A phase II study of 5-fluorouracil, leucovorin and cisplatin (FLP) for metastatic gastric cancer

The modulation of 5-fluorouracil (5-FU) with folinic acid (leucovorin, LV) is more efficacious than 5-FU alone in the treatment of metastatic colorectal cancer, and the combination of 5-FU with cisplatin is currently one of the most active regimens in advanced gastric cancer. A phase II study was therefore conducted to test the efficacy and toxicity of the combination of 5-FU, LV and cisplatin (FLP) in metastatic gastric cancer. 28 patients entered the study. Metastatic sites were observed in the liver (in 21 patients), the peritoneum (in 8), the lymph nodes (in 7) or the bones (in 1) and a local recurrence was noted in 4 cases. The performance status (using World Health Organisation criteria) was 0 for 13 patients and 1 or 2 for the others. Cycles of treatment were administered every 28 days and consisted of LV 200 mg/m2/day for 5 days followed by 5-FU 400 mg/m2/day for 5 days with cisplatin 100 mg/m2 on day 2. The response rate for the 27 evaluable patients was 51.8% (95% confidence interval (CI), 33-70.6%). There were four complete responses (14.8%) and 10 partial responses (37%). Median survival was 11 months and 4 patients were alive at 2 years. Both response rate and survival were better for patients with a good performance status. The overall toxicity was very low, except for 1 patient who died of dehydration and cardiac failure. In conclusion, the FLP protocol was effective and well tolerated in patients with metastatic gastric cancer.     

Final report of a phase II study of chemotherapy with bleomycin, epirubicin, and cisplatin for locally advanced and metastatic/recurrent undifferentiated carcinoma of the nasopharyngeal type

PURPOSE: This article presents an assessment of the combination of bleomycin, epirubicin, and cisplatin as induction chemotherapy before radiotherapy in the treatment of undifferentiated carcinoma of the nasopharyngeal type in patients with recurrent/metastatic disease (group A), and in previously untreated patients with locoregionally advanced disease (UICC-AJCC 87, N2-3, M0) (group B) in terms of toxicity, antitumoral activity, and therapeutic efficacy. PATIENTS AND METHODS: From January 1987 to September 1990, 111 consecutive patients with histologically proven UCNT were treated with six cycles of intravenous cisplatin (100 mg/m2 day 1) epirubicin (80 mg/m2 day 1), and bleomycin (15 mg bolus day 1), followed by 16 mg/m2/day continuous infusion for 5 days, repeated every 21 days for three cycles. Three further cycles without bleomycin were given to 44 patients in group A. In group B (67 patients), only three cycles of the same protocol were given, with a slightly lower dose of epirubicin (70 mg/m2), followed by conventional radiotherapy (70 Gy/7 weeks). RESULTS: Of 44 patients entered in group A, 38 were evaluable for response. We observed 9 (20%) complete responses and 11 (25%) partial responses, for a 45% overall response rate. In 12 patients not previously given chemotherapy, there were 4 complete responses, compared to 5 complete responses in 32 patients previously treated with chemotherapy. Four patients are alive with no evidence of disease after 53+, 60+, 61+, and 72+ months. In group B the overall response rate to chemotherapy was 98% with 42 complete (62%) and 24 partial responses (36%). Three months after the end of radiotherapy, the overall complete response rate was 94% (63 patients). After a median follow-up time of 77 months (range, 53-94), the 4-year overall survival and disease-free survival rates for this group are 66% and 60%, respectively. The median disease-free survival has not been reached at 90 months. CONCLUSION: The results of the BEC combination trial are very encouraging in metastatic and recurrrent UCNT, with durable remissions in this poor-prognosis population. The results in patients with locally advanced disease have motivated prospective phase III testing of the neoadjuvant chemotherapy approach to evaluate its impact on locoregionally advanced disease (> or =N2MO UICC-AJCC 87).     

Treatment of advanced adenocarcinomas of the exocrine pancreas and the gallbladder with 5-fluorouracil, high dose levofolinic acid and oral hydroxyurea on a weekly schedule. Results of a multicenter study of the Southern Italy Oncology Group (G.O.I.M.)

BACKGROUND: To date there is no established chemotherapeutic treatment for patients with unresectable locally advanced and/or metastatic carcinomas of the exocrine pancreas or the gallbladder. A multicenter Phase II trial has been performed by the Southern Italy Oncology Group with the aim of evaluating the clinical effectiveness and tolerability of weekly 5-fluorouracil (5-FU) in modulation with intravenous (i.v.) high dose levofolinic acid and oral hydroxyurea. METHODS: A total of 70 patients fulfilling the standard eligibility for a Phase II study were enrolled in the trial. Forty patients had advanced pancreatic adenocarcinoma and 30 had advanced gallbladder carcinoma. The treatment schedule was: levofolinic acid, 100 mg/m2, in 500 mL of normal saline over 2-hour infusion followed by 5-FU, 600 mg/m2 i.v. bolus, and oral hydroxyurea, 1000 mg/m2, for 1 day every week for 6 consecutive weeks followed by 15 days of rest. RESULTS: Among the 40 patients with pancreatic adenocarcinoma, 5 (12.5%; 95% confidence level [CL], 8.5-16.5%) showed a partial response with a median duration of 5.6+ months, and 13 had stable disease. Twenty-two patients progressed. Median survival was 5.8 months. Among patients with advanced gallbladder carcinoma, 9 of 30 had a partial response (30%; 95% CL, 26-34%) with a median duration of 6.5 months, and 8 (27%) had stabilization of disease. Thirteen patients showed progressive disease. Median overall survival was 8 months. Toxicity was mild, with Grade 1 to 2 leukopenia and gastrointestinal toxicity the most frequent side effects. No chemotherapy-related deaths were observed. CONCLUSIONS: 5-FU in modulation with i.v. levofolinic acid and oral hydroxyurea on a weekly schedule is well tolerated by the vast majority of patients with locally advanced and/or metastatic carcinoma of the pancreas or the gallbladder. Although response rate and overall survival for patients with pancreatic adenocarcinoma are far from acceptable, the 30% overall response rate achieved in patients with advanced gallbladder carcinoma suggests that 5-FU in modulation with levofolinic acid and hydroxyurea is active in this neoplasm. The combination of modulated 5-FU with other antineoplastic drugs seems worthy of clinical testing in further controlled trials.     

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.     

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.     

Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity

PURPOSE: A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen. PATIENTS AND METHODS: Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity. RESULTS: Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy. CONCLUSION: The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.     

Effect of anordrin on the development of mouse preimplantation embryos in vitro

The aim of this study was to establish the feasibility, evaluate the response rate, and assess the impact on local control and survival in locally advanced (bulky nodal) squamous cell carcinoma of the head and neck (SCCHN) patients treated with neoadjuvant chemotherapy consisting of cisplatin followed by continuous infusion of vindesine and fluorouracil with intermittent i.v. folinic acid. Eligibility criteria included histologically proven SCCHN, previously untreated locally advanced stage III-IV with measurable or evaluable disease, no distant metastases, an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, patient age of at least 18 years, and adequate bone marrow, hepatic, and renal functions. The protocol consisted of three cycles (day 1, day 21, day 42) of Cisplatin (CDDP) 100 mg/m2/day i.v. on day 1 immediately followed by 4 days (96 h) of continuous infusion of vindesine 0.8 mg/m2/day and 5-fluorouracil (5-FU) 600-700 mg/m2/day with folinic acid 150 mg/m2 i.v. every 6 h x 16 doses before locoregional treatment with radiotherapy preceded by radical surgery when appropriate. Twenty-nine patients were enrolled in this study, and 28 were evaluable for activity; an objective response rate of 55% (four complete responses, 12 partial responses) was achieved. Leukopenia and mucositis were the most frequent and severe toxicities. The addition of vindesine did not improve the activity of the CDDP-FU-folinic acid combination, but this may be partly because of the particularly poor prognosis of the present patient population, with 75% of stage IV bulky nodal disease (N2c-N3).     

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.     

Hyperreactio luteinalis in a normal pregnancy: sonographic and MRI findings

We investigated the efficacy of combination chemo-therapy using 5-fluorouracil (5-FU), cisplatin (CDDP), and dipyridamole (DP), which is based on the concept of double biochemical modulation. Twenty-eight patients with advanced gastric cancer were treated with the simultaneous continuous intravenous (i.v.) infusion of 5-FU (800 mg/m2/day) and DP (4 mg/kg/day), and i.v. infusion of CDDP (20 mg/m2/day) for 5 days. The cycles were repeated every 4 weeks. Twelve patients (43%) had a partial response (PR), while stable disease (NC) occurred in 13 patients (46%), and progression (PD) in 3 patients (11%). An improved performance status was observed in 20 patients (71%). The carcinoembryonic antigen (CEA) level was markedly decreased in 75% of the CEA-positive patients. Toxicity was acceptable. The mean steady state plasma concentration of total DP was 6.40.5 microM, which thus seemed adequate to potentiate the cytotoxicity of 5-FU. The treatment regimen described herein thus appears to be effective, safe and well tolerated by patients with advanced gastric cancer.     

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.     

Risk factors for thrombotic events in giant cell arteritis and polymyalgia rheumatica

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

Hemodynamic response to oxygen administration in chronic heart failure: role of chemoreflexes

OBJECTIVE: To determine the applicability and safety of an ifosfamide, cisplatin, and etoposide (VIP) regimen as a neoadjuvant chemotherapy to a concomitant thoracic radiotherapy and cisplatin continuous infusion in locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Forty-four patients (stage IIIb in 43 and stage IIIa in 1) entered a study of VIP, followed by concomitant thoracic radiotherapy and cisplatin continuous infusion. Chemotherapy consisted of three courses of cisplatin 25 mg/m2, ifosfamide 1.5 g/m2 (with uroprotection), and etoposide 100 mg/m2 given on days 1 to 4 of a 21-day cycle with hematopoietic support using recombinant human methionyl granulocyte colony stimulating factor. Patients who achieved a response or a stabilization were planned to receive a split-course normofractionated thoracic radiotherapy (first course: 30 Gy/10; 4-week rest period; second course: 25 Gy/10). A continuous cisplatin infusion of 6 mg/m2 daily was administered using an autonomous chemotherapy delivery device. Total plasma platinum titration was performed daily during the two courses in five of the patients. Analyses were done on an intent-to-treat basis. RESULTS: Thirty-nine of the 44 patients received the three-cycle chemotherapy program. Received dose intensity was 82%. Thirty-eight patients received the radiotherapy and, among them, 35 received the complete concomitant continuous cisplatin infusion. Objective (complete) response rates were 48% (7%) at the end of chemotherapy and increased up to 61% (16%) by the end of radiotherapy. At the end of the first radiotherapy cycle, the mean total plasma platinum concentration was twice as high as that of the residual postinduction chemotherapy concentration. During induction chemotherapy, myelosuppression was the limiting toxicity requiring hospital readmission in 23 patients. During radiotherapy, the main toxicity was acute esophagitis. A relatively high rate of pulmonary fibrosis was observed using the subjective objective management analytic--late effects of normal tissue score without life-threatening pulmonary function impairment. None of the patients died from toxic reactions. Probability of survival at 1, 2, and 3 years was 49%, 19%, and 5%, respectively. Primary cause of failure was a local relapse in 63% of the patients, brain metastases in 24%, and hematogeneous metastases to other sites in 13%. CONCLUSION: Neoadjuvant VIP followed by concomitant radiotherapy-chemotherapy is feasible, but the split-course radiotherapy did not prevent a high rate of local recurrences. The high rate of toxic reactions requiring hospital readmission limits further development of such an aggressive regimen in NSCLC.     

A phase II study of DaunoXome in advanced urothelial transitional cell carcinoma

Liposomal encapsulation of anthracyclines is claimed to reduce toxicity and to improve pharmacokinetics. Therefore, 15 patients with locally advanced or metastatic transitional cell cancer (TCC) of the urinary tract were entered into a phase II study assessing the response rate (WHO criteria) and toxicity of DaunoXome 100 mg/m2 given as a 1 h infusion every third week. During treatment, 6 patients remained stable and 8 had progressive disease. 1 patient died of pulmonary embolism after the first cycle and was not evaluable for response. No patient developed grade 4 myelotoxicity. Grade 3 leucopenia was seen in 5 patients and grade 1 thrombocytopenia in 1 patient, with no treatment-related changes of biochemical liver and kidney function tests. 4 patients complained of angina pectoris-like chest pain during the initial phase of the first or second infusion. The event was associated with a decrease in systolic blood pressure by 20-30 mm in 1 patient leading to permanent treatment discontinuation. In the other 3 and all subsequent patients, intramuscular application of 100 mg hydrocortisone 1 h prior to DaunoXome infusion prevented similar hypotensive reactions. In this study, intravenous (i.v.) DaunoXome 100 mg/m2 every third week showed no anticancer activity in advanced TCC.     

Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.     

Neo-adjuvant chemotherapy +/- immunotherapy with s.c. IL 2 in advanced squamous cell carcinoma of the head and neck: a pilot study

We carried out a pilot nonrandomized phase II study to compare the neo-adjuvant chemotherapic regimen with cisplatin, 5-FU and vinorelbine with the same combination plus s.c. IL 2 in advanced head and neck squamous cell carcinoma (HNSCC). The primary goals of the trial were to evaluate the feasibility and response rates of the two regimens. The study design consisted of a patient's assignment to either of the two following arms: Arm A: Cisplatin 80 mg/m2 i.v. on day 1; 5-FU 600 mg/m2 i.v. on days 2-5; and vinorelbine 20 mg/m2 i.v. on days 2 and 8, Arm B: the same chemotherapic regimen plus recombinant IL 2 (Proleukin, Eurocetus) 9 MIU s.c. daily from day 9 to 13 and from day 16 to 20 for every cycle. From March 1993 to November 1993 twenty three patients with Stage III-IV HNSCC were enrolled in the study. Patients could be evaluated for response to treatment if they had received at least 2 complete cycles of therapy. The overall response rate (ORR) was 63% in Arm A and 100% in Arm B. The differences for ORR and CR rates were statistically significant in favor of Arm B. The analysis for each of the three drugs included in the chemotherapy schedule shows that both the actually received average dose-intensity and the actually delivered average cumulative doses/patient were higher for Arm B (chemo-plus IL 2 therapy) (approximately 80% of programmed dose-intensity) than for Arm A (approximately 70% of programmed dose-intensity). Both the actually received average dose-intensity and the actually delivered average cumulative doses/patient for IL 2 were more than 80%. In both arms the most frequent side effects were myelosuppression, phlebitis and electrolyte disturbances. There were 2 toxic deaths, 1 in Arm A and 1 in Arm B, both for hematologic toxicity. Our "pilot" study suggests that the combination of cisplatin, 5-FU, vinorelbine plus IL 2 is a highly active, but rather toxic, neo-adjuvant treatment in advanced HNSCC with very high ORR and CR rates.     

Chemotherapy with methotrexate, vinblastine, epirubicin and carboplatin (Carbo-MVE) in transitional cell urothelial cancer. A Hellenic Co-Operative Oncology Group study

OBJECTIVES: We conducted a phase II study in order to assess the efficacy and toxicity of Carbo-MVE (carboplatin 250 mg/m2 i.v. day 1, methotrexate 25 mg/m2 i.v. days 1, 15 and 22, vinblastine 2.5 mg/m2 i.v. days 1, 15 and 22 and epirubicin 25 mg/m2 day 1). The regimen ws to be repeated every 28 days. METHODS: Forty-six patients with transitional cell carcinoma of the bladder entered the study. Patients with metastatic disease were treated for 6 cycles, while patients with locally advanced or locoregional disease had 4 cycles of induction chemotherapy followed by cystectomy or radiotherapy. RESULTS: Toxicity was generally mild and treatment well tolerated. The overall response rate was 54.4%, with 26% complete and 28.3% partial response rates. The median survival was 17.5 months with the complete responders to live significantly longer (64.82 months) than those who had a partial response (20.5 months), stable disease (15 months) or progressive disease (8.5 months). Survival was also significantly longer in patients with good performance status as well as in patients with locally advanced or locoregional disease. Finally, patients who had cystectomy as definitive treatment survived significantly longer (32 months) than those who had been irradiated (16 months). CONCLUSIONS: The Carbo-MVE regimen appears to be an effective and well-tolerated treatment in patients with transitional cell carcinoma of the bladder.     

Two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil, cisplatin and cytarabine

We reported two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil (5-FU), cisplatin (CDDP) and cytarabine (Ara-C), 5-FU (300-350 mg/body) was given by continuous intravenous infusion. Ara-C (20-40 mg/body) by continuous infusion and CDDP (15-20 mg/body) were added intravenously for 3-6 days. For case 1, epirubicin (30 mg/body) was also given on the first day of each therapy course. Case 1 was a 62-year-old female who had gastric cancer with liver metastasis, ovarian metastasis and peritonitis carcinomatosa. After 3 courses of the chemotherapy, reduction of ovarian metastasis greater than 75% was observed. The value of CA125 decreased from 6,800 U/ml to 527 U/ml and ascites disappeared. Case 2 was a 54-year-old male who had type 3 advanced gastric cancer with multiple liver metastases. He received 6 courses of the therapy. Both primary and metastatic tumors showed over 50% reduction in tumor size. These suggested that this combination therapy was effective for inoperable advanced gastric cancers.     

Acute myocardial infarction in a patient during dobutamine stress echocardiography

Combined chemotherapy/radiotherapy treatments appear to yield better results in locally advanced non-small-cell lung cancer (NSCLC) than radiotherapy alone. The optimal induction chemotherapy regimen remains to be established. In the present study, chemotherapy with cisplatin and vinorelbine was used prior to radical radiotherapy in Stage III-B NSCLC. Thirty-three patients were entered prospectively into a Phase II study. Treatment consisted of three cycles of chemotherapy with cisplatin 100 mg/m2 on day 1 and vinorelbine 30 mg/m2 on days 1 and 8, followed by thoracic radiotherapy (60 Gy). Twenty-two percent of the 33 patients had grade 3-4 leukopenia, and there were six episodes (in 4 patients) of neutropenia-associated fever. Gastrointestinal toxicity was generally moderate. Peripheral neuropathy was present in 42% of the patients, although in most of them it was slight. The main radiotherapy toxicity was esophagitis grade I-II. Evaluation of response after the third chemotherapy course showed an objective response in 16 patients (48%), whereas in three patients (9%) the disease progressed during therapy. The median survival of the entire group was 13 months. Cisplatin plus vinorelbine followed by radiotherapy is an effective schedule for patients with locally advanced non-small-cell lung cancer.     

Cardiovascular disease prevention in eastern Europe

A phase II trial was conducted to evaluate the efficacy and toxicity of a modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) (with leucovorin (LV) rescue) as first-line chemotherapy in patients with locally advanced (inoperable) or metastatic gastric carcinoma. From July 1993 through August 1996, 36 patients with advanced gastric carcinoma received a regimen that consisted of: MTX 200 mg/m2 diluted in 250 ml normal saline by intravenous infusion over 20 minutes at hour 0; 5-FU 1,200 mg/m2 intravenous push injection at hour 20. Beginning 24 hours after MTX administration all patients received LV 15 mg/m2 intramuscularly every 6 hours for six doses. Cycles were repeated every 15 days. One patient was not assessable for response. Objective regression was observed in 15 of 37 patients (43%; 95% confidence interval, 26%-60%). One patient (3%) achieved complete response and 14 (40%) achieved partial response. No change was recorded in 14 patients (40%) and progressive disease was noted in six patients (17%). The median time to treatment failure was 7 months and the median survival was 12 months. Toxicity was within acceptable limits but one therapy-related death resulting from severe leukopenia occurred. The dose-limiting toxicity was mucositis. Five episodes of grade 3 or 4 stomatitis were observed and caused dosage modifications of MTX and 5-FU. Biochemical modulation of 5-FU by MTX appears as an attractive modality in patients with advanced gastric cancer. Further investigation both in experimental and clinical fields is needed to clearly define its role and to design the best modulatory strategy.     

Prognostic implications of downstaging following preoperative radiation therapy for operable T3-T4 rectal cancer

PURPOSE: Squamous cancer of the upper aerodigestive tract is a disheartening disease. Despite our best efforts, the long-term survival rate remains only 15% to 40%, and surgical cures often decrease the quality of life owing to the loss of swallowing and speech organs. A better understanding of tumor dynamics and the discovery that thiosulfate can neutralize cisplatin led us to develop a treatment plan that combines a rapid superselective high-dose intraarterial delivery of cisplatin (CDDP), simultaneous intravenous infusion of its antagonist, thiosulfate, and radiation therapy. METHODS: Patients with advanced head and neck squamous cancer were entered into the protocol after a multidisciplinary evaluation that included CT or MR imaging. Forty-two patients constituted the first cohort. After baseline angiography, an arterial acceptance test determined the maximum infusion rate that the tumor's nutrient artery would accept. CDDP was then infused at that rate, usually within 3 to 5 minutes, while the antagonist thiosulfate was given intravenously. In the second cohort of 85 patients with stage 3 or 4 previously untreated and unresectable disease, local radiation was added to the treatment plan. The radiation dose (180-200 cGy/d x 35) was delivered regionally on the basis of the known radiosensitizing effect of CDDP. RESULTS: Cohort 1 allowed us to develop the infusion technique and to establish a dose quantity and delivery frequency. When 150 mg/m2 was administered weekly for 4 weeks, no severe toxicity was found. In cohort 2, 72 (92%) of the remaining 78 patients had complete disappearance of their tumor. Seventeen severe toxic events were associated with 323 femoral catheterizations. One patient died of pulmonary embolus, precluding follow-up evaluation. Six patients had neurologic sequelae, three with transient and three with permanent strokes. CONCLUSION: Rapid superselective chemotherapy with CDDP combined with a circulatory systemic antagonist allowed delivery of an antitumoral drug directly into the lesion while protecting the kidneys and bone marrow from the agent's systemic effects. Use of a dose regimen of 150 mg CDDP/m2 per week for 4 weeks resulted in the disappearance of a large percentage of advanced squamous cancers.