摘要:

Colorectal cancer is one of the most frequent cancers in the western world. Approximately half of the patients will die of their disease because of metastases. The most active cytotoxic agent used to date is 5-fluorouracil (5-FU). However, clinical responses are achieved only in a minority of patients. Based on the current knowledge of the mechanism of action of 5-FU, many attempts have been made to improve the clinical results. These include the use of biochemical modulators and different methods of administration, and these are the subject of this review. Specifically, of five different modulators, i.e. leucovorin, methotrexate, iriterferon -α, N-(phosphonacetyl)-L-aspartate and trimetrexate glucuronate, the biochemical background and the clinical results - obtained with these modulators are discussed. In order to get more insight, an overview of the 5-FU metabolism has been given. In addition, the different methods of systemic administration of 5-FU as well as possible mechanisms underlying 5-FU resistance are described

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

A multicenter, open-label, compassionate-use trial studied the antiemetlc efficacy and tolerability of granisetron In patients who had failed other antiemetic therapies In previous cycles of cytostatic chemotherapy. The antiemetics that had been used previously included metoclopramide, dexamethasone and ondansetron. A total of 517 patients, 456 of whom had failed other antiemetics, were treated in up to 15 successive cycles of chemotherapy. The numbers of patients treated In the first six of these cycles were large enough to allow the drawing of meaningful conclusions from the results. During that period, a complete response was achieved in 53-60% of patients. In addition, antiemetic efficacy was sustained throughout these six repeated treatment cycles. Granisetron was less effective against high-dose clsplatin chemotherapy than against other cytostatic regimens. The treatment was well tolerated— the main adverse events reported were headache and constipation; no serious adverse events were considered to be attributable to the drug. It is concluded that granisetron treatment was effective and well tolerated In patients who had previously failed other antiemetic therapies, including treatment with 5-hydroxytryptamine3antagonists

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

This double-blind,double-dummy,randomized study compared the 24h efficacy and safety of granisetron alone (3 mg i.v. over 30 s) or in combination with methylprednisolone (250 mg I.v. twice daily) in preventing nausea and vomiting in 308 patients (254 males) receiving high-dose cisplatin (100 mg/m2or above) for mainly lung, and head and neck cancers. All patients received oral follow-on therapy comprising oral granisetron and methylprednisolone during the following 6 days. Primary efficacy variables were the proportions of complete responses (CR; no vomiting, no worse than mild nausea, no rescue and no withdrawal), no vomiting and no nausea over the first 24 h following initiation of the cisplatin Infusion. The two treatment groups were well matched for demographics, cancer site, cisplatin dose and duration of Infusion. Granisetron plus methylprednisolone was significantly more effective than granisetron alone for all primary efficacy variables: CR 78 versus 59% (p<0.001), no vomiting 80 versus 61% (p< 0.001) and no nausea 74 versus 57% (p< 0.002). Significantly more patients receiving the combination were free of any emetic symptoms (74 versus 54%, p< 0.001). Significantly fewer patients receiving combination therapy also required rescue therapy with i.v. granisetron (12.2 versus 21.7%, p=0.026). During the followon period, complete response rates varied day by day from 50 to 71%. Both treatments were well tolerated, with constipation, abdominal pain and headache as the most frequent adverse events

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

From October 1995 to June 1997, 19 chemotherapy-naive patients with pathology-proven locally advanced or metastatic biliary tract carcinomas (BTC) were enrolled. The regimen consisted of 5-fluorouracil (5-FU) 2600 mg/m2and leucovorin (LV) 150 mg by weekly 24 h Infusion for 6 weeks and followed by a 2 week break. The treatment was terminated if disease progressed, the patient refused or unacceptable toxicity occurred. All patients required a Port-A catheter insertion and were treated at outpatient clinics by portable infusion pumps. There were 12 males and seven females with a median age of 62 years (range 45-77). The primary tumor sites were nine intrahepatic cholanglocarclnomas (CC), three perihilar CC, one distal BTC and six gallbladder cancers. A total of 179 chemotherapy sessions were given with a mean of 9.5 (range 2-18). Eighteen patients were evaluable for response. The response rates were: 33% (six of 18) partial response (PR), 39% (seven of 18) stable disease (SD) and 28% (five of 18) progressive disease (PD). All of the patients were evaluable for toxicity. The most common toxicities were mild fatigue (nine of 19,47%), loss of appetite (nine of 19,47%), skin hyperpigmentation (five of 19, 26%) and diarrhea (two of 19, 11%). Only one patient had grade IV myelotoxicity with sepsis but without treatmentrelated death. The median time to progression was 4 months. The overall median survival time was 7.0 months. The median survival time of the PR was not reached, SD was 8.0 months and PD 3.5 months. In conclusion, weekly highdose 5-FU with LV by 24 h infusion in an outpatient setting for patients with BTC is effective, only mildly toxic and deserves further study

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

This study was aimed at evaluating the tolerance to an intermittently administered oral UFT for hepatocellular carcinoma (HCC) with chronic liver disease (CLD). Ten patients who had received curative therapy for HCC with CLD (Child's classification A or B) were randomly assigned either an intermittent schedule (IS), oral administration of UFT (130 mg/m2/b.l.d.) with 2 days rest a week, or a continuous schedule (CS), consecutive administration of UFT with the same dose. On day 12, the serum concentration of 5-fluorouracil (5-FU) was measured. After 2 weeks rest, the patients were switched to the other schedule for 10 weeks and the concentration of 5-FU was measured on day 12. The median values of the area under the curve (AUC) and maximum concentration (Cmax) of 5-FU in IS and CS were 187.7 and 263.2 ng/ml/h, 57.1 and 93.0 ng/ml, respectively. Both the AUC and Cmaxfor IS were significantly lower than those for CS. One IS patient had tolerable diarrhea, while three of the CS patients had intolerable nausea and one had hemorrhagic gastritis. IS seemed to be a suitable measure for CLD

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

CI-980 is a synthetic mitotic inhibitor that binds to tubulin at the colchicine site, inhibiting the polymerization of microtubules and arresting cellular division in metaphase. Myelosuppression and neurotoxicity were dose-limiting in phase I studies. Sixteen patients with stage III and IV platinumrefractory ovarian cancer received 4.5 mg/m2/day of CI-980 as a continuous i.v. infusion for 72 h, repeated every 3 weeks. Eleven patients had progression and four patients had stable disease. One patient (6%; 95% Cl 0-25%) achieved a partial response after 9 months of treatment which lasted for 27 months. The overall median survival was 7 months. Grade 4 granulocytopenia occurred In five patients, with two episodes of neutropenic fever. Neurological toxicity was mild with 12 episodes of transient subclinical recent memory loss documented In four patients by specialized neuropsychological evaluations. One patient each had hallucinations and mild truncal ataxia, and four patients had mild, reversible neurosensory toxicity. One episode of severe hypoxemia and dyspnea occurred In a patient with chronic obstructive pulmonary disease. CI-980 has minimal activity and is tolerable In a population of heavily pretreated patients with platinum refractory ovarian cancer

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Precllnlcal schedule dependency suggests that prolonged maintenance of low plasma levels of topotecan, a specific Inhibitor of the nuclear enzyme topoisomerase I, results in optimal antitumor activity. The pharmacokinetics and pharmacodynamics of topotecan, administered as single agent in second-line therapy as a continuous low-dose infusion for 21 days, were evaluated in nine patients with small cell lung cancer (SCLC). Topotecan was administered i.v. as a 21 day continuous infusion every 28 days via an ambulatory pump. Dosages ranged from 0.4 to 0.6 mg/m2/ day. Plasma levels of topotecan, the sum of topotecan, and Its hydroxy acid congener and the N-desmethyl metabolite were determined at 1, 7, 14 and 21 days during infusion, using a validated high-performance liquid chromatography method with fluorescence detection. Myelosuppression was the most important toxicity. All patients experienced anemia, being severe (grade 3/4) In 55% of all courses. Other adverse effects were relatively mild and reversible, and included nausea, vomiting, diarrhea and fatigue. Three patients achieved a partial response. Mean steady-state concentrations of topotecan (Cn) in the first course were 0.46 ±0.17 and 0.47 ±0.19 ng/ml after doses of 0.4 and 0.5 mg/m2/day, respectively. Steady-state levels of the total of topotecan and hydroxy acid (Cu,t«) were 1.28 ±0.25 (range 0.93-1.58) and 1.570.19 (range 1.43-1.70) ng/ml at doses of 0.4 and 0.5 mg/m2/day, respectively. The percentage of the administered topotecan dose excreted in the urine within 24 h was 40 ±14 and 1.2 ±1.0% for total topotecan and N-desmethyltopotecan, respectively. During the second course, CM,tot was significantly higher (p=0.032, paired Mest), which suggests altered topotecan disposition. A sigmoidal relationship was found between CMitM and the percent decrease in platelets (fe0.76, p=0.018). We conclude that topotecan administered as a 21 day continuous low-dose infusion has activity as single-agent, second-line therapy in patients with SCLC. There was considerable Interpatient and Intrapatient variability in systemic exposure to topotecan. Differences in organ function might contribute to this variation. Serum aspartate aminotransferase and albumin levels were predictive of topotecan pharmacokinetics

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The new non-steroidal aromatase inhibitor vorozole (R83842) was administered orally at a single dally dose of 2.5 mg to 27 postmenopausal women with advanced breast cancer in a phase II trial as second-line endocrine treatment. The observed objective response rate of 30% and good tolerability of the drug confirm other recent reports. Endocrine determinations during 6 months of treatment demonstrated reduction of serum estrogens: estrone sulfate by more than 60%, estrone by 30-40%, but estradlol by only 10-20%. The ratios of serum androstenedlone/estrone and testosterone/ estradiol increased significantly, consistent with the inhibition of peripheral aromatase activity. Levels of progesterone, 17-03B1hydroxyprogesterone, cortisol, dehydroepiandrosterone sulfate, androstenedione and aldosterone remained normal, Indicating no interference with adrenocortical steroid synthesis. A general lack of correlation between the observed serum concentrations of vorozole and Its effect on hormone serum levels or clinical response was found. This suggests that the determination of such serum levels gives a poor impression of the unambiguous anti-tumor activity of vorozole which may well have Its main effect with the tumor tissue Itself. The present results are In support of aromatase inhibition, but the possibility of an additional effect on the sulfation of estrogens merits further Investigation

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We evaluated the therapeutic activity and safety of continuously infused mitomycin C in patients with metastatic colorectal cancer who had recurred (less than 3 months) or progressed following first- or second-line 5-fluorouracllbased chemotherapy. Treatment consisted of mitomycin C 20 mg/m2i.v. given over 120 h (5 days) followed by a 3 week rest period. Fifty-two consecutively enrolled patients were assessable for toxicity and 49 for response evaluation (three patients evaluable but not measurable), completing at least one full course of chemotherapy. Previous chemotherapy regimens consisted of bolus 5-fluorouracil/follnlc acid (5-FU0B1 FA) (Machover) n=26 (50%) or continuous (24 h) 5-FU± FAlnterferon n=26 (50%). Forty-two percent of patients had received one previous chemotherapy regimen and 58% more than one. One partial remission (2%) lasting 7 months and 11 disease stabilizations (23%) with a median duration of 3.2 months (range 1-8) were achieved in 49 patients. Median survival time since start of mitomycin C was 4.7 months (1.2- 28.1) resulting in a 6 month survival rate of 36%. The progression-free Interval was 10 weeks (range 4-36). Delayed and cumulative thrombo- and leukocytopenla (WHO grade III/IV) were observed In 19 and 6%, and anemia in 2% of patients. WHO grade III/IV mucosttis, diarrhea and fever/Infection occurred each In 6% of patients. Treatment delays and dose reductions were necessary in 11 (21%) and 21 (40%) patients, respectively. In three cases treatment was stopped due to cumulative thrombocytopenia (6%). Continuous infusion of single-agent mitomycin C displays modest activity in heavily preheated 5-FU refractory colorectal cancer patients combined with a low toxicity level

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In rare cases mitomycin C (MMC) may induce cancer-associated hemolytic uremic syndrome, which is characterized by hemolytic anemia, thrombocytopenia and progressive renal failure. Treatment possibilities of this multisystem disease up to now remain disappointing. We report a case of MMC-related hemolytic uremic syndrome, and discuss the etiologic parameters, clinical aspects, prognosis and treatment modalities of this severe syndrome

ISSN:0959-4973    

出版商:OVID    

年代:1998

数据来源: OVID