Two different first-line 5-fluorouracil regimens with or without oxaliplatin in patients with metastatic colorectal cancer.

BACKGROUND: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) are standard first-line treatments for patients with metastatic colorectal cancer (mCRC). The aim of this multicentre, open-label, phase IIIb study was to assess the addition of oxaliplatin to two different 5-FU regimens. PATIENTS AND METHODS: Patients with previously untreated mCRC were randomised to arm A [two-weekly oxaliplatin 85 mg/m(2) + either continuous intravenous infusion (CIV) of 5-FU without LV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B (5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was planned on progression. RESULTS: A total of 725 patients were enrolled. After a fixed follow-up of 2 years for each patient, 2-year survival rates were 27.3% and 24.8% in arms A and B, respectively (hazard ratio 0.93; 95% confidence interval 0.78-1.10). The addition of oxaliplatin significantly improved response rates (54.1 versus 29.8%; P < 0.0001) and median progression-free survival (7.9 versus 5.9 months; P < 0.0001). The most common grade 3-4 toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea (arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%). CONCLUSIONS: Despite improved rates of tumour control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.

Randomized phase III study comparing irinotecan combined with 5-fluorouracil and folinic acid to cisplatin combined with 5-fluorouracil in chemotherapy naive patients with advanced adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: We aimed to establish the superiority (or noninferiority if superiority was not achieved) in terms of time to progression (TTP) of irinotecan/5-fluorouracil (IF) over cisplatin/5-fluorouracil (CF) in chemonaive patients with adenocarcinoma of the stomach/esophagogastric junction. PATIENTS AND METHODS: Patients received either IF: i.v. irinotecan 80 mg/m(2) 30 min, folinic acid 500 mg/m(2) 2 h, 5-fluorouracil (5-FU) 2000 mg/m(2) 22 h, for 6/7 weeks or CF: cisplatin 100 mg/m(2) 1-3 h, with 5-FU 1000 mg/m(2)/day 24 h, days 1-5, every 4 weeks. RESULTS: In all, 333 patients were randomized and treated (IF 170, CF 163). Patient characteristics were balanced except more IF patients had Karnofsky performance status 100%. TTP for IF was 5.0 months [95% confidence interval (CI) 3.8-5.8] and 4.2 months (95% CI 3.7-5.5) for CF (P = 0.088). Overall survival (OS) was 9.0 versus 8.7 months, response rate 31.8% versus 25.8%, time to treatment failure (TTF) 4.0 versus 3.4 months for IF and CF, respectively. The difference in TTF was statistically significant (P = 0.018). IF was better in terms of toxic deaths (0.6% versus 3%), discontinuation for toxicity (10.0% versus 21.5%), severe neutropenia, thrombocytopenia and stomatitis, but not diarrhea. CONCLUSION: IF did not yield a significant TTP or OS superiority over CF, and the results of noninferiority of IF were borderline. However, IF may provide a viable, platinum-free front-line treatment alternative for metastatic gastric cancer.

Toxicity and health-related quality of life in breast cancer patients receiving adjuvant docetaxel, doxorubicin, cyclophosphamide (TAC) or 5-fluorouracil, doxorubicin and cyclophosphamide (FAC): impact of adding primary prophylactic granulocyte-colony stimulating factor to the TAC regimen.

BACKGROUND: The aim of the study was to analyse the toxicity and health related quality of life (HRQoL) of breast cancer patients treated with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) and TAC (docetaxel, doxorubicin, cyclophosphamide) with and without primary prophylactic G-CSF (PPG). PATIENTS AND METHODS: This was a phase III study to compare FAC and TAC as adjuvant treatment of high-risk node-negative breast cancer patients. After the entry of the first 237 patients, the protocol was amended to include PPG in the TAC arm due to the high incidence of febrile neutropenia. A total of 1047 evaluable patients from 49 centres in Spain, two in Poland and four in Germany were included in the trial. Side-effects and the scores of the EORTC QLQ-C30 and QLQ BR-23 questionnaires were compared in the three groups (FAC, TAC pre-amendment and TAC post-amendment). RESULTS: The addition of PPG to TAC significantly reduced the incidence of neutropenic fever, grade 2-4 anaemia, asthenia, anorexia, nail disorders, stomatitis, myalgia and dysgeusia. Patient QoL decreased during chemotherapy, more with TAC than FAC, but returned to baseline values afterwards. The addition of PPG to TAC significantly reduced the percentage of patients with clinically relevant Global Health Status deterioration (10 or more points over baseline value) at the end of chemotherapy (64% versus 46%, P<0.03). CONCLUSIONS: The addition of PPG significantly reduces the incidence of neutropenic fever associated with TAC chemotherapy as well as that of some TAC-induced haematological and extrahaematological side-effects. The HRQoL of patients treated with TAC is worse than that of those treated with FAC but improves with the addition of PPG, particularly in the final part of chemotherapy treatment.

Irinotecan in combination with 5-fluorouracil and folinic acid or with cisplatin in patients with advanced gastric or esophageal-gastric junction adenocarcinoma: results of a randomized phase II study.

BACKGROUND: To identify the most effective of two combinations, irinotecan/5-fluorouracil (5-FU)/folinic acid (FA) and irinotecan/cisplatin, in the treatment of advanced gastric cancer, for investigation in a phase III trial. PATIENTS AND METHODS: Patients were randomized to receive irinotecan [80 mg/m2 intravenously (i.v.)], FA (500 mg/m2 i.v.) and a 22-h infusion of 5-FU (2000 mg/m2 i.v.), weekly for 6 weeks with a 1-week rest, or irinotecan (200 mg/m2 i.v.) and cisplatin (60 mg/m2 i.v.), on day 1 for 3 weeks. RESULTS: A total of 115 patients were eligible for analysis in the per-protocol population. The overall response rate in the irinotecan/5-FU/FA arm (n=59) was 42.4%, with a complete response rate of 5.1%. Corresponding figures for the irinotecan/cisplatin arm (n=56) were 32.1% and 1.8%, respectively. The median time to progression was 6.5 months (irinotecan/5-FU/FA) and 4.2 months (irinotecan/cisplatin) (P < 0.0001), with median survival times of 10.7 and 6.9 months, respectively (P=0.0018). The major toxicity was grade 3/4 neutropenia, which was more pronounced with irinotecan/cisplatin than with irinotecan/5-FU/FA (65.7% versus 27%). Diarrhea was the main grade 3/4 non-hematological toxicity with both irinotecan/5-FU/FA (27.0%) and irinotecan/cisplatin (18.1%). CONCLUSIONS: Both combinations were active, with acceptable safety profiles. Irinotecan/5-FU/FA was selected as the most effective combination for investigation in a phase III trial in advanced gastric cancer.

Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial.

BACKGROUND: Oral capecitabine achieves a superior response rate with an improved safety profile compared with bolus 5-fluorouracil-leucovorin (5-FU/LV) as first-line treatment for patients with metastatic colorectal cancer. We report here the results of a large phase III trial investigating adjuvant oral capecitabine compared with 5-FU/LV (Mayo Clinic regimen) in Dukes' C colon cancer. PATIENTS AND METHODS: Patients aged 18-75 years with resected Dukes' C colon carcinoma were randomized to receive 24 weeks of treatment with either oral capecitabine 1250 mg/m(2) twice daily, days 1-14 every 21 days (n = 993), or i.v. bolus 5-FU 425 mg/m(2) with i.v. leucovorin 20 mg/m(2) on days 1-5, repeated every 28 days (n = 974). RESULTS: Patients receiving capecitabine experienced significantly (P <0.001) less diarrhea, stomatitis, nausea/vomiting, alopecia and neutropenia, but more hand-foot syndrome than those receiving 5-FU/LV. Fewer patients receiving capecitabine experienced grade 3 or 4 neutropenia, febrile neutropenia/sepsis and stomatitis (P <0.001), although more experienced grade 3 hand-foot syndrome than those treated with 5-FU/LV (P <0.001). Capecitabine demonstrates a similar, favorable safety profile in patients aged <65 years or > or = 65 years old. CONCLUSIONS: Based on its improved safety profile, capecitabine has the potential to replace 5-FU/LV as standard adjuvant treatment for patients with colon cancer. Efficacy results are expected to be available in Keywords: Adjuvant treatment, capecitabine, chemotherapy, colorectal cancer

A phase II study of intravenous navelbine and doxorubicin combination in previously untreated advanced breast carcinoma.

PURPOSE: The combination of vinorelbine and doxorubicin, two very active drugs in metastatic breast cancer, has demonstrated impressive results in terms of efficacy, at the price of cardiac toxicity (10% grades 2-4) due to the cumulative dose of doxorubicin delivered. This study was designed to divide the dose of doxorubicin into two administrations (day 1 and 8) in order to reduce the toxicity profile, while keeping the same level of efficacy. PATIENTS AND METHODS: Thirty-eight chemotherapy-naïve metastatic breast cancer patients entered into the study and were treated with vinorelbine, 25 mg/m(2), and doxorubicin, 25 mg/m(2), both on days 1 and 8, every 3 weeks. Thirty-seven patients were evaluable for efficacy and 38 for tolerance; 71% of the patients presented with visceral metastases. RESULTS: Patients received a median of seven cycles and 94.9% of the intended dose intensity of both drugs. Grade 3-4 neutropenia was reported in 10% of cycles. Alopecia was reported in 89.5% of the patients, and grade 2 nausea/vomiting in 9.3% of the cycles. Grade 1-2 cardiac toxicity was noted in 23.7% of the patients. The objective response rate of the patients was 78.4% (nearly 81% for patients with visceral metastases); the median duration of response was 11.6 months, the median survival 21.6 months, and the 1-year survival 75.2%. CONCLUSION: This schedule of vinorelbine/doxorubicin represents an active and well-tolerated combination.

Rituximab (Mabthera, Rituxan) in patients with recurrent indolent lymphoma: evaluation of safety and efficacy in a multicenter study.

The objective of this multiinstitutional study was to evaluate the safety and efficacy of rituximab at standard four weekly doses in patients with recurrent indolent lymphoma. Thirty-eight patients entered into this study, 63% had follicular lymphoma and 61% had an IPI score of 2 or more. Median disease duration was 3 yr, median number of prior treatments was three, and 66% of patients responded to the immediate past treatment with a median remission duration of 3 mo. A total of 158 antibody doses were given, including two patients who received two courses of four infusions each. One patient developed acute respiratory failure after the second dose and required assisted ventilation. There was no immediate relationship to the antibody infusion and no evidence of infection. This complication resolved and the patient successfully completed the full course of the antibody treatment. Another patient discontinued therapy after the second dose owing to intolerable fever and painful erythema. Sixty percent of the first, and 20% of subsequent rituximab infusions were associated with infusion-related reactions including mild fever, chills, and occasional skin eruptions. Complete and partial responses were achieved in 24% and 35% of 34 evaluable patients, respectively, for an overall response rate of 59%. The median time to progression/relapse in responding patients was 16 mo (95% CI, 6.4, 25.6) compared with a median of 3 mo duration of response to the immediate previous therapy in these patients. Longer response duration post rituximab monotherapy than with previous treatment in this series of heavily pretreated patients suggests a major role for the antibody in the therapy of patients with indolent lymphoma.

[Combined treatment of large bowel cancer]. / Skojarzone leczenie raka jelita grubego.

During the years 1989 to 1994, in the Department of General Surgery we performed surgery on 800 cases of large bowel cancer. The cases comprised 412 men (51.5%) and 388 women (48.5%), aged 25 to 85, the most numerous age group ranging from 50 to 70 (60%). Radical surgery was carried out on 501 cases (62.7%) and palliative surgery on 299 cases (37.3%). In cases with histopathological evaluation pTNM-T1N0M0 or T2N0M0 we refrained from chemo- and radiotherapy. In cases of rectal cancer with advanced staging T3N1M0 or T4N2M1 we applied radiotherapy, whereas in cases of cancer localized on other parts of large bowel we had recourse to chemotherapy as combined treatment. Radiotherapy was applied irrespective of grading, whereas chemotherapy was applied in cases of cancer with grading G2 and G3. Radiative energy was used in 65 cases and chemotherapy in 120 cases. Postoperational mortality amounted to 6%. Five years survival after radical surgery achieved 57.4%. Local recurrence took place in 21% of the cases. The control group consisted of the cases subjected to surgery in the years 1984-1989 when only surgery was performed and 5-years survival after radical surgery amounted to 48% and local recurrence was found in 30% of the cases.

Methotrexate binding to human plasma proteins.

The percentage of methotrexate (MTX) binding to plasma protein was 50.4 +/- 1.9 in healthy subject, and 32.3 +/- 3.6 in patients with cancer (breast carcinoma in most cases). Drugs used in combination with MTX in therapy (vincristine, vinblastine, cyclophosphamide, 5-fluorouracil, prednisone) depress the MTX binding to albumins. MTX binds to two kinds of albumins binding sites, with different binding constants: K1 = 8.88 mM-1 and K2 = 1.76 mM-1.