Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer.

PURPOSE: The long-term survival probability of patients who undergo surgery for stage 3 and 4 gastric cancer is poor, predominantly due to metastatic spread of the tumor. Depending on the type of tumor histology, the pathway of metastases is mainly peritoneal or hepatic dissemination. Interruption of this mechanism may be possible by intraperitoneal chemotherapy (IPT). PATIENTS AND METHODS: In a prospective randomized trial of 67 patients undergoing surgery for stage 3 and 4 gastric cancer, 33 patients underwent adjuvant postoperative IPT with cisplatin, while 34 control subjects remained untreated. RESULTS: Patients in the treatment group received a median of four IPT perfusions. Apart from frequent nausea, no adverse reactions or complications were noted. The median disease-free survival durations were 12.7 months and 9.7 months in treated patients and controls, respectively (P = .8). After a median follow-up duration of 72 months, 54 patients (80%) had died of primary disease or related complications. The median survival duration for IPT patients was 17.3 months as compared with 16.0 months for controls (P = .6). Autopsies were performed on 12 (18%) of 54 patients who died, and showed tumor spread to the peritoneal cavity and/or to the liver, irrespective of the application of IPT. CONCLUSION: IPT with cisplatin monotherapy does not improve survival probability after surgery for stage 3 and 4 gastric cancer. The reasons for ineffectiveness of IPT may be the choice of an unsuitable chemotherapeutic agent, an inefficient modus of application, or a lack of sufficient drug penetration into the serosa or peritoneal metastasis.

Fluorouracil plus racemic leucovorin versus fluorouracil combined with the pure l-isomer of leucovorin for the treatment of advanced colorectal cancer: a randomized phase III study.

PURPOSE: To compare the efficacy and toxicity of fluorouracil (FU) and racemic leucovorin (d,l-LV) versus FU combined with the l-isomer of leucovorin (l-LV) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 248 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either FU (400 mg/m2/d by intravenous [I.V.] infusion for 2 hours) and racemic LV (100 mg/m2/d by I.V. bolus injection) given for 5 consecutive days, or the combination of FU and the pure l-isomer of LV using the same dose schedule. In both treatment arms, courses were administered every 28 days if toxicity allowed for a total of 6 months, unless evidence of tumor progression was documented earlier. RESULTS: There were no significant differences between the FU/racemic LV and the FU/l-LV arm in the overall response rate (25% v 32%), duration of response (7.2 v 8.0 months), median time to progression or death (6.25 v 8.0 months), or median overall survival time (14.5 v 15.0 months). Except for minor myeloid toxic effects associated with FU/l-LV, there was also no significant difference in terms of adverse reactions. Gastrointestinal symptoms, specifically mucasitis and diarrhea, were less frequent and less severe in both treatment arms compared with other trials with FU/racemic LV reported in the literature, which might be because of the prolonged administration of FU used in both arms. CONCLUSION: The combination of FU/l-LV produced response rates, response durations, and survival times similar to those with FU/d,l-LV. Biochemical modulation of FU by either pure l-LV or racemic LV thus appears to result in equivalent clinical efficacy.

Treatment of advanced breast cancer with vinorelbine and docetaxel with or without human granulocyte colony-stimulating factor.

PURPOSE: A multicenter phase II trial was performed to investigate the efficacy and tolerance of docetaxel, vinorelbine with or without recombinant human granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. PATIENTS AND METHODS: Between February 1998 and March 1999, 57 patients participated in this trial. Forty-two patients received this combination as first-line and 15 patients as second-line chemotherapy, including 10 patients who had failed anthracyclines. Therapy consisted of vinorelbine 30 mg/m(2) on days 1 and 15 and docetaxel 30 mg/m(2) on days 1, 8, and 15 every 4 weeks. Depending on the absolute neutrophil counts on the day of scheduled chemotherapeutic drug administration, a 5-day course of G-CSF 5 microg/kg/d was given. RESULTS: The overall response rate was 64.3% (95% confidence interval, 48.1% to 78.4%) in patients receiving docetaxel plus vinorelbine as first-line chemotherapy, including eight complete (19%) and 19 partial remissions (45.3%); 11 patients (26.2%) had disease stabilization, and only four (9.5%) progressed. Second-line treatment with this regimen resulted in eight (53.3%) of 15 objective responses, four had stable disease, and three had progressive disease. The median time to progression was 12 months in the first-line and 9.8 months in the second-line setting, respectively. After a median follow-up time of 18 months, 38 patients (65%) were still alive with metastatic disease. Myelosuppression was commonly observed; World Health Organization grade 3 or 4 neutropenia both occurred in 18 patients (32%) and was complicated by septicemia in four cases; grade 3 or 4 thrombocytopenia was seen in two patients (4%), and grade 3 anemia was seen in only one patient (2%). Severe (grade 3) nonhematologic toxicity, except for alopecia, was rarely observed and included nausea/vomiting in two patients (4%), and stomatitis, peripheral neuropathy, and skin toxicity each in one patient. CONCLUSION: Our data suggest that docetaxel and vinorelbine with or without G-CSF is an effective and fairly well tolerated regimen for the treatment of advanced breast cancer. It might be particularly useful in patients previously exposed to adjuvant or palliative anthracyclines and/or alkylating agents.

Combined irinotecan and oxaliplatin plus granulocyte colony-stimulating factor in patients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.

PURPOSE: To evaluate the efficacy and tolerance of combined irinotecan and oxaliplatin in patients with advanced colorectal cancer pretreated with leucovorin-modulated fluoropyrimidines. PATIENTS AND METHODS: Thirty-six patients with metastatic colorectal cancer, who progressed while receiving or within 6 months after discontinuing palliative chemotherapy with fluoropyrimidines/leucovorin, were enrolled onto this study. Treatment consisted of oxaliplatin 85 mg/m2 on days 1 + 15 and irinotecan 80 mg/m2 on days 1 + 8 + 15 every 4 weeks. Depending on the absolute neutrophil counts (ANC) on the day of scheduled chemotherapeutic drug administration, a 5-day course of granulocyte colony-stimulating factor (G-CSF) 5 microg/kg/d was given. RESULTS: The overall response rate was 42% for all 36 assessable patients (95% confidence interval, 26% to 59%), including two complete remissions (6%). Thirteen additional patients (36%) had stable disease, and only eight (22%) progressed. The median time to treatment failure was 7.5 months (range, 1 to 13.5+ months). After a median follow-up time of 14 months, 19 patients (53%) are still alive. Hematologic toxicity was commonly observed, although according to the ANC-adapted use of G-CSF (in 31 patients during 81 of 174 courses), it was generally mild: grade 3 and 4 granulocytopenia occurred in only five and two cases, respectively. The most frequent nonhematologic adverse reactions were nausea/emesis and diarrhea, which were rated severe in 17% and 19%, respectively. CONCLUSION: Our data suggest that the combination of irinotecan and oxaliplatin with or without G-CSF has substantial antitumor activity in patients with progressive fluoropyrimidine/leucovorin-pretreated colorectal cancer. Overall toxicity was modest, with gastrointestinal symptoms constituting the dose-limiting side effects. Further evaluation of this regimen seems warranted.

MRP and MDR1 gene expression in primary breast carcinomas.

To evaluate the clinically important mechanisms of drug resistance in breast cancer, the expression of the MRP gene and the corresponding one for the MDR1 gene were determined in primary breast carcinoma specimens by both reverse transcription-PCR (n = 134) and immunohistochemistry (n = 63). Expression of MRP RNA was observed in all breast cancer specimens. MDR1 RNA was detected in 80 (60%) of the carcinomas. Staining with monoclonal antibodies QCRL-1 and QCRL-3, which both recognize MRP, was strong in 15 (24%) and weak in the remaining 48 specimens (76%). Staining with C219, which recognizes P-glycoprotein, was strong in 6 (9%), weak in 30 (48%), and negative in 27 (43%) of the samples. Strong MRP staining was more frequent in T3 and T4 tumors than in T1 and T2 tumors and in the primary tumors of patients with distant metastases but was independent of age, menopausal status, histology, histological grade, estrogen receptor, progesterone receptor, and lymph node involvement. No correlation between MRP staining and expression of MDR1 RNA or P-glycoprotein was observed. Thus, these results indicate expression of both the MRP gene and the MDR1 gene in primary breast carcinomas and suggest that clinical drug resistance in breast cancer is most likely multifactorial.

Amonafide as first-line chemotherapy for metastatic breast cancer.

In a phase II study, 32 patients with advanced breast cancer previously unexposed to palliative cytotoxic chemotherapy were treated with amonafide, 800-900 mg intravenously over 3 h repeated every 4 weeks. Objective response was seen in 8 patients including 1 complete response, 10 patients had stable disease and 14 patients progressed so the overall response was 25% (95% confidence interval, 11-43%). The most frequently encountered side-effects were haematological (granulocytopenia > or = WHO grade 3 was encountered in 7/24 patients at 800 mg/m2 and in 3/8 patients at 900 mg/m2 amonafide) and nausea/vomiting (62%), despite prophylactic use of ondansetron. Non-haematological severe adverse reactions included neurotoxicity WHO grade 3 in 1 patient and orthostatic hypotension WHO grade 4 in another. In summary, the results of this trial suggest a limited therapeutic index of amonafide if used at this dose with this administration schedule.

MDR1 gene expression and prognostic factors in primary breast carcinomas.

To prospectively assess the role of the MDR1 gene in breast carcinomas, MDR1 RNA levels of breast carcinoma specimens were determined by slot blot analysis. In 59 evaluable patients with primary breast carcinomas, MDR1 RNA levels of the carcinomas were negative in 54%, low in 29% and high in 17% of the patients. No differences in age, menopause status, oestrogen and progesterone receptor levels, tumour size, lymph node involvement and c-erbB-2/neu gene expression were observed between MDR1 RNA negative patients and MDR1 RNA positive patients.

MDR1 RNA transcripts do not indicate long-term prognosis in colorectal carcinomas.

Because P-glycoprotein expression might be associated with a more aggressive behaviour of colorectal carcinomas (Weinstein et al., Cancer Res, 1991, 51, 2720-2726), we determined the relationship between MDR1 RNA expression of the carcinomas and the survival of the patients. At a median duration of follow-up of 86 months, event-free survival of patients with MDR1 RNA-negative tumours (n = 35) was not significantly different to that of patients with MDR1 RNA positive tumours (n = 67). Among the different tumour stages, event-free survival of the patients was also independent of MDR1 gene expression of the tumours. Thus, these findings do not support the hypothesis that local aggressiveness of P-glycoprotein positive tumour cells translates into worse clinical outcome.

Combined intraperitoneal plus intravenous chemotherapy after curative resection for colonic adenocarcinoma.

Patients who underwent potential curative surgery for colonic adenocarcinoma were enrolled in a prospectively randomised, controlled clinical trial of combined intraperitoneal (i.p.) plus systemic intravenous (i.v.) chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV). We investigated whether this adjuvant treatment approach, specifically addressing the risk of peritoneal and hepatic recurrence, could improve disease-free and overall survival. Between May 1988 and December 1990, 121 patients with resected stage III or high-risk stage II (T4N0M0) colon cancer were randomly assigned for observation (which was considered standard care until the NIH consensus conference) or adjuvant chemotherapy with LV (200 mg/m2) plus 5-FU (350 mg/m2), both given i.v. (days 1-4) and i.p. (days 1 and 3) every 4 weeks for a total of six courses. After a median follow-up time of 4.6 years, a comparative analysis between the two groups of patients suggested both an improvement in disease-free survival (75% versus 58%; P = 0.06) and a survival advantage (78% versus 63%; P = 0.05) in favour of adjuvant chemotherapy. The sites of recurrence were also different, i.e. local regional and intrahepatic tumour recurrences were observed in only 6/58 (10%) and 5/58 (9%) adjuvant treated patients as compared to 11/60 (18%) and 10/60 (17%) observed patients. The overall benefit of adjuvant therapy appeared to be greatest in patients with stage III colon cancer. Treatment-associated toxicity was infrequent and generally mild with only 5% experiencing severe (WHO grade 3) adverse reactions. Interim results of this adjuvant trial suggest that combined i.p. plus systemic i.v. chemotherapy with 5-FU and LV represents a potentially effective adjuvant regimen in stage II/III colon cancer.

Comparative analysis of cancer-associated antigen CA-195, CA 19-9 and carcinoembryonic antigen in diagnosis, follow-up and monitoring of response to chemotherapy in patients with gastrointestinal cancer.

To establish further the clinical significance of the CA-195 tandem immunoradiometric assay in gastro-intestinal malignancies, the sera of a total of 222 subjects have been analysed and compared with assays of the "classical gastrointestinal tumour markers", CA19-9 and carcinoembryonic antigen (CEA). CA-195 elevations above normal (greater than 10 U/ml) were noted in 51/72 (70.8%) colorectal, 15/15 (100%) pancreatic, and in 6/12 (50%) gastric cancer patients. Whereas CA19-9 was increased (greater than 37 U/ml) in 65%, 93%, and 42% of cases, only 54% colorectal, 45% pancreatic, and 42% gastric cancer patients had pathologically elevated serum CEA levels (greater than 5 ng/ml). No abnormal increase of both CA-195 and CA19-9 was found in healthy volunteers, whereas 3/20 (smoking) individuals had CEA levels slightly above normal. With a 29% false-positive rate noted among 103 patients with benign gastrointestinal disorders, the specificity of CA-195 was superior to that of CA19-9 (58%) and comparable with that of CEA (31%). A significant correlation between CA-195 levels and the clinical/pathological stage of disease was noted in colorectal (P less than 0.01) and pancreatic cancer patients (P less than 0.007). Preliminary results of serial measurements of CA-195 in colorectal cancer suggest that this new marker protein, which has no cross-reactivity with CEA, may be useful as a non-invasive test for postoperative surveillance of patients to detect disease recurrence, and serve to complement (though certainly not replace) standard clinical measurements of response to chemotherapy.

Comparative analysis of CA72-4, CA195 and carcinoembryonic antigen in patients with gastrointestinal malignancies.

To establish further the clinical significance of the novel quantitative immunoradiometric assay system CA72-4 in patients with gastric and other digestive tract malignancies, the sera of a total of 208 subjects have been analysed and levels of carcinoembryonic antigen (CEA) and another promising new tumour marker, CA195, have been compared. Twenty patients had gastric (GC), 60 colorectal (CC), and 14 pancreatic carcinomas (CC); 94 patients had benign disorders, and 20 were healthy volunteers. CA72-4 elevations above normal (greater than 4 U/ml) were observed in 6 (30%) GC, 17 (28%) CC, and 8 (57%) PC patients. CA195 appeared more sensitive and was increased (greater than 10 U/ml) in 35% GC, 70% CC, and in 100% PC patients; CEA levels above normal (greater than 5 ng/ml) were noted in 35%, 45%, and 66% of patients respectively. CA72-4 had a rather high specificity and was increased in only 6/94 (6%) patients with benign diseases, whereas CA195 had a false positive rate of 23%, and CEA of 33%. Among 20 healthy donors, none had elevated levels of CA72-4 or CA195, but marginal elevations of CEA were noted in 3 smokers. Despite some advantage of the new tumour marker CA72-4 in terms of specificity, its value as a serodiagnostic test in gastrointestinal cancer patients seems inferior to that of CA195 and CEA.

Long-term follow-up of surgically treated gallbladder cancer patients.

AIMS: Palliative attempts have traditionally led treatment of gallbladder cancer but resection offers the only chance for long-term survival. This study investigates the impact of surgery with curative intent in gallbladder cancer treatment and evaluates prognostic factors for survival. METHODS: Two hundred and sixty-seven patients were admitted for surgical therapy. Sixty received resection with curative intent and form the basis of this analysis. RESULTS: R0 resection (n=45) was a highly significant independent survival predictor (P<0.001). All 5-year survivors (n=10) had tumour-free resection margins. Early T stage (P=0.017) and highly differentiated cancer (P=0.008) had a significant better outcome. Nodal spreading increased by local tumour extension and lymphatic involvement decreased patient survival (P=0.018). Patients' age (>75 years) was without influence on long-term survival. CONCLUSIONS: Long-term survival is possible both in elderly patients and in advanced cancer.

Expression of the lung resistance protein (LRP) in primary breast cancer.

BACKGROUND: To determine the clinical significance of the lung resistance protein (LRP) in breast cancer, we have studied its expression in primary breast carcinomas (n = 99) and assessed the association of this expression with clinical parameters of the patients. MATERIALS AND METHODS: LRP expression was immunohistochemically determined by means of the monoclonal antibody LRP-56 on frozen tumor sections. RESULTS: LRP expression was negative in 12%, low in 20%, intermediate in 47% and high in 21% of the carcinomas. LRP expression was independent of age of the patients, histology, tumor grade, estrogen receptor as well as progesterone receptor status, tumor size and lymph node involvement. Kaplan-Meier analyses revealed that both overall survival and disease-free survival were independent of the degree of LRP expression. CONCLUSIONS: LRP is frequently expressed in breast carcinomas, but is neither associated with known prognostic factors, nor a prognostic factor by itself.

Expression of the lung resistance protein in primary colorectal carcinomas.

To assess whether the lung resistance protein (LRP) is of clinical significance in colorectal carcinomas, we immunohistochemically determined LRP expression of colorectal carcinoma specimens (n = 68) by means of the monoclonal antibody LRP-56 and compared this expression with clinical parameters. LRP expression was negative in 7 (10%), low in 36 (52%) and high in 25 (38%) carcinomas. LRP expression was independent of histological grade, tumor size, lymph node involvement and distant metastasis. Survival of the patients with LRP-positive tumors was similar to the survival of patients with LRP-negative tumors. However, patients with high LRP expression in their carcinomas had a prolonged survival. Thus LRP is frequently expressed in colorectal carcinomas and high expression might indicate improved survival.

Expression of the multidrug resistance protein (MRP1) in breast cancer.

BACKGROUND: The multidrug resistance protein (MRP1) is expressed in human breast carcinomas but its clinical significance remains unclear. The aim of the present study was to determine the clinical significance of MRP1 in breast cancer patients. MATERIALS AND METHODS: MRP1 expression of primary carcinomas from 100 breast cancer patients was immunohistochemically determined by means of the monoclonal antibodies QCRL-1/QCRL-3. RESULTS: MRP1 was negative in 20 (20%) and positive in 80 (80%) breast carcinomas. MRP1 expression was more frequent in both estrogen receptor-negative carcinomas and progesterone receptor-negative carcinomas (p = 0.1 in both cases), but was independent of tumor size and lymph node involvement. Patients with MRP1-negative carcinomas had prolongations of overall survival (p = 0.01 for death due to any cause, p = 0.04 for breast cancer-related death) and disease-free survival (p = 0.07) as compared to those with MRP1-positive carcinomas. Also in subsets of patients (negative lymph nodes; positive lymph nodes; positive estrogen receptor; T1/T2 tumors), overall survival was longer for patients with MRP1-negative carcinomas. In univariate Cox regression analyses, MRP1 positivity was associated with relative risks of 4.9 (95% CI 1.2-20.6; p = 0.03) for death due to any cause, 6.4 (95% CI 0.9-48.0; p = 0.07) for breast cancer-related death and 3.5 (95% CI 0.8-14.9; p = 0.09) for relapse. In multivariate Cox regression analyses, MRP1 positivity had relative risks of 5.1 (95% CI 1.2-21.7; p = 0.03) for death due to any cause, 6.5 (95% CI 0.8-50.1; p = 0.07) for breast cancer-related death and 3.4 (95% CI 0.8-15.1; p = 0.1) for relapse. CONCLUSIONS: Our results suggest that MRP1 might be an important factor in breast cancer indicating excellent prognosis for patients with MRP1-negative carcinomas.

[Spontaneous mesenteric venous thrombosis, a rare complication of oral contraceptives (author's transl)]. / Primäre Mesenterialvenenthrombose, eine seltene Komplikation oraler Ovulationshemmer.

Spontaneous mesenteric venous thrombosis without recognizable aetiology is a rare condition. Only 10 cases have been described in world literature as a complication of oral contraceptives. The case report is presented of a 51 year-old married woman who had been taking oral contraceptives for 7 years. After abdominal pain for weeks segmental mesenteric venous thrombosis with a gangrenous small bowel loop was diagnosed. The gangrenous small bowel loop was treated by resection. Subsequently after discontinuance of contraceptive medication she was symptom free. The problems of diagnosis are pointed out and it is suggested that immediate discontinuance of oral contraceptives in women with unexplained abdominal pain might prevent gangrene of small bowel.

PIP: A 51-year-old woman who had used the oral contraceptive Lyndiol for 7 years developed severe abdominal pains that lasted for several weeks. There were no unequivocal clinical, laboratory test, or X-ray results to determine the cause of the pains. The patient was operated on for resection of a gangrenous loop of the small intestine, caused by a mesenteric venous thrombosis. It is possible that discontinuation of oral contraceptive use may have prevented the gangrene. Discontinuation of oral contraceptive use is recommended for women with unexplained abdominal pains.

[Chemotherapy of highly malignant thyroid tumors]. / Chemotherapie hochmaligner Schilddrüsentumore.

In a prospective phase II study 15 patients suffering from anaplastic thyroid carcinoma or thyroid sarcoma were treated by surgery and chemotherapy. Chemotherapy varied according to age of the patient and histological subtype of the tumour. The following regimen was used: 100 mg/m2 BSA CDDP, 20 mg/m2 mitoxantrone and 1.5 mg/m2 vincristine. 10 patients responded to chemotherapy, 4 of whom had a complete response. Responders showed a longer mean and median survival time (20.8 months versus 4.5 ms, 15.5 ms vs. 3.8 ms, respectively) than non-responders. In the group responding to chemotherapy no evidence of metachronous metastases was found. Local recurrence was absent only in the patients showing a complete response. Anaplastic carcinomas with areas of differentiated thyroid carcinoma and small cell carcinomas (after exclusion of malignant lymphoma of the thyroid) showed a higher response rate to chemotherapy than spindle or giant cell carcinoma or thyroid sarcoma.

[Corrective surgical procedures following partial gastrectomy for gastro-duodenal ulcer (authors transl)]. / Korrektureingriffe nach Magenresektion wegen peptischem Gastroduodenalulkus

Corrective surgical procedures for postgastrectomy syndromes are well-established in abdominal surgery. The indications for early corrective intervention are clearly defined on the basis of the patients' postoperative course. Corrections at a later date should only be considered in presence of major symptoms which did not respond to conservative therapy and following careful morphological and functional assessment of the patient. An analysis of gastric acid secretion should be carried out before and after the operation. The aim of corrective interventions is the restitution, as far as possible, of physiological conditions: prevention of rapid gastric emptying and reduction of gastric hypersecretion. Through postoperative follow-up examination of the patients over many years is essential. The case history, operation technique and outcome is presented in this review of 92 patients treated at the First Department of Surgery, University of Vienna and the findings are discussed.

[Papillary carcinoma of the thyroid gland (author's transl)]. / Das papilläre Schilddrüsenkarzinom.

Records were examined of 174 patients with papillary thyroid carcinoma operated on at the 1st Department of Surgery of the University Hospital in Vienna between 1948 and 1976. The overall mortality rates amount to 20 +/- 8% after 5 years, rising to 70 +/- 21% after 20 years. Clear relationships are demonstrated between lymph node metastases, distant metastases, extrathyroid tumours and higher mortality rates. An older age correlates in the extrathyroid tumour group only with a higher risk of death. In our material reclassified by the criteria of the WHO classification (1974) between 1965 and 1976 the incidence of papillary carcinoma is 25% of all thyroid carcinomas. The incidence of this tumour subgroup varies in the literature between 25 and 90% and is influenced by regional differences in the use of childhood radiation on the one hand and iodine uptake on the other hand, different methods of thyroid examination and the subjectivity of the pathologist.

[Paraneoplastic syndromes affecting the nervous system and the musculature associated with malignant tumours of the thyroid gland (author's transl)]. / Paraneoplasien des Nervensystems und der Muskulatur bei Struma maligna

Two cases are presented of the paraneoplastic syndrome in patients with a malignant tumour of the thyroid gland. The first case presented with a pseudomyasthenic syndrome (in conjunction with a haemangio endothelioma) and the second case with a form of neuromyopathy (in conjunction with a partly solid and partly hormone-producing thyroid carcinoma). The pathogenesis and classification of the so-called carcinomatous neuropathies is briefly outlined and the initially atypical course taken by the first case is discussed.