The dead end of 5-fluorouracil double modulation and promise of continuous infusion schedules in the treatment of metastatic colorectal cancer.
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Adenocarcinoma↗
Biomedical subjects
H Wilke
Publications and source records attributed to H Wilke.
Weekly infusional 5-fluorouracil plus/minus other drugs for the treatment of advanced gastric cancer.
Based on preclinical data and the promising results being achieved with infusional 5-FU in colorectal and breast cancer, we investigated a weekly schedule of a 24-hour infusion of 5-FU plus folinic acid (HD-FU/FA) in patients failing to first-line chemotherapy and HD-FU/FA plus cisplatin (C) or plus cisplatin/epidoxorubicin (C/E) in chemo-naive patients with advanced gastric cancer. In all three trials the results achieved with the tested chemotherapy regimens indicated high activity and good tolerability. All three protocols were administered as outpatient treatment. With HD-FU/FA and overall response rate of 24% and a median survival time of 5 months was observed in 17 patients refractory to or relapsing after first-line chemotherapy. HD-FU/FA/C induced an overall response rate of 66% and a median survival time of 13 months. Of note was the high activity of this regimen in patients with malignant ascites. HD-FU/FA/C/E also proved to be an interesting regimen similar active as HD-FU/FA/C but it was subjectively less well tolerated. In patients with locally advanced disease the response rate was 90% (10/11), and in patients with distant metastases 50% (8/16).
Adult↗
Weekly high-dose infusional 5-fluorouracil (HD-5-FU) combinations in the treatment of advanced breast cancer: results of phase I/II studies with weekly 24-hour infusion of HD-5-FU plus high-dose folinic acid (FA) alone and in combination with paclitaxel and cisplatin.
UNLABELLED: Our Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (HD5-FU/FA) in intensively pretreated metastatic breast cancer prompted addition of paclitaxel to this regimen in a phase I/II study in outpatients. TREATMENT: Patients were treated with HD5-FU (24-hour infusion)/FA (2h infusion prior to FU) weekly for 6 weeks (d1, 8, 15, 22, 29, 36) and Paclitaxel (3-hour infusion) was administered additionally on day 1 and day 22, q day 50. During Phase I we chose the following dose levels (dl): Fixed doses of FA d11-4 500 mg/m2 followed by HDFU, 24-hour infusion d11: 1.5, d12: 1.8, d13 and d14: 2.0 g/m2. .3-hour infusion of Paclitaxel on day 1 and day 22 d11 to d13: 135. d14: 175 mg/m2. D14 was chosen to be further evaluated during phase II. Results of an interim analysis were presented. PATIENT CHARACTERISTICS: 46 patients entered this trial during phase II and had the following characteristics: age 46 years (26 to 70) WHO performance status 0/1, metastatic disease sites 2.5(1 to 4). All patients had bidimensionally measurable disease. PRETREATMENT: 9 patients had received adjuvant chemotherapy, 16 patients prior chemotherapy for metastasis, and 21 both adjuvantly and for metastasis. Of 29 anthracycline-pretreated patients, 25 had anthracycline-resistant disease. RESULTS: We observed the following results in 35 evaluable patients: CR 3% (1/35), PR 51% (18/35), SD 40% (14/35). PD 6% (2/35). RR (Response rate) was 54%, 95% confidence interval 36 to 76%. The response concerning 20 patients with anthracycline resistant disease was: RR 55% (11/20). Median number of treatment cycles per patient was 3 (1 to 5), time to maximum response 2 months (1 to 5), remission duration 8+ months (2 to 17). Median survival time is not yet reached. CONCLUSIONS: The combination of paclitaxel with weekly HDFU/FA is well tolerated in the second-line treatment of metastatic breast cancer and indicates high efficacy also in anthracycline-resistant disease. In an ongoing phase II study, we examine the addition of cisplatin to the regimen in the first-line treatment of metastatic breast cancer. Those trials confirm that infusional weekly HD-5-FU plus folinic acid is of considerable interest in the treatment of advanced breast cancer. Randomized studies are warranted.
Adult↗
Schedule-dependent antagonism of paclitaxel and cisplatin in human gastric and ovarian carcinoma cell lines in vitro.
Paclitaxel has demonstrated broad clinical activity in a variety of malignancies both alone and in combination with other chemotherapeutic agents. The in vitro cytotoxicity of paclitaxel and cisplatin alone, in combination and in sequence, were evaluated against established human gastric and ovarian carcinoma cell lines using 2-h drug exposure. The combination of cisplatin and paclitaxel was found to be additive or even synergistic when paclitaxel was given 24 h prior to cisplatin as demonstrated by isobologram analysis. However, when both drugs were given simultaneously or when cisplatin was given prior to paclitaxel, a strong antagonistic interaction was observed. This antagonism was evident for up to 72 h after a 2-h exposure to cisplatin. Pretreatment with cisplatin caused no alteration in [3H]paclitaxel uptake in HM2 gastric carcinoma cells, but resulted in decreased intracellular retention of paclitaxel. Since cisplatin treatment led to a reduction in cellular glutathione content in these cells and reduced levels of glutathione have been associated with protection against cytotoxicity of paclitaxel, cells were pretreated with L-buthionine sulfoximine (L-BSO). However, depletion of glutathione had no influence on the activity of paclitaxel. A significant accumulation of cells in S-phase was observed 24 h after cisplatin, which resolved after 48 h and resulted in a pronounced increase of G2M phase. These data demonstrate that the interactions of paclitaxel and cisplatin are highly schedule-dependent and applications of cisplatin simultaneously with or prior to paclitaxel may result in pronounced antagonism. These findings could have implications for the design of further clinical protocols.
Cell Cycle↗
Interferon-alpha does not improve the antineoplastic efficacy of high-dose infusional 5-fluorouracil plus folinic acid in advanced colorectal cancer. First results of a randomized multicenter study by the Association of Medical Oncology of the German Cancer Society (AIO).
BACKGROUND: High-dose 5-FU given weekly as a 24-h infusion in combination with folinic acid (FA) has been associated with low toxicity and a high response rate. Interferon-alpha (IFN) either alone or in combination with FA has also improved treatment results by modulating 5-FU activity. We therefore initiated a randomized multicenter trial comparing the ability of FA or IFN to modulate infusional 5-FU. The statistical design using a sequential analysis allows us to report on the comparison of 5-FU/FA vs. 5-FU/FA/IFN while randomization of patients into 5-FU/FA vs. 5 FU/IFN continues. METHODS: Chemotherapy-naive patients with advanced progressive colorectal cancer and measurable metastatic lesions were randomized to receive 5-FU 2600 mg/m2 i.v. as a 24-h infusion, combined with either FA 500 mg/m2 as a 2-h infusion (A), or IFN 3 x 10(6) U s.c. 3 x/week (B), or the combination of FA plus IFN as in arms A and B (C). Treatment arms were repeated weekly for 6 weeks followed by a 2-week rest period. These 8-week cycles were administered until tumor progression. Because of the occurrence of 2 toxic deaths among the first 17 patients treated in arm C, 5-FU was reduced to 2000 mg/m2 for all patients in arm C. Sequential analysis according to Whitehead for objective response was planned with alpha = 0.05/3 and a power of 80% (beta = 0.2) to detect a difference of > or = 25% (delta = 0.25) or equivalence of response rates. For pairwise comparison of treatment arms a minimum of 30 patients per arm and a maximum of 90 patients per arm were expected in case of equivalence or difference. RESULTS: An interim analysis was performed after the first 93 of 149 randomized patients were evaluable for response and toxicity (A 31 pts, B 33 pts, C 29 pts). Despite the 5-FU dose reduction in arm C, 28% of patients experienced grade 3/4 toxicity (CTC) including diarrhea, mucositis and handfoot syndrome compared to 16% in arm A and 12% in arm B (not significant). No treatment related toxic death occurred in arms A or B, but 3 patients (10%) in arm C died of diarrhea and septicemia. Among patients treated with 5-FU/FA objective tumor response occurred in 12/31 patients (39%) (21%-56%, 95% confidence interval) (3 CR, 9 PR), no change in 13/31 (42%) and PD in 6/31 (19%) patients. Eleven of 29 patients (38%) (20%-56%, 95% confidence interval) receiving 5-FU/FA/IFN achieved complete (3 patients) or partial (8 patients) remissions, 10/29 patients (34%) had stable disease and 8/29 patients (28%) tumor progression. According to the sequential analysis the rates of objective responses observed in patients treated with 5-FU/FA or 5-FU/FA/IFN were equivalent. CONCLUSION: This interim analysis allows the conclusion that infusional 5-FU plus FA/IFN is no more active than infusional 5-FU plus FA alone. However, 5-FU/FA/IFN despite 5-FU dose reduction was associated with unacceptably high toxicity, including 10% deaths. Therefore, further investigation of this regimen is not justified. The study is continued with the comparison of 5-FU/FA vs. 5-FU/IFN.
Adult↗
Activity of N-benzyl-adriamycin-14-valerate (AD198), a new anthracycline derivate, in multidrug resistant human ovarian and breast carcinoma cell lines.
The new lipophilic anthracycline N-benzyl-adriamycin-14-valerate (AD198) was evaluated for its activity in comparison to doxorubicin in P-glycoprotein (Pgp)-positive and -negative cell lines. AD198 and doxorubicin showed comparable antitumor activity in the Pgp-negative breast cancer cell line MCF-7 and the Pgp-negative ovarian carcinoma cell line A2780. By contrast, AD198 was significantly more active than doxorubicin in the Pgp-positive breast cancer cell line MCF7AD (IC50 values 2.5 and 0.15 microM for 96 h continuous exposure) and the Pgp-positive ovarian carcinoma cell line A2780 DX5 (IC50 values 0.6 and 0.07 microM, respectively). Unlike doxorubicin, the activity of AD198 was not increased by concommittant application of cyclosporin A in cell line MCF7AD. Flow cytometry studies showed that, in contrast to doxorubicin, AD198 was not transported by Pgp and that verapamil did not change the intracellular pharmacokinetics of this new anthracycline. These data provide evidence that AD198 possesses high activity in human solid tumor cell lines expressing the classical multidrug resistant phenotype. Its further clinical development appears to be warranted.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Routine application of the polymerase chain reaction for detection of Mycobacterium tuberculosis in clinical samples.
AIM: To investigate the use of the polymerase chain reaction (PCR) in the routine laboratory for the detection of Mycobacterium tuberculosis in clinical samples. METHODS: Samples were divided and processed separately for the detection of M tuberculosis by microscopy, culture and PCR. After DNA extraction, PCR was performed with primers specific for the insertion element IS6110 and the product was analysed by agarose gel electrophoresis, Southern blotting or dot blotting and hybridisation with a digoxigenin labelled internal probe. Each sample was tested for inhibitors of Taq polymerase with the aid of an internal control. Multiple negative and positive controls were used to monitor each step of the procedure. RESULTS: The data from two laboratories, using the same operating procedures, were combined. Of 1957 specimens, 79 (4%) were culture and PCR positive, while 1839 (93.9%) were negative in both tests. Thirty specimens (1.5%) were PCR positive only and nine (0.5%) were culture positive but PCR negative. CONCLUSION: Using culture and clinical history as the gold standard, sensitivity and specificity for PCR were 92.1% and 99.8%, respectively. With elaborate precautions, PCR is a suitable and reliable method for the detection of M tuberculosis in clinical samples in a routine microbiology laboratory.
Bacteriological Techniques↗
Failure of orally administered dipyridamole to enhance the antineoplastic activity of fluorouracil in combination with leucovorin in patients with advanced colorectal cancer: a prospective randomized trial.
PURPOSE: A randomized trial was performed to investigate the ability of the nucleoside transport inhibitor dipyridamole (DP) to enhance the antitumor activity of fluorouracil (5-FU)/leucovorin (folinic acid [FA]). PATIENTS AND METHODS: One hundred eighty-one untreated patients with advanced colorectal cancer were randomized to receive 5-FU 600 mg/m2 plus FA 300 mg/m2 on days 2 to 4 with or without DP 75 mg orally three times daily on days 1 to 5. Cycles were repeated every 3 weeks. Only patients with documented tumor progression before therapy were eligible. 5-FU pharmacokinetics using high-performance liquid chromatography (HPLC) were assessed in 11 nonrandomized patients receiving paired cycles with or without DP. RESULTS: One hundred seventy-four patients were assessable for toxicity and response. There was no significant difference in toxicity, except DP-related headache in 24% of patients. An objective response rate of 15% (one complete response [CR] and 13 partial responses [PRs]) for 5-FU/FA and 13% (two CRs and nine PRs) for 5-FU/FA/DP was observed. The dose-intensity of 5-FU delivered was significantly higher (1.09- to 1.16-fold) for the DP-containing arm. Pharmacokinetic parameters of 5-FU did not differ significantly, except for a prolonged half-life (t1/2) induced by DP. The median time to progression (P = .8) and the median survival time (11.6 months for 5-FU/FA v 9.3 months for 5-FU/FA/DP; P = .14, log-rank test) were not different between treatment arms. CONCLUSION: Orally administered DP did not improve the antineoplastic activity of 5-FU/FA in patients with advanced colorectal cancer when used at this dose and schedule. The observed increase in 5-FU dose-intensity for FU/FA/DP was not clinically relevant.
Administration, Oral↗
[Preoperative (neoadjuvant) chemotherapy in multimodality treatment concept of stomach carcinoma].
In spite of standardization of surgical procedures in the treatment of gastric carcinomas including increased resection rates as well as decreased postoperative mortality long-term survival rates are poor. An improvement of the prognosis by surgery alone can be expected only by tumor free R0-resection. In locally advanced gastric carcinomas with questionable R0-resection some studies could show promissing results using preoperative chemotherapy. This treatment modality enabled increased R0-resection rates with a positive impact on median survival in relation to surgery alone. Randomized trials have to start in the future to verify or to modify these results incorporating new options of multimodality treatment.
Antineoplastic Agents↗
Phase I/II study with paclitaxel in combination with weekly high-dose 5-fluorouracil/folinic acid in the treatment of metastatic breast cancer: an interim analysis.
Phase II study results demonstrating high efficacy and low toxicity for a weekly schedule of high-dose 5-fluorouracil/folinic acid (5-FU/FA) in intensively pretreated metastatic breast cancer patients prompted the addition of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to this regimen in a phase I/II trial in outpatients: high-dose 5-FU (24-hour infusion)/FA (2-hour infusion preceding 5-FU) is given for 6 weeks (days 1, 8, 15, 22, 29, and 36), with paclitaxel (3-hour infusion) administered on days 1 and 22; 2 weeks' rest follows. Folinic acid 500 mg/m2 was administered throughout; the respective 5-FU doses for dose levels 1 through 3 were 1.5, 1.8, and 2.0 g/m2 with paclitaxel 135 mg/m2. Dose level 4 (500 mg/m2 FA, 2.0 g/m2 5-FU, and 175 mg/m2 paclitaxel) was chosen for phase II evaluation. To date, 46 patients with bidimensionally measurable disease (four each at dose levels 1, 2, and 3, and 34 at dose level 4) have been entered. The 12 patients treated at dose levels 1 through 3 were titrated to level 4 doses when phase II began; 35 patients are evaluable for response. The median age is 46 years, and the median number of metastatic sites is 2.5. Fourteen patients had received adjuvant chemotherapy, nine chemotherapy for metastasis, and 23 chemotherapy both adjuvantly and for metastasis. Of 31 anthracycline-treated patients, 27 had anthracycline-resistant disease. No dose-limiting toxicity appeared until dose level 4, when grade 3 or 4 leukopenia and diarrhea occurred in 15 and eight, respectively, of 108 cycles. Mild to moderate mucositis, hand-foot syndrome, myalgia, and nausea/vomiting occurred in 20% to 40% of cycles. One (3%) of the 35 patients had a complete response, 18 (51%) had partial responses, 14 (40%) had stable disease, and two (6%) had disease progression. Eleven (55%) of 20 evaluable patients with anthracycline-resistant disease responded (95% confidence interval, 34% to 76%). Median time to maximum response was 2 months, and the remission duration was 8+ months. Median survival time has not been reached. Paclitaxel and weekly high-dose 5-FU/FA was well tolerated and highly effective, even in patients with anthracycline-resistant metastatic breast cancer. The regimen can be administered safely to outpatients.
Adult↗
5-Fluorouracil, folinic acid, etoposide and cisplatin chemotherapy for locally advanced or metastatic carcinoma of the oesophagus.
38 patients with advanced oesophageal carcinoma were treated with intravenous (i.v.) folinic acid (300 mg/m2), 5-fluorouracil (500 mg/m2), etoposide (100 mg/m2), and cisplatin (30 mg/m2) (FLEP), on days 1, 2 and 3, every 22-28 days. 26 patients had locally advanced disease (LAD) and 12 had metastatic disease (M1). Oesophagectomy was planned for patients with LAD in case of tumour regression after chemotherapy, while patients with M1 disease received chemotherapy only. The overall remission rate was 45% (17/38) including four clinical and two pathologically confirmed complete remissions. 16 patients underwent oesophagectomy, 12 after response to FLEP, and 4 after FLEP and subsequent irradiation +/- 5-fluorouracil/mitomycin. Toxicity was mainly haematological, with WHO grade 3 and 4 leukocytopenia in 50% and thrombocytopenia in 31% of the patients. Two treatment-related deaths were observed; one due to chemotherapy and one postoperatively. Median survival time of LAD patients was 13 months, and actuarial 2-year survival was 31%. Patients with complete tumour resection after FLEP had a median survival time of 18 months and a 2-year survival rate of 42%. Median survival of M1 patients was 6 months. FLEP is an active combination for oesophageal cancer, especially when used preoperatively in LAD.
Adenocarcinoma↗
Current status and future directions in the treatment of localized esophageal cancer.
Due to insufficient local tumor control in the majority of esophageal carcinoma (EC) patients and due to distant recurrences, the dismal prognosis of patients with EC has not essentially changed during the past two decades. This holds true despite extended surgical procedures and improved radiation techniques. The 2-year survival rates in stage IIB/III which represent two-thirds of the patients with localized EC is still less than 20%. Therefore, clinical efforts in the management of EC focus on combined modality treatment (CTM), usually preoperative chemotherapy (CTx)/chemoradiotherapy (CTx/RTx) or CTx/RTx alone. Up to now, results of CTM in potentially resectable EC have not shown that preoperative CTx or CTx/RTx is superior to surgery alone with respect to resectability, local tumor control and overall survival. However, CTx responders who subsequently underwent a complete tumor resection had a markedly improved long term survival indicating that the inclusion of CTx in the treatment of EC may improve the prognosis. The benefit of CTx could also be demonstrated in a randomized trial comparing RTx alone versus CTx/RTx with a reduction of local and distant failures and significantly improved survival in the CTM arm. Similar observations were made with CTM in locally advanced disease. To date, there is sufficient evidence that preoperative treatment of EC may improve prognosis at least of subgroups of patients with this tumor. However, this has to be confirmed in well designed (proper staging including endoscopic ultrasound, etc.) randomized trials.(ABSTRACT TRUNCATED AT 250 WORDS)
Antineoplastic Agents↗
Current status and future directions in the treatment of localized gastric cancer.
Although extended surgery plus systematic lymphadenectomy may improve the prognosis of patients with stage II/IIIa (UICC classification) tumors, there is no doubt, that the results of surgery of gastric cancer have reached a plateau. An improvement of the current situation can be expected at best by additional treatment modalities in order to reduce local recurrences and distant metastases. For locally advanced gastric cancer (LAGC), which includes approximately two-thirds of patients with locoregionally confined tumors, preoperative chemotherapy represents a promising approach. In surgically or clinically staged inoperable LAGC, approximately half of the patients underwent complete (R0) resection after downstaging induced by active modern chemotherapy. The long-term survival of these patients appears to be about 20%. Well designed randomized studies, however, comparing surgery alone versus preoperative chemotherapy, should be undertaken in LAGC. In view of the high local recurrence rate being observed in published preoperative chemotherapy trials, the inclusion of radiotherapy (intraoperative radiotherapy, simultaneous chemoradiotherapy) or intraperitoneal chemotherapy should be considered for future investigations. In more early stages, curatively resected, adjuvant chemotherapy has no proven impact so far. Whether this will change with the use of more active chemotherapy or better timing of adjuvant treatment remains to be seen. Neoadjuvant chemotherapy has proven to be feasible and active also in potentially resectable tumors. Therefore, preoperative chemotherapy appears to be an attractive tool for clinical investigations also in earlier stages of gastric cancer.
Antineoplastic Agents↗
Current status and future directions in the perioperative treatment of pancreatic cancer.
Pancreatic cancer is associated with an extremely poor prognosis. Even after resection with curative intent, the 5-year survival rates usually do not exceed 5%, and neither radiotherapy (RT) nor chemotherapy (CT) improve long term survival. Because of the poor outcome of patients with localized disease, studies should be directed to selected patients who benefit from surgery and from combined treatment of surgery with chemo-irradiation. Future developments in the treatment of locoregionally confined pancreatic cancer will have to focus on treatment modalities which improve the local tumor control as well as the control of occult distant disease. Combined CT/RT seems to be the most promising approach for these patients. However, to date there are more questions than clearcut answers about what such a multimodality treatment should look like. This concerns the selection of patients, the dosages, time schedules, and routes of administration of CT and RT. Last but not least, there is a need for more effective CT in pancreatic cancer. New drugs and multiple drug combinations should be studied in patients who are not candidates for multimodality treatment because of distant metastases. Well designed trials that address these issues are urgently needed in the forthcoming years.
Antineoplastic Combined Chemotherapy Protocols↗
Weekly high-dose 5-fluorouracil and folinic acid as salvage treatment in advanced gastric cancer.
BACKGROUND: A weekly schedule of a 24-h high-dose 5-FU infusion in combination with folinic acid was investigated as salvage therapy in patients with advanced gastric cancer. PATIENTS AND METHODS: Seventeen patients with progressive disease after chemotherapy were treated with a weekly schedule of 500 mg folinic acid/sqm by i.v. 2-h infusion followed by an i.v. 24-h infusion of 2.6 g 5-FU/sqm times six. Fourteen of the 17 patients (82%) had been pretreated in regimens which included 5-FU/folinic acid i.v. bolus. RESULTS: Toxicity was mild, with diarrhea, mucositis and nausea; WHO grade III/IV diarrhea was observed in only two patients. Three patients achieved partial remissions (18%; 95% confidence interval: 0%-38%) and 7 patients stable disease (41%; 95% confidence interval: 17%-64%). Their median survival time was five months (range 1.5-10 months) after the onset of salvage therapy. CONCLUSIONS: This schedule of weekly 24-h infusions of high-dose 5-FU and folinic acid is effective, even in patients pretreated with or resistant to regimens including 5-FU/folinic acid i.v. bolus. Based on these data, it appears that this schedule of high-dose 5-FU/folinic acid in first-line combination chemotherapy merits investigation.
Adult↗
[Surgery of locally advanced non-small-cell bronchial cancer after intensive preoperative chemo-/radiotherapy].
From March 1991 to June 1993 50 patients with local advanced NSCLC (mediastinoscopy obligatory) have been entered into an ongoing trial with preoperative chemotherapy and simultaneous chemo-/radiotherapy, followed by re-mediastinoscopy and surgery. Clinical response rates after chemotherapy amounted to 66.8% after chemo/radiotherapy 77.5%, no severe toxicity was observed. 36 patients ultimately underwent operation, 29 with a curative, 5 with a palliative resection and 2 with an explorative thoracotomy. Pathological complete remission rates of the primary tumor were found in 11 (32.3%), R0-resection in 18 (52.9%) and R1-resection in 5 (14.7%) cases. Sterilisation rates of mediastinal nodes were found in 86.3% of N2 tumors and 66.6% of N3 tumors. Median survival time ranged between 21 months for stage III a and 16 months for III b disease. This intensive preoperative neoadjuvant treatment is tolerable and effective, the requirements for a randomised comparative trial was met.
Adult↗
Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer.
BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.
Adult↗
Single-agent carboplatinum for advanced seminoma. A phase II study.
BACKGROUND: To reduce the side effects of cisplatin-based combination chemotherapy, the activity of carboplatinum was evaluated in patients with advanced seminoma. METHODS: Forty-two evaluable patients with advanced seminoma (defined as abdominal lymph nodes > 5 cm or supradiaphragmatic or visceral disease) received single-agent carboplatinum at a dose of 400 mg/m2 intravenously every 4 weeks for a maximum of six cycles. The median follow-up was 31 months (18-67 months). RESULTS: Thirty patients (71%) achieved a complete remission (CR; 21 chemotherapy alone, 9 with additional surgery), 8 patients (19%) a partial remission (PR), and 4 patients had disease progression (10%). Patients with metastases confined to the lymph nodes had a significantly higher remission rate than patients with visceral metastases (97% versus 50%; P < 0.002). Elevation of lactate dehydrogenase or human chorionic gonadotropin before radiation therapy had no influence on response rate. Eight patients have relapsed (five from CR and three from PR). All 12 patients failing carboplatinum therapy received cisplatin-based combination regimens. Ten patients achieved a stable favorable response (eight CR, two PR), whereas two patients died of their disease. Currently, 30 patients (71%) are continuously free from progression (25 CR, 5 PR), and 40 patients are alive (survival 93%). Toxicity was mild with no neurotoxicity or nephrotoxicity. CONCLUSIONS: The use of up-front carboplatinum therapy appears not to compromise the ultimate curability of patients with advanced seminoma. Randomized trials, however, will have to demonstrate the effectiveness of carboplatinum with regard to survival, and help to identify prognostic subgroups of patients who require up-front cisplatinum-based combination chemotherapy.
Adult↗