Current perspectives on pyridoxine-dependent seizures

An advanced gastric cancer patient with T3N1M0 successfully underwent a curatively total gastrectomy combined with distal pancreatectomy and lymphnode dissection following ELF-P combined chemotherapy. The patient received two courses of etoposide (75 mg/m2, Day 1-5, i.v.), leucovorin (30 mg/body, Day 2-5, i.v.), 5-FU (500 mg/m2, Day 2-5, i.v.) and CDDP (60 mg/m2, Day 1, i.v.). A partial response for the primary lesion and lymphnode metastasis was obtained, and a successful curative resection of the stomach was performed. No drug adverse responses occurred. The effect of ELF-P chemotherapy was confirmed with grade 1b by histopathological examinations. Neoadjuvant chemotherapy with ELF-P may be useful as an inductive approach for advanced gastric cancer.     

A phase I study of paclitaxel and 5-fluorouracil in advanced gastric cancer

This is a phase I study to determine the maximum tolerated dose (MTD) and toxicity of a combination of paclitaxel and 5-Fluorouracil (5-FU) in advanced gastric cancer patients. The patients, refractory to the PELF regimen (5-FU, leucovorin, cisplatin, epidoxorubicin), received weekly 5-FU at the fixed dose of 500 mg/m2, and escalating doses of paclitaxel every 3 weeks with a starting dose of 150 mg/m2 given as in 3-h infusion. The dose was escalated by 25 mg/m2 every 3 patients. Fifteen patients entered the study. The upper paclitaxel dose (225 mg/m2) was given to 6 patients. Up to this dose, no severe toxicity (grade 3-4) was recorded. Apart from alopecia, grade 1-2 leukopenia occurred in 5 patients and grade 1-2 neurotoxicity in 2 patients. All patients were evaluable for response (at least 2 cycles): 2 patients achieved an objective response (200 and 225 mg/m2). In 6 patients, treatment resulted in notable relief from symptoms. Out-patient paclitaxel given over 3 h and 5-FU may be combined safely for the treatment of patients with advanced gastric cancer. The recommended doses for phase II study are paclitaxel 225 mg/m2 and 5-FU 500 mg/m2.     

In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers

From February 1995 through October 1996, 25 patients with metastatic colorectal cancer showing a clinical resistance to 5-fluorouracil (5-FU) entered this study. Thirteen received oxaliplatin alone and 12 received it in combination with 5-FU. Oxaliplatin was administered at 130 mg/m2 over a 2-hour infusion every 3 weeks, alone or added either to 5-FU as a continuous infusion at 200 mg/m2 to 300 mg/m2 (six patients) or to a 5-FU bolus, 375 mg/m2, plus leucovorin, 100 mg/m2, daily for 5 days every 3 weeks (6 patients). Eighty-six of 98 administered cycles were evaluable for toxicity (47 for oxaliplatin plus 5-FU and 39 for oxaliplatin alone). Hematologic toxicity was mild, occurring as grade 2 leukopenia in 23% of the cycles of 5-FU and oxaliplatin and in 5% of the cycles of oxaliplatin alone. The most common toxicity was neurologic (grade 1 to 2 in 60%-6% of the cycles of the combination, respectively, and 68%-10% of oxaliplatin given alone) as hand-foot paresthesia or hypersensitivity to cold. No grade 4 toxicity was reported and only three patients in the 5-FU group developed grade 3 diarrhea. Grade 2 nausea and vomiting occurred in 33% of the cycles when both drugs were given and in 15% when oxaliplatin was administered alone. The combination of oxaliplatin and 5-FU induced four partial remissions (33%; 95% confidence interval, 6%-60%), whereas eight patients of the whole group had stable disease. No response occurred when oxaliplatin was administered as a single agent. The results of this study confirm the antitumor activity of oxaliplatin when added to 5-FU in patients who have metastatic colorectal cancer previously refractory to 5-FU. The possible therapeutic synergy with 5-FU was not accompanied by increased toxicity.     

Etoposide, epirubicin and cisplatin (EEP) combination in metastatic cancers of the cardia and the stomach. Groupe de recherche en cancérologie du Nord (GRECNO)

This study was aimed to confirm the therapeutic activity of the combination of etoposide, doxorubicin and cisplatin which has shown some clinical efficiency as first line therapy in advanced gastric cancer. Seventeen patients with metastatic gastric cancer were treated with etoposide (120 mg/m2, i.v., on day 5, 6 and 7), epirubicin (20 mg/m2, i.v., on day 1 and 7) and cisplatin (40 mg/m2, i.v., on day 2 and 8), q 4 weeks. In 16 patients evaluable for response, three (19%) obtained a partial response lasting from 93 to 360 days. Fifteen patients were evaluable for toxicity. Main toxicities > grade 2 included anemia (2/15), neutropenia (5/15), alopecia (8/15), fatigue (3/15), diarrhea (2/15), vomiting (2/15). Twenty nine per cent of severe toxic events were documented all along 52 cycles. Therefore we failed to confirm that this regimen could be of clinical efficiency in advanced gastric cancer as regards the benefits/toxicity ratio.     

Specialty maldistribution. The next nursing crisis?

80 patients with previously untreated stage III-IV non-small cell lung cancer (NSCLC) were randomly assigned to receive chemotherapy (CT) alone (arm I: 26 patients) or the same CT combined with either interferon (IFN)-gamma (arm II: 27 patients) or with both IFN-gamma and IFN-alpha (arm III: 27 patients). The CT comprised cisplatin 60 mg/m2 intravenously (i.v.) day 1 and etoposide 100 mg/m2 i.v. days 1, 3 and 5, once every 28 days; the IFN therapy comprised either recombinant IFN-gamma 1b 0.2 mg/m2, subcutaneously, three times a week until day 25, or recombinant IFN-alpha 2c 6 x 10(6) U given according to the same schedule, and simultaneously with IFN-gamma. A maximum of six cycles were given. The treatment was discontinued if progressive disease (PD) was demonstrated. The mean numbers of cycles per patient given in the different arms were 3.6 (arm I), 3.0 (arm II) and 2.9 (arm III). The main reason for discontinuation in all arms was PD. 17 (28%) of the 61 evaluable patients achieved partial responses (35% in arm I, 29% in arm II and 35% in arm III, non-significant). No complete response was recorded. Haematological toxicity was dose-limiting in all arms: leucopenia (WHO grade 3) was observed universally, but more frequently in arm III (in 18% of cycles given). Only two episodes of grade 4 leucopenia were seen (arms II and III) and six episodes of grade 3-4 thrombocytopenia (arm III). Median survival was 6-7 months in all arms. The survival curve for arm II was slightly more favourable (non-significant) than those for other arms. The addition of IFN-gamma alone or IFN-alpha plus IFN-gamma to platinum-based CT did not improve response rates nor did it produce any significant survival benefit for patients with NSCLC. Increased haematological toxicity was observed when both IFNs were administered concomitantly with CT.     

Concurrent cisplatin, prolonged oral etoposide, and vincristine plus chest and brain irradiation for limited small cell lung cancer: a phase II study of the Southwest Oncology Group (SWOG-9229)

PURPOSE: The primary objectives of the study were to evaluate the efficacy and safety of prolonged oral (PO) etoposide as part of cisplatin-based chemotherapy plus concurrent chest/brain irradiation induction, followed by CAV consolidation, in the treatment of patients with limited-stage small cell lung cancer (SCLC-LD) within a cooperative group setting. METHODS AND MATERIALS: Fifty-six eligible patients with SCLC-LD received three 28-day cycles of cisplatin 50 mg/m2 i.v. (days 1, 8; 29, 36; and 57, 64), PO etoposide 50 mg/m2 (days 1-14, 29-42, and 57-70), and vincristine 2 mg i.v. (days 1, 29, and 57). Thoracic irradiation (TRT) was administered at 1.8 Gy in 25 daily fractions to a total dose of 45 Gy via an AP:PA arrangement, to begin concomitantly with induction chemotherapy. Prophylactic cranial irradiation (PCI) was started on day 15 of induction therapy. Fifteen daily fractions of 2.0 Gy were administered to the entire brain to a total dose of 30 Gy to finish at approximately the same time as TRT. Two 21-day cycles of consolidation cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 2 mg i.v. (all on days 1 and 22), were given beginning on day 106 or week 16, from the start of induction therapy. RESULTS: Among 56 eligible patients, 93% had SWOG performance status 0-1. All had adequate organ function and had not received prior therapy. The overall confirmed response rate was 46%, including 16% complete responders and 30% partial responders. After a minimum follow-up duration of 17 months, the Kaplan-Meier median progression-free (PFS) and overall survival (OS) were 10 and 15 months, respectively. Two-year survival is 28%. Only 28 of 56 patients (50%) completed chemotherapy per protocol, while 52 of 56 patients (93%) completed radiation per protocol. Eleven patients (20%) discontinued secondary to toxicity and two patients died from treatment. The major toxicity was hematologic. The two deaths were secondary to infection. Of the nonhematologic toxicities, there were 10 cases of pulmonary fibrosis (including one Grade 3) and six cases of pneumonitis (including one Grade 3). CONCLUSION: Concomitant chemoradiation with oral etoposide as part of a platinum-based chemotherapy and TRT induction regimen is toxic. The CR rate is not better than our prior best group-wide experience. The progression-free and overall survival are similar to published trials utilizing short-course i.v. etoposide. As in chemotherapy for extensive-stage SCLC, there is no apparent advantage to prolonged exposure to etoposide, and toxicity resulted in an inferior therapeutic index compared to programs with shortened exposure.     

Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients

PURPOSE: A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial. PATIENTS AND METHODS: Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined. RESULTS: A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase. CONCLUSION: Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.     

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.     

A phase II study of irinotecan alternated with five days bolus of 5-fluorouracil and leucovorin in first-line chemotherapy of metastatic colorectal cancer

PURPOSE: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of irinotecan (CPT-11) with bolus 5-fluorouracil (5-FU) and leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients with histologically proven metastatic colorectal cancer, and at least one bidimensionally measurable lesion, aged 18-70, with performance status < or = 2, normal baseline biological values and no prior chemotherapy (or only adjuvant chemotherapy completed > or = 6 months before study entry) were selected. Treatment was irinotecan 350 mg/m2, i.v., day 1, alternating with leucovorin 20 mg/m2 i.v. and 5-FU 425 mg/m2, i.v. daily for five consecutive days, day 22-26 (Mayo Clinic regimen). One alternating cycle was to be performed every six weeks. Patients were evaluated for efficacy every alternating cycle. Treatment was administered until five alternating cycles, disease progression, unacceptable toxicity or patient refusal. RESULTS: Thirty-three patients (28 chemotherapy-na?ve and five with prior adjuvant treatment completed > 1 year prior to accrual) were enrolled. The objective response rate (RR) was 30% (95% CI: 16-49; 10 patients/33; nine partial response and one complete response). All responses were reviewed by an independent external review committee. An additional 49% of patients had stable disease. The median survival was 16 months, the one year survival amounted to 58% and the median progression free survival was 7.2 months. Relative dose intensity was nearly 90% for both drugs. Grade 3-4 diarrhea and neutropenia were the most frequent severe toxic events, seen in 24% and 64% of patients, respectively. CONCLUSIONS: The alternating schedule of CPT-11 350 mg/m2 with five days bolus of 5-FU and low dose LV is an active and feasible regimen as front-line therapy for metastatic CRC. It is well tolerated, without evidence of overlapping toxicity. The response rate appears promising with regard to that expected with either single agent. This regimen warrants further assessment in randomized trials.     

A pilot study of nedaplatin and etoposide for recurrent gynecological malignancies

Nedaplatin is a new analogue of cisplatin with similar efficacy but less renal toxicity. We assessed the efficacy and toxicity of nedaplatin and etoposide for recurrent gynecological malignancies. Eight patients were treated with 100 mg/m2 of nedaplatin (day 1) and 70 mg/m2 of etoposide (days 1, 3, and 5 ) every 4 weeks. A total of 17 courses was given. Grade 3/4 leucopenia and thrombocytopenia occurred, but was manageable. The response rate was 37.5% (partial response n=3; no change n=4; progressive disease n=1). In conclusion, a phase II study of this regimen for recurrent gynecological malignancies is warranted.     

A phase II study of all-trans-retinoic acid plus cisplatin and etoposide in patients with extensive stage small cell lung carcinoma: an Eastern Cooperative Oncology Group Study

BACKGROUND: The dysregulation of both myc gene expression and retinoid signaling pathways commonly occurs in small cell lung carcinoma (SCLC). Because preclinical data showed that all-trans-retinoic acid (RA) inhibited SCLC growth, altered myc expression, and blocked transition to a treatment-resistant phenotype, a Phase II trial was designed to determine the effects of the combination of RA, cisplatin, and etoposide in patients with SCLC. METHODS: Patients with untreated, extensive stage SCLC were treated with up to 8 cycles of cisplatin, 60 mg/m2, intravenously (i.v.) on Day 1 and etoposide, 120 mg/m2, i.v. on Days 1-3 in addition to up to 1 year of oral RA, 150 mg/m2/day. RESULTS: Of 22 assessable patients 1 had a complete response and 9 had a partial response, for an overall response rate of 45% (95% confidence interval, 24-68%). The median survival was 10.9 months and the 1-year survival was 41%. The median duration of chemotherapy was 6 cycles and the median duration of RA treatment was 2.8 months. Thirteen patients discontinued RA prematurely due to toxicity and only 4 responders were receiving RA at the time of recurrence. Toxicity-limiting RA treatment mainly was comprised of mucocutaneous changes and headaches. CONCLUSIONS: RA at a dose of 150 mg/m2/day was tolerated poorly in combination with cisplatin plus etoposide, leading to early discontinuation of RA in the majority of patients. The hematologic toxicity, response rate, and survival were similar to those associated with cisplatin and etoposide in prior trials. Further studies with more active and less toxic agents will be required to determine the role of retinoids in the treatment of SCLC.     

Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.     

Drug resistance patterns among tuberculosis patients in Rome, 1990-1992

PURPOSE: A Phase II study to evaluate the effect of a five-drug regimen, VP-16, ifosfamide, cisplatin, vinblastine, and bleomycin (VIP/VB) on complete response rate, continuous disease-free survival, and toxicity in patients with advanced germ-cell tumor. PATIENTS AND METHODS: Twenty male patients with a histologic diagnosis of advanced-stage germ-cell cancer, previously untreated with chemotherapy, received the following: etoposide 75 mg/m2 i.v. days 1-5; ifosfamide (with mesna uroprotection) 1.2 g/m2 i.v. days 1-5; cisplatin 20 mg/m2 i.v. days 1-5; vinblastine 0.18 mg/kg i.v. day 1; bleomycin 30 units i.v. day 1; filgrastim 5 micrograms/kg days 7-16. Chemotherapy was given every 3 weeks (bleomycin weekly x 12) for four courses. RESULTS: All patients entered were evaluable for toxicity, response, and survival. Eleven of 20 (55%) achieved complete remissions with chemotherapy alone and an additional 5 (25%) were rendered disease-free with surgical resection of teratoma (3) or viable cancer (2). Two patients relapsed at 4 and 5 months from complete remission (CR). There was one treatment-related death, from bleomycin lung toxicity after thoracotomy. Thirteen patients (65%) are alive and continuously free of disease, with a median follow-up of 20 months and a minimal follow-up of 12 months. Hematologic toxicity was most common, with 16 patients (80%) having grade 3 or 4 leukopenia. CONCLUSIONS: VIP/VB appears to be a very active regimen in advanced disseminated germ-cell cancer. Hematological toxicity was severe but manageable.     

Cisplatin plus oral etoposide in the treatment of patients with advanced small cell lung cancer. Japan Clinical Oncology Group

BACKGROUND: Etoposide is a highly schedule-dependent drug. We investigated combination chemotherapy of oral etoposide and intravenous cisplatin for small cell lung cancer (SCLC). METHODS: Fifty-seven patients with SCLC with extensive disease (ED) or limited disease (LD) with pleural effusion registered in the 21 institutions of the Japan Clinical Oncology Group were treated with oral etoposide 40 mg/m2/d for 21 days and cisplatin 80 mg/m2 on day 1 of every 28-period day. The entry period was between February 1992 and August 1995. The actual percentages of patients treated with etoposide were 93.6, 89.5, 92.3 and 96.9% in the first, second, third and fourth cycles, respectively. RESULTS: Nine patients (15.8%) achieved a complete response resulting in an overall response rate of 82.5% (95% confidence interval, 70.1-91.3%). Leukopenia and thrombocytopenia of grade 3 or 4 were observed in 36 (49.1%) and 8 (14.0%) patients, respectively. Anemia of grade 3 or 4 occurred in 28 (49.1%) patients. Nausea, vomiting, anorexia and alopecia were common adverse events. One patient died of hemoptysis due to grade 4 thrombocytopenia. The mean survival time was 47.0 weeks. CONCLUSIONS: This dose and schedule of administration of etoposide in combination with cisplatin are considered to be clinically active. However, prolonged gastrointestinal toxicity of oral etoposide was a problem in comparison with the standard etoposide platinum regimen given by intravenous administration.     

Tandem and triple high-dose chemotherapy with autologous stem cell rescue in metastatic breast cancer

The purpose of this phase II study was to evaluate the therapeutic efficacy and toxicity of a tandem or triple high-dose chemotherapy (HDC) with autologous peripheral blood stem cell transplantation (PBSCT) in patients with metastatic breast cancer (MBC) as first line chemotherapy. Conventional chemotherapy consisted of two cycles of epirubicin 120 mg/m2 and ifosfamide 7500 mg/m2 in the case of tandem HDC and one cycle of paclitaxel 135 mg/m2, epirubicin 90 mg/m2 and ifosfamide 6000 mg/m2 in the case of triple HDC. Tandem HDC was composed of two cycles of epirubicin 180 mg/m2, ifosfamide 12000 mg/m2 and carboplatin 900 mg/m2. In the case of triple HDC, paclitaxel 180 mg/m2, etoposide 1500 mg/m2 and thiotepa 600 mg/m2 was added as the third cycle. Patients with tandem HDC (n = 20) were evaluable for both survival and toxicity, and patients with triple HDC (n = 21) only for toxicity because of short-term follow-up. Both tandem and triple HDC were well tolerated and could be safely administered. Non-hematological WHO grade 3 or 4 toxicities were mucositis (8), temporary renal insufficiency (1), myocardial infarction (1), and neuropathy (1). No toxic death occurred. The Kaplan-Meier estimates for 44-months without progression and the overall survival were 12% and 38% respectively. The median survival was 22 months (95% CI: 7.4-51.7 months) and the median progression-free interval 14 months (95% CI: 5.1-43.7 months). In a population with an unfavorable prognosis, tandem HDC showed similar efficacy as to that described in other phase II studies. Triple HDC seems not to improve patient outcome compared to tandem HDC, but a long-term follow up is required.     

Biventricular repair in neonates with hypoplastic left heart complex

PURPOSE: We previously developed an inpatient regimen that consisted of infusional fluorouracil (5-FU), epirubicin, and cisplatin (ECisF), with a response rate of 86% in advanced breast cancer. The current phase II 2:1 randomized study investigated whether cyclophosphamide can be substituted for cisplatin (ECycloF) to reduce toxicity and allow the regimen to be administered on an outpatient basis without loss of efficacy. PATIENTS AND METHODS: Ninety-six women (median age, 49 years; range, 28 to 73) with breast cancer (59 metastatic, 37 locally advanced) received continuous infusional 5-FU (200 mg/m2/d via Hickman line) and six cycles of epirubicin (60 mg/m2 every 21 days) with either cyclophosphamide 600 mg/m2 every 21 days (38 metastatic, 24 locally advanced) or cisplatin 60 mg/m2 every 21 days (21 metastatic, 13 locally advanced). There were no significant differences in patient characteristics between these groups. RESULTS: ECycloF was better tolerated than ECisF in terms of lethargy (P = .005), stomatitis (P = .008), plantar palmar erythema (P = .02), constipation (P < .001), thrombosis (P = .0014), and nausea and vomiting (P = .05). Although there was a trend toward more anemia and leukopenia with ECisF (P =. 1), there was no significant difference in the rates of infection. Efficacy was comparable in terms of overall response (69% v 68%), complete response (CR; 13% v 15%), and median progression-free survival (9 v 8 months). CONCLUSION: ECycloF is an outpatient regimen with a lower incidence of severe nonhematologic toxicity than inpatient ECisF; it has comparable efficacy and is considerably more economical.     

High expression of thymidylate synthase is associated with the drug resistance of gastric carcinoma to high dose 5-fluorouracil-based systemic chemotherapy

BACKGROUND: In the past 4 years, the weekly 24-hour infusion of high dose 5-fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced gastric carcinoma has been prospectively studied at the authors' institution. This has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of gastric carcinoma to 5-FU-based chemotherapy. METHODS: To be eligible for this study, patients were required to have received high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU, 2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system, which ranged from 0 to 3+, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression. RESULTS: Between 1993 and 1996, a total of 30 patients, 18 men and 12 women, with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and 14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients (12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low expression of TS responded to chemotherapy (P < 0.001, chi-square test). The median overall survival was 10 months for patients with low TS expression and 4 months for patients with high TS expression (P < 0.01, log rank test). CONCLUSIONS: The data from this study suggest that the expression of TS, as determined by immunohistochemistry, is a relatively reliable indicator of whether 5-FU should be used in the treatment of patients with gastric carcinoma.     

Paclitaxel with mitoxantrone, fluorouracil, and high-dose leucovorin in the treatment of metastatic breast cancer: a phase II trial

PURPOSE: Paclitaxel is a highly active single agent in the treatment of breast cancer. However, its optimal incorporation into combination regimens awaits definition. In this phase II study, we added paclitaxel, administered by 1-hour infusion, to a previously described combination regimen that included mitoxantrone, fluorouracil (5-FU), and high-dose leucovorin (NFL). PATIENTS AND METHODS: Forty-six patients with metastatic breast cancer received the following regimen as first- or second-line treatment: paclitaxel 135 mg/m2 by 1-hour intravenous (i.v.) infusion on day 1, mitoxantrone 10 mg/m2 by i.v. bolus on day 1, 5-FU 350 mg2/m by i.v. bolus on days 1, 2, and 3, and leucovorin 300 mg i.v. over 30 to 60 minutes immediately preceding 5-FU on days 1, 2, and 3. Courses were administered at 3-week intervals for a total of eight courses in responding patients. RESULTS: Twenty-three of 45 assessable patients (51%) had major responses. Previous chemotherapy, and in particular previous treatment with doxorubicin, did not affect response rate. The median response duration was 7.5 months. Myelosuppression was moderately severe, with 76% of courses resulting in grade 3 or 4 leukopenia. Hospitalization for treatment of fever during neutropenia was required in 13% of courses, and two patients died as a result of sepsis. Two patients developed severe congestive heart failure after a large cumulative anthracycline dose. CONCLUSION: This combination regimen was active as first- or second-line therapy for metastatic breast cancer, although its activity compared with other combination regimens or with paclitaxel alone is unclear. Myelosuppression was more severe than anticipated based on previous results with the NFL regimen or with paclitaxel administered at this dose and schedule as a single agent. The infrequent development of cardiotoxicity in these patients suggests that the paclitaxel/mitoxantrone combination may not share the problems previously reported with the paclitaxel/doxorubicin combination.     

Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study

The aim of the study was to define the maximum tolerated dose (MTD) of vinorelbine given as one or two weekly doses in combination with epirubicin 60 mg/m2 every third week. The MTD was defined as the dose resulting in a WHO grade III or IV leucopenia exceeding 50% of patients. Patients were treated in groups of 10 at escalating doses of vinorelbine. The number of patients at the final dose level was expanded to 20. The dose of epirubicin was kept constant at 60 mg/m2 every third week. At dose level 1, 15 mg/m2 vinorelbine was given on day 1 at level 2, 20 mg/m2 was given on day 1 and at level 3, 20 mg/m2 was given on days 1 and 8. The MTD was reached at dose level 3. WHO haematological toxicity grade IV occurred in 0, 10 and 45% and grade III at 60, 30 and 30% of patients at dose levels 1, 2 and 3, respectively. Despite the common occurrence of grade IV haematological toxicity, only two serious infections were noted. Non-haematological toxicity of vinorelbine included neurotoxicity, manifesting as muscle weakness, constipation and paresthesias in the majority of patients. Neurotoxicity was usually mild and did not require treatment discontinuation. Phlebitis at the injection site was troublesome in many patients. Alopecia and nausea, probably due to epirubicin, occurred in most patients. The response rates were 22% (95% CI (confidence interval) 3-60%), 40% (12-74%) and 60% (36-81%) at levels 1, 2 and 3, respectively (non-significant).     

Cervical meningoceles and myelocystoceles: a unifying hypothesis

We initiated a pilot study of adjuvant hepatic arterial infusion chemotherapy (AHAIC) using 5-fluorouracil (5-FU) and leucovorin. Hepatic arterial infusion ports were placed in 15 consecutive patients undergoing curative resection of colorectal liver metastases. The chemotherapy regimen consisted of a weekly infusion of 5-FU (12 mg m 2 per day) and leucovorin (200 mg m 2 per day) for 12 months. The mean follow-up was 22 months (range 3-62 months, SD 21-37 months). There were no clinical or biological complications related to chemotherapy, except for sharp epigastric burns in four patients immediately after 5-FU infusions. Catheter irreversible occlusions led to early cessation of the treatment in three patients. Four of the 15 evaluable patients developed recurrent disease. The site of relapse was the liver in two patients and extra-hepatic sites in the two remaining patients. Three of these four patients died of their recurrent disease. These results suggest that 5-FU and leucovorin can be combined for AHAIC in a long duration regimen with a very low rate of side-effects. This protocol could be safely employed in a prospective randomized study in combination with 5-FU systemic infusions.