pelvic node dissection in the treatment of rectal cancer is demonstrated in Japanese retrospective studies to induce considerable urogenital problems, whereas the risk for local recurrence is still present. CONCLUSIONS: No firm conclusions can be drawn based on data as available from the studied literature. Trial results will have to be awaited. Specific subgroups such as gastric and rectal cancer might benefit from these more extensive procedures.