Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III.

Based on the first favourable results of adjuvant therapy of 5FU plus levamisole in Dukes C colonic cancer in 1990, we conducted a prospective trial. 1029 patients were randomised to receive one year 5FU plus levamisole or no further treatment following curative surgery for stage II or III colon (n = 730) or rectal cancer (n = 299). 45% were in stage II and 55% in stage III. With a median follow-up of 4 years and 9 months a significant reduction in odds of death (25%, SD 9%, P = 0.007) was observed for those with adjuvant treatment (65% at 5 year) compared to the observation group (55%). Improved relative survival was present in stage III (56% vs 44%), and in stage II patients (78% vs 70%). In rectal cancer a non-significant difference in disease-free or overall survival was observed. Distant metastases developed in 76%, while local recurrence alone occurred in 14%. An early start of adjuvant treatment (< 4 weeks) did not affect results. Compliance to 5FU plus levamisole was 69%. Severe toxicity did not occur. In conclusion, one year 5FU plus levamisole was of benefit in stage II and III colonic cancer; in rectal cancer a significant positive effect could not be demonstrated.

Sequence-dependent toxicity profile in modified FAMTX (fluorouracil-adriamycin-methotrexate) chemotherapy with lenograstim support for advanced gastric cancer: a feasibility study.

For advanced irresectible gastric cancer, sequential high-dose methotrexate and 5-fluorouracil (both on day 1) combined with adriamycin on day 15 (FAMTX regimen), cycled every 28 days, is a fairly effective but toxic treatment, with a high incidence of neutropenic fever, dose reductions and dose delays. In order to improve FAMTX toxicity, we studied the feasibility of two modified FAMTX regimens with lenograstim support. Seven advanced gastric cancer patients were treated with all three FAMTX drugs on day 1 followed by lenograstim 150 microgm(-2)for 10 days, in 21-day cycles (FUMA regimen). The next seven patients were treated with the same drugs at the same doses, but with adriamycin 1 day prior to methotrexate and 5-fluorouracil administration (AFUM regimen). Patients were monitored for toxicity, response, and survival. The total number of courses was 27 for FUMA and 35 for AFUM with a median of four courses per patient in each cohort. In the FUMA regimen, considerable toxicity consisting of mucositis and fatigue as well as grade 4 neutropenia occurred, and forced four out of seven patients to stop treatment. The consecutive AFUM regimen showed only mild toxicity, and all patients could finish treatment without dose reductions or delays. We found unanticipated and probably sequence-dependent toxicity profiles in two investigational, modified FAMTX schedules with lenograstim support, leading to high rates of dose-limiting toxicity in the FUMA regimen as opposed to mild toxicity in the AFUM regimen, even though the same total drug doses and treatment cycle length (dose intensity) were employed.

Thymidylate synthase expression in patients with colorectal carcinoma using a polyclonal thymidylate synthase antibody in comparison to the TS 106 monoclonal antibody.

Colorectal cancer is one of the most common human cancers, for which 5-fluorouracil (5FU) is usually part of the treatment. Thymidylate synthase (TS), the target enzyme for 5FU, can be predictive for the outcome of 5FU-based therapy. TS levels in tumor samples can be determined with radiochemical enzyme assays, RT-PCR, and immunohistochemical staining. We validated TS immunohistochemistry with a polyclonal rabbit anti-human TS antibody using the avidin-biotin method. This antibody can be used on paraffin-embedded, formalin-fixed material using an antigen retrieval method with citrate buffer and microwave treatment. The antibody shows a granular cytosolic staining pattern. The reproducibility in cross-sections from colorectal tumors from 50 patients was 90% and the interobserver variability was acceptable with a kappa of 0.45. On Western blotting it detects purified TS at 36 kD, while in 5FU-treated cells the ternary complex between FdUMP, TS, and 5, 10-methylene-tetrahydrofolate is clearly visible at 38 kD, with no other interfering bands. In a separate set of tumors, immunostaining was compared with enzyme levels; Western blots correlated with enzyme levels. Because both this polyclonal antibody and the monoclonal antibody TS-106 are being used for large-scale studies, we also determined whether they could be used interchangeably. No differences were observed. This polyclonal antibody is specific and gives reproducible results. A study on a larger scale is ongoing to determine the role of TS as a predictive parameter in patients with colorectal cancer treated either with postoperative adjuvant 5FU/levamisole or with surgery only.

Controversies and consensus in the diagnosis, work-up and treatment of gastric lymphoma: an international survey.

BACKGROUND: Variations in diagnostic criteria and staging procedures in cancer patients have important consequences for patient selection and often preclude meaningful comparison of published series. In gastric lymphoma, these effects will play a role, since diagnostic criteria are controversial. Moreover, staging procedures and therapeutic choices are influenced by insights from different clinical specialisms. METHODS: To review the management of gastric lymphoma, formatted questionnaires were mailed to leading institutes with a special interest in this field in Europe, the United States and Japan. RESULTS: Nineteen centers agreed to contribute. Minimum histological criteria varied among pathologists with a notable influence of the classification system used in the different countries. Detailed evaluation of the lymphoma distribution in the gastric wall and routine staging of the GI-tract differed between groups leaded by medical oncologists and gastroenterologists. This results in basically different patient selections and bias in treatment outcome. Similar effects were recorded for the role of gastric resection and radiotherapy. CONCLUSIONS: This study gives insight in the basis of the decisions that result in different approaches in the management of gastric MALT-NHL and in the effects for patient selection and treatment results and may help in the design of future clinical trials.

Combined diagnostic imaging with 131I-metaiodobenzylguanidine and 111In-pentetreotide in carcinoid tumours.

Carcinoid tumours derived from the neural crest are usually associated with the symptoms of flushing and diarrhoea in the presence of liver metastases. Scintigraphs with 131I-metaiodobenzylguanidine (131I-MIBG) which is accumulated in the argentaffin granules of the cell, as well as with 111In-pentetreotide for the imaging of somatostatin receptors on the cell surface, are positive in a large proportion of carcinoid patients. To evaluate the complementary role of both radionuclide tests, we studied 20 consecutive carcinoid patients: 14 with the characteristic carcinoid syndrome and 6 with tumour symptoms, such as pain or obstruction. A positive test was found in 84% with either 131I-MIBG or 111In-pentetreotide; the combination yielded a sensitivity of 95%. A positive correlation was found with the presence of the carcinoid syndrome, but not with 5-HIAA excretion. A positive test may help in adjusting treatment: either to predict the response to octreotide or to select patients for 131I-labelled MIBG treatment. Application of a therapeutic dose of 111In-pentetreotide may be limited by the high normal uptake in the kidneys.

Hereditary nonpolyposis colorectal cancer: results of long-term surveillance in 50 families.

A surveillance programme comprising either colonoscopy of sigmoidoscopy plus barium enema every 2-3 years was instituted in 50 hereditary nonpolyposis colorectal cancer (HNPCC) families. The families included 238 patients with colorectal cancer (CRC) (mean age at diagnosis: 43.7 years; range: 16-86 years). These patients had 597 first-degree relatives of whom 493 could be traced and 388 (79%) accepted the invitation for screening. The control group were relatives (index patients) with symptomatic CRC. The average follow-up duration was 5 years (1-20 years). Screening led to the detection of adenomas in 33 patients and CRC in 11 patients. Pathological examination revealed 1 Dukes' A, 7 Dukes' B and 3 Dukes' C cancers. In contrast, among the control group 47% had advanced CRC (Dukes' C or distant metastases). The 5-year survival of the screen-detected cases was 87% versus 63% in the control group. Of the 11 CRC cases in the screening group, 4 were detected within 1-4 years after a negative colonic examination. A large proportion of the polyps found in the screening and control groups showed a villous growth pattern and/or a high degree of dysplasia. We conclude that periodic examination of HNPCC families allows the detection of cancer at an earlier stage than in patients not under surveillance. Because of the possibly more aggressive nature of polyps associated with HNPCC, we recommend a screening interval of 1-2 years.

Metastatic ovarian or colonic cancer: a clinical challenge.

Clinical problems arise when histology is unable to differentiate between an ovarian carcinoma infiltrating into the rectosigmoid region and a colonic cancer with ovarian metastases. To evaluate the discriminative value of immunohistochemistry we studied four groups: (A) ovarian carcinoma (n = 21), (B) ovarian carcinoma with sigmoid stenosis (n = 18), (C) colonic carcinoma (n = 20) and (D) a group in which the differential diagnosis was a problem (n = 19). Paraffin sections stained with a panel of monoclonal antibodies revealed specific patterns: in group A and B a negative Parlam-4 and positive OC-125; in group C the opposite; in group D the 'colonic' pattern in 15 cases, and the 'ovarian' pattern in only 2. The clinical diagnosis in group D during follow-up was ovarian carcinoma in 7, colonic carcinoma in 8, double tumour in 1 and still unknown in 3. This was based on high levels of serum tumour markers such as carcinoembryonic antigen (n = 5) and CA-125 (n = 4), laparotomy (n = 4), autopsy (n = 1), barium enema and/or endoscopy (n = 5). The response to chemotherapy in group D was extremely poor.

Rectosigmoid obstruction caused by ovarian cancer.

Out of a total of 379 patients with ovarian carcinoma a rectosigmoid stenosis was detected in 44 (12%). A barium enema was available in 27 cases, which revealed a severe stenosis (less than 1/2 lumen open) in 23, with an average length of 17 cm (5-40 cm). Five characteristic types of stenosis were found: solitary stenosis (n = 6), large spherical impression (n = 6), multiple stenoses (n = 4), long narrow tract (n = 6) and a total obstruction (n = 5). Desmoplastic reaction with tethering and/or parallel folds (n = 16) or fixation and/or angulation (n = 18) were frequently found, but tumour invasion was rare (n = 3). A sigmoid resection (n = 1) or colostomy (n = 3) was seldom needed, due to beneficial response to combined therapy.