[Extrapulmonary small-cell carcinoma--a rarity?].
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Carcinoma, Small Cell↗
Biomedical subjects
W Scheithauer
Publications and source records attributed to W Scheithauer.
Vasoactive intestinal peptide-receptor imaging for the localization of intestinal adenocarcinomas and endocrine tumors.
BACKGROUND: Intestinal adenocarcinomas and various endocrine tumors express large numbers of high-affinity receptors for vasoactive intestinal peptide (VIP). We have evaluated the usefulness of scanning with VIP labeled with iodine-123 for tumor localization in patients with gastrointestinal tumors. METHODS: Radioiodinated VIP was purified by high-pressure liquid chromatography and administered as a single intravenous bolus injection (300 pmol [1 microgram]). Scanning with radiolabeled VIP was compared with computed tomography and scanning with somatostatin analogues in 79 patients with colorectal cancer, pancreatic carcinoma, gastric cancer, carcinoid tumor, or insulinoma. RESULTS: Visualization of gastrointestinal tumors and metastases was obtained with radiolabeled VIP. Binding of the labeled peptide by primary tumors and metastases was visible shortly after the injection and was still demonstrable at 24 hours. In patients with colorectal adenocarcinomas, primary or recurrent tumors were visualized in 10 of 10, liver metastases in 15 of 18, lung metastases in 2 of 3, and lymph-node metastases in 4 of 4. Primary pancreatic adenocarcinomas were visualized by imaging in 10 of 12 patients, and liver metastases were seen in 7 of 7. Primary or recurrent gastric adenocarcinomas were visualized in 5 of 5 patients, and liver metastases were seen in 2 of 2 patients. VIP scans were positive in 9 of 10 patients with carcinoid tumors and in 4 of 4 patients with insulinomas. Some tumors with positive VIP scans were also visualized with somatostatin analogues (4 of 17 colorectal adenocarcinomas, 8 of 9 carcinoids, and 2 of 2 insulinomas). In vitro binding studies confirmed the presence of VIP receptors on gastrointestinal tumors. CONCLUSIONS: Scanning with radiolabeled VIP can visualize intestinal tumors and metastases that express receptors for VIP.
Adenocarcinoma↗
Ondansetron for pruritus due to cholestasis.
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Cholestasis↗
Randomized comparison of fluorouracil and leucovorin therapy versus fluorouracil, leucovorin, and cisplatin therapy in patients with advanced colorectal cancer.
BACKGROUND: Because of experimental and preliminary clinical evidence that additional modulation of the biochemical pharmacology and cytotoxicity of 5-fluorouracil (5-FU) and leucovorin (LV) may be possible by combination of these agents with cisplatin (CDDP), the authors undertook a prospective randomized trial in patients with colorectal cancer. METHODS: Between 1989 and 1992, 138 patients with advanced measurable colorectal cancer previously unexposed to chemotherapy were randomly assigned to treatment with either 5-FU (425 mg/m2) and LV (20 mg/m2) for 5 days, or the combination of 5-FU and LV in the same daily dose plus cisplatin (20 mg/m2), each drug given for 4 consecutive days. In both treatment arms, courses were administered every 28 days, if toxicity allowed, for a total of 6 months or until evidence of tumor progression. RESULTS: The overall responses (complete and partial response) were 19% and 28% for the 5-FU/LV and the 5-FU/LV/CDDP treatment arms, respectively. Although the three-drug combination appeared superior to 5-FU/LV for time to progression or death (8.5 versus 5.2 months; P = 0.042), there was no evidence that the adoption of cisplatin will translate into a definite survival advantage. A comparative analysis of the toxicities experienced by the patients in the two treatment groups showed a comparable rate, although severe side effects (P < 0.05), specifically stomatitis (P = 0.013), were noticed more frequently in patients treated with 5-FU/LV for 5 days. CONCLUSIONS: These results suggest that the therapeutic index of 5-FU/LV in metastatic colorectal cancer may be improved with the addition of cisplatin. However, the somewhat better therapeutic activity and lower incidence of severe gastrointestinal side effects have to be weighed against additional pharmaceutical charges and the need for a more intense antiemetic regimen.
Adult↗
Cross-competition between vasoactive intestinal peptide and somatostatin for binding to tumor cell membrane receptors.
Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of 123I-labeled VIP and 123I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of 123I-labeled VIP binding to intact A431 cells was VIP [concentration causing half-maximal inhibition (IC50) = 2.9 +/- 1.9 (SD) nM] > OCT (IC50 = 9.3 +/- 1.7 nM) = SST > substance P = secretin (IC50 = 1 microM). Binding of 123I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by OCT = Tyr-3-OCT (IC50 = 1.5 +/- 0.3 nM) = SST > VIP (IC50 = 4.9 +/- 1.1 nM). This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [3H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC50 values < 10 nM. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.
Adenosine Triphosphate↗
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.
Adenine↗
Postchemotherapy rheumatism following adjuvant therapy for ovarian cancer.
The occurrence of a recently discovered musculosceletal pain syndrome, termed postchemotherapy rheumatism, is described in a 52-year-old female who had received adjuvant therapy for ovarian cancer. Although the etiology as well as the pathophysiologic mechanisms of this syndrome remain uncertain, our data support the hypothesis that the alkylating agent cyclophosphamide rather than other chemotherapeutic drugs, corticosteroid withdrawal, or chemically-induced menopause may represent a causal factor.
Antineoplastic Combined Chemotherapy Protocols↗
[Possibilities and limits of cytostatic chemotherapy in pancreatic carcinoma].
The investigation of chemotherapy for pancreatic cancer has been hampered by the fact that most patients present with severe general illness and thus tolerate this form of treatment poorly. Furthermore, because of the relative inaccessibility of the pancreas it has been difficult to monitor objective response rates. In patients with disseminated disease only few drugs have shown antitumour activity and the response rates generally do not exceed 20%. Several combination regimens have been tested. Of those assessed in randomized trials, the median survival has ranged from 2 to 6.5 months, which is not significantly better than with supportive therapy alone. Endocrine treatment measures and certain experimental treatment approaches such as reversal of multidrug resistance, photodynamic therapy and radioimmunotherapy may represent promising fields for future research. Encouraging preliminary results, however, warrant confirmation in controlled clinical trials. In patients with unresectable though localized pancreatic tumours the use of conventional external-beam radiation therapy plus 5-fluorouracil can significantly increase survival. Combined radiochemotherapy also seems to play an important role in the postoperative adjuvant treatment of potentially curative tumours, increasing the long-term results of surgical management.
Antineoplastic Agents↗
[Helicobacter pylori, a risk factor for stomach cancer and primary stomach lymphoma?].
Helicobacter pylori has been implicated as a possible etiologic factor in gastric cancer. Recent epidemiologic studies, in fact, have demonstrated that there is a significantly higher prevalence of H. pylori in patients with gastric cancer than in matched controls. In addition to these and other epidemiologic findings, there is evidence that several of the pathogenic consequences of H. pylori infection may be relevant to carcinogenesis. In accordance with the theory that the etiology of gastric cancer is likely to be multifactorial, it is believed that the overall risk is determined by dietary, genetic and other cofactors. A causal relationship between H. pylori and gastric cancer, however, remains to be proven by randomized intervention trials of the long-term effects of H. pylori eradication. Until conclusive results become available from these studies, bacterial eradication cannot be recommended as prophylactic measure to reducing the risk of gastric cancer. In patients with low-grade B-cell gastric lymphomas of the mucosa-associated lymphoid tissue type (MALT) a causal pathogenic association with H. pylori-associated gastritis was demonstrable not only in cell culture but also in preliminary clinical trials. Several investigators have reported that eradication of H. pylori results in complete regression of early stage gastric MALT lymphomas. Answers to the questions whether healing is permanent, whether lymphomas at a more advanced stage will respond as well, and how regression comes about will have to be established in future studies.
Cell Transformation, Neoplastic↗
Clinical trials of agents that reverse multidrug resistance. A literature review.
BACKGROUND: The discovery of the P-170 glycoprotein as a mediator of multidrug resistance (MDR) represents one of the most important research accomplishments in antineoplastic pharmacology during the last decade. Demonstration of P-170 in epithelial tissues, untreated and chemotherapeutically pretreated human malignancies, and identification of various agents capable of reversing resistance in vitro generated enthusiasm for clinical studies throughout the world. The authors provide an overview of the current status of clinical investigations of MDR1 reversing agents in hematologic and solid malignancies. METHODS: The authors performed an extensive literature search and selected more than 70 articles concerning the potential clinical relevance of P-glycoprotein/MDR1 modulating agents. Information abstracted included type of reverting agent and chemotherapeutic regimen, number of patients, tumor type, histologic proof of P-glycoprotein expression, and objective response rates. RESULTS: Proof of the involvement of MDR1 in clinical drug resistance has been slow to accumulate, primarily because of difficulties in adapting assays of MDR1 expression and in planning appropriate trials. Pilot studies have shown that verapamil, cyclosporine, and other chemosensitizers may reverse resistance in a subset of patients, but significant (cardiovascular) side effects are common. For leukemias, lymphomas, and multiple myeloma, response rates of 60-80% may be achieved with the potential for cure, whereas in solid tumors, only a few patients appear to benefit. CONCLUSIONS: Because of predominantly negative results and unanswered fundamental questions regarding the biology of P-glycoprotein, additional clinical trials with less toxic modulators or their combination are appropriate to delineate optimal strategies for MDR1 reversal and to define the spectrum of responsive tumors. Additional attention also must be given to the coexistence of other resistance mechanisms that may offer separate opportunities for modulation.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
[Advances in the prevention and therapy of common chemotherapy-induced side effects].
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Antiemetics↗
A phase I-II study of epirubicin, 5-fluorouracil, and leucovorin in advanced adenocarcinoma of the stomach.
BACKGROUND: To determine the maximum tolerated dose of epirubicin for use in combination with 5-fluorouracil (5-FU) and low-dose leucovorin (LV), a Phase I-II trial was conducted in 37 patients with advanced gastric carcinoma. METHODS: The doses of 5-FU (425 mg/m2) and LV (20 mg/m2), both given intravenously on days 1-5, were held constant while the dose of epirubicin was escalated in cohorts of patients (beginning dose, 50 mg/m2 on day 1). Cycles were repeated every 4 weeks. RESULTS: Significant gastrointestinal symptoms and myelosuppression were observed infrequently at the initial dose level. At a dose of 60 mg/m2 of epirubicin on day 1, however, five of eight patients had significant mucosal toxic effects during the first cycle of therapy. In addition, two patients treated at this dose level had Grade 4 granulocytopenia with insufficient recovery to permit a second course by day 28, and one patient each had severe diarrhea and nausea and vomiting. Among 37 patients with assessable disease, there were 3 complete and 11 partial responses (response rate, 38%). CONCLUSIONS: LV modulation of 5-FU can be incorporated safely into combination chemotherapy with epirubicin and provides a relatively active regimen for treatment of disseminated gastric cancer.
Adenocarcinoma↗
Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer.
OBJECTIVES: To compare the length of survival and quality of life in patients given combination chemotherapy in addition to supportive care and in patients given only supportive care. DESIGN: Randomised study. SETTING: Gastrointestinal oncology departments. PATIENTS: 40 previously untreated patients with histologically confirmed, measurable colorectal cancer that was locally recurrent or metastatic. INTERVENTIONS: Patients were allocated randomly to receive chemotherapy or only supportive care in a ratio of 2:1 according to performance status, metastatic disease of the liver, and weight loss in the six months before entering the study. Chemotherapy consisted of four week cycles of intravenous leucovorin (200 mg/m2/day) followed by 5-fluorouracil (550 mg/m2/day) and cisplatin (20 mg/m2/day), each drug being given on the first four days of the cycle. MAIN OUTCOME MEASURES: Length of survival and quality of life score with an optimised functional living index-cancer scale. RESULTS: Overall survival was significantly longer for patients given chemotherapy (11.0 months) than for those receiving supportive care alone (5.0 months; p = 0.006). Despite common association of chemotherapy with mild to moderate gastrointestinal symptoms, there was no significant difference between the two groups in global or subgroup quality of life scores. In patients with abnormal scores before treatment, quality of life seemed better in the chemotherapy arm. CONCLUSIONS: In this sample of patients with disseminated colorectal cancer the chemotherapy regimen was an effective form of palliative treatment.
Adenocarcinoma↗
Effective second line chemotherapy of advanced breast cancer with navelbine and mitomycin C.
The efficacy and toxicity of navelbine 30 mg/m2 administered intravenously (IV) over 30 minutes every 3 weeks, and mitomycin C 15 mg/m2 administered IV every 6 weeks was assessed in 34 patients with metastatic breast cancer refractory to first-line chemotherapy. An overall objective response rate of 35% was achieved (95% confidence interval, 20% to 53%), with an additional 47% of patients maintaining stable disease (SD). Four of 12 patients who responded had received previous anthracycline therapy. Median time to progression for responders and patients with SD was 6.3 months. The median survival of all patients was 8.8 months. Tolerance of this regimen was remarkable. WHO grade 3/4 side effects consisted of granulocytopenia in 12% and thrombocytopenia in 15%, and included only 1 patient each with grade 3 neurotoxicity and local toxicity due to extravasation. Delay of treatment was required for hematologic toxicity in 7 patients, and 5 required dose reductions. In conclusion, navelbine/mitomycin C is an active and well-tolerated regimen that may be considered for second-line treatment. If our results are confirmed by larger analyses of other patients studies, this combination might also warrant further exploration in combination with other active agents for front line chemotherapy of advanced breast cancer.
Adult↗
Phase II study of D-verapamil and doxorubicin in patients with metastatic colorectal cancer.
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Aged↗
Pharmacokinetic interaction between epirubicin and the multidrug resistance reverting agent D-verapamil.
The potential for a pharmacokinetic interaction between epirubicin and the second-generation multidrug resistance modulating agent D-verapamil (DVPM) has been investigated in six patients with advanced colorectal cancer. Our results indicate that a significant interaction takes place. Enhanced distribution of epirubicin from the serum and altered disposition might, in fact, explain the increased level of myelotoxicity in this pilot as well as in other clinical phase II studies involving DVPM.
Colonic Neoplasms↗
Scintigraphic evaluation of functional hepatic mass in patients with advanced breast cancer.
Recent studies suggest a high specificity of 99mTc-galactosyl neoglycoalbumin (99mTc-NGA) receptor scanning in vivo by providing both morphological and functional diagnosis of liver disease. In 22 patients with advanced breast cancer 99mTc-NGA (150 MBq; 50 nmol) was exclusively trapped by the liver, the images showing 'cold spots' in areas of liver metastases formation. A two-tailed analysis was performed: the time activity curves recorded for the liver and precordial area were subjected to a kinetic receptor-calculating model allowing an estimation of the NGA-receptor concentration of the liver (i.e. hepatic binding protein, HBP) as well as calculation of the residual functional liver volume (RFLV) via the S.P.E.C.T.-study. In breast cancer patients with liver metastases a significantly (P < 0.01) lower HBP-concentration was estimated (0.65 +/- 0.16 vs 0.82 +/- 0.17 mumol l-1) as evidenced by a lower 99mTc-NGA-accumulation in the liver resulting also in a significantly (P < 0.001) lower RFLV (739 +/- 348 vs 1336 +/- 184 ml). In four amonafide-treated patients (800 mg m-2 intravenous infusion over 3 h) approximately one week after one chemotherapy cycle a significant (P < 0.05) increase in HBP-concentration (0.56 +/- 0.10 vs 0.72 +/- 0.06 mumol l-1) of the liver was found corresponding with an increase in RVLF (546 +/- 297 vs 670 +/- 265 ml). These regulatory mechanisms at the HBP level measured in vivo provide further evidence that 99mTc-NGA should have promise as a clinically useful receptor radiopharmaceutical for both quantification of liver function and assessment of liver morphology.
Aged↗
MDR1 gene expression in primary colorectal carcinomas.
The expression of the MDR1 gene, a multidrug resistance gene, was prospectively determined in 113 primary colorectal carcinoma specimens and correlated with clinical data including survival durations of the patients. MDR1 RNA was detected in 65% of the carcinomas. No expression of the MDR2 gene was seen, MDR1 gene expression was independent of age and sex of the patients, size and histologic grading of the tumour, lymph node involvement and distant metastasis. Kaplan-Meier analysis revealed that the durations of both relapse-free survival and overall survival were not different between patients with MDR1 RNA positive tumours and those with MDR1 RNA negative tumours.
Adenocarcinoma↗