S-1 monotherapy as second line chemotherapy in advanced gastric cancer patients previously treated with cisplatin/infusional fluorouracil

The treatment choice of advanced gastric carcinoma after failure from first-line therapy is quite limited. To evaluate the efficacy and toxicity of S-1 monotherapy in patients with advanced gastric cancer after failure of first line cisplatin and fluorouracil combination (CF). S-1 monotherapy as a second line treatment was given to the patients who had failed to CF combination in SC-101 study. The efficacy and toxicity of S-1 monotherapy were evaluated exploratory. The results indicated that forty-one patients received S-1 as a second line therapy after disease progression. The overall response rate and disease control rate were 14.6% and 41.5%, respectively. The median progression free survival (PFS) was 5.1 months (ange: 2.9~6.2 month). The median overall survival time was 6.4 months. The survival rates at 6 month and 1 year were 56% and 7.3%, respectively. Grade 3/4 adverse events were uncommonly occurred, including anemia (2.4%), neutropenia (2.4%), thrombocytopenia (4.9%) and rash (2.4%). There were no unexpected or life-threatening toxicities. Only one patient experienced dose reduction due to grade 3 rash. In conclusion, S-1 monotherapy provided a mild response rate and overall survival, and a favorable toxicity profile in the second line setting after the first line failure to cisplatin and fluorouracil combination.     

Squamous oesophageal cancer can be downstaged using protracted venous infusion of 5-fluorouracil with epirubicin and cisplatin (ECF)

21 patients with squamous oesophageal carcinoma were treated with a new regimen designed in our unit and effective in treating gastric adenocarcinoma, consisting of continuous venous infusion of 5-fluorouracil for up to 24 weeks (200 mg/m²/day) with epirubicin (50 mg/m²) and cisplatin (60 mg/m²) every 3 weeks. 12 patients (57%) had an objective response. The median relapse free period was 7 months, median survival from start of chemotherapy 8.4 months, and median survival from diagnosis, 14 months. Symptomatic improvements were reported by 10/11 patients with pain (91%), 8/9 with anorexia (89%), 8/10 with reflux (80%) and 10/14 with dysphagia (71%). Grade 3 or 4 toxicity was reported by 11 patients: 5 had haematological toxicity, 3 vomiting, 2 infection and 1 diarrhoea. One patient developed peripheral neuropathy, 1 renal impairment and another peripheral vascular disease. Following chemotherapy, surgery was attempted in 5 patients. One remains well 3 years on, 2 had macroscopic clearance of tumour but died of postoperative complications. In 2, disease was irresectable. This regimen of moderate toxicity is effective at improving symptoms in the majority of patients. In some patients, tumours are briefly downstaged so that inoperable tumours may become operable.     

Pegylated liposomal doxorubicin in combination with mitomycin C, infusional 5-fluorouracil and sodium folinic acid. A phase-I-study in patients with upper gastrointestinal cancer

Mitomycin C (MMC) in combination with infusional 5-fluorouracil (FU) plus folinic acid (FA) is an effective treatment for metastatic gastrointestinal cancer. Anthracyclines are commonly used in the treatment of upper gastrointestinal cancer. The aim of this study was to determine the maximum tolerated dose of liposomal, pegylated doxorubicin (Caelyx) in combination with infusional 5-FU/sodium FA and MMC. Escalating doses of Caelyx (15-25-30-35 mg m(-2) corresponding to dose levels I-IV) were applied on days 1 and 29, given to fixed doses of 24-h 5-FU (2000 mg m(-2)) and sodium FA (500 mg m(-2), mixed with 5-FU in one pump) weekly for 6 weeks, and MMC 7 mg m(-2) on days 8 and 36. At least three patients were treated at each dose level. A total of 25 patients are evaluable. No dose-limiting toxicity (DLT) was observed on level I (n=3). On level II, DLT occurred in three out of five patients (mucositis and leucopenia). Owing to the early DLTs at this dose, we added a 20 mg m(-2) Caelyx dose level (Ia). In total, 17 patients were treated at this dose level. Among these, only two patients experienced DLT in cycle one and 37 complete cycles have been administered in association with a low toxicity profile. The median dose intensity was 100% for each drug during the first course and no treatment delay exceeding 7 days was required. The recommended dose of 4-weekly Caelyx in combination with weekly 24-h 5-FU/sodium FA and 4-weekly MMC is 20 mg m(-2). Preliminary antitumour activity has been observed in patients with pretreated pancreatic cancer and in untreated gastric cancer.     

A phase I trial of gemcitabine administered as a 96-h continuous intravenous infusion in patients with advanced carcinoma and lymphoma

Background and objective Preclinical data suggest gemcitabine may have schedule-dependent activity fovoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h. Patients and methods Gemcitabine was initially given at 1 mg/m²/d for 48, then, 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m²/d. Dose levels of 7, 8, 9 mg/m²/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule. we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk. Results Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1–10 cycles). The RPTD, was 8 mg/m²/d every 3 wk, and 6 mg/m²/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (>- grade 2) included fever (n=14), dyspnea (n=7). mucositis (n=6), hypotension (n=6), nausea/vomiting (n=6), and fatigue (n=5). Neutropeni and/or thrombocytopenia were uncommon. Conclusion A dministration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m²/d (32 mg/m²/course) when given every 3 wk, or 6 mg/m²/d (24 mg/m²/course) when given every 2 wk.     

Phase I study of biweekly gemcitabine followed by oxaliplatin and simplified 48-h infusion of fluorouracil/leucovorin for advanced pancreatic cancer

OBJECTIVES: To evaluate the feasibility and maximal tolerated dose (MTD) of oxaliplatin of a triplet regimen consisting of gemcitabine, oxaliplatin and infusional fluorouracil (5-FU)/leucovorin (LV) (GOFL) for advanced pancreatic cancer. PATIENTS AND METHODS: Patients with histologically proven metastatic or unresectable, locally advanced pancreatic adenocarcinoma were eligible to take part in the study. The treatment consisted of fixed-rate infusion (10 mg/m2/minute) of 800 mg/m2 gemcitabine followed by 2-h infusion of oxaliplatin and then 48-h infusion of 5-FU/LV day 1 and day 15 every 4 weeks. The oxaliplatin would be evaluated at three dose levels, 65, 75 and 85 mg/m2. RESULTS: A total of 15 patients were enrolled at three dose levels. Dose-limiting toxicity of neutropenic fever and grade 4 thrombocytopenia occurred in one of each six patients at oxaliplatin dose level of 65 mg/m2 and 85 mg/m2, respectively. The MTD of oxaliplatin for this combination was 85 mg/m2. After a median four cycles of treatment, grade 3/4 neutropenia occurred in 46.7% of patients and thrombocytopenia in 13.3%. Non-hematological toxicities were generally of grade 1/2. Objective tumor response was observed in five patients (33.3%, 95% confidence interval, 6.3-60.4%). CONCLUSION: Biweekly GOFL is a feasible regimen for advanced pancreatic cancer. For further phase II studies, the recommended dose of oxaliplatin is 85 mg/m2.     

Reações infusionais imediatas a agentes imunobiológicos endovenosos no tratamento de doenças autoimunes: experiência de 2.126 procedimentos em um centro de infusão não oncológico

IntroductionWith the increasing use of immunobiological drugs (IBD), the knowledge about their effectiveness and safety has increased.ObjectiveTo analyze the immediate infusional reactions (IIR) to intravenous IBD: infliximab (IFX), rituximab (RTX), abatacept (ABT) and tocilizumab (TCZ) on the treatment of autoim- mune diseases.Method2126 infusions performed in the Infusion Centre - CID in 268 patients were ana- lyzed. The used drug, its clinical indication, infusion time, and use of premedication were determined by the prescribing physician. All intercurrences presented during infusion and/ or during a thirty minutes observation period were considered as IIR. The approach ad- opted in IIR followed the protocols of the Infusion Centre - CID.ResultsRegarding the type of IBD, the infused drugs given were: IFX (1584, 74.5%), TCZ (226, 10.63%), RTX (185, 8.7%) and ABT (131, 6,16%). IIR were described in 87 procedures (9.4%): 77 - IFX group and 10 - RTX group. IIR were not described in ABT and TCZ groups. Most were considered as mild (n = 5; 41.17%) or moderate (n = 50, 58.81%) reactions; there were no seri- ous reactions. Regarding to discontinue infusions, 79 (92.9%) were resumed and completed successfully. Only six (0.28% of infusions) were not completed because of IIR.ConclusionDespite the differences between the number of procedures per drug, ours is a “real life” analysis, where the incidence of IIR was similar to that described in the literature. The low incidence of IIR corroborates the safety data, both quantitatively and qualitatively, and underscores the importance of specialized medical support during infusion.     

Bimonthly 24 h Infusion of High-Dose 5-Fluorouracil vs EAP Regimen in Patients with Advanced Gastric Cancer

Background: To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. Patients and methods: Histologically confirmed measurable advanced gastric cancer, age < 72 yr, ECOG performance status 0–2, no prior chemo- and radiotherapy, adequate organ functions. Treatment: EAP arm: doxorubicin (40 mg/m²), etoposide (360 mg/m²), and cisplatin (80 mg/m²) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m² 24 h infusion, biweekly. Results: Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2–8), HD 5-FU arm 2 (1–8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16–50%]/HD 5-FU arm 10% (0–21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3–27], HD 5-FU arm 6 mo (4–25). Conclusions: Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.     

A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma

In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP; n =75) or with additional cyclophosphamide, C-VAMP ( n =129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1–11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher ( P =0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.     

Infusional Cyclophosphamide, Doxorubicin and Etoposide in HIV-Related Non-Hodgkin's Lymphoma: a Follow-Up Report of a Highly Active Regimen

Based on our prior data suggesting a therapeutic advantage for infusional administration of cyclophosphamide (C), doxorubicin (D), and etoposide (E) in patients with relapsed and resistant non-Hodgkin's lymphoma (NHL), we administered C (750 mg/m²), D (50 mg/m²), and E (240 mg/m²) via continuous intravenous infusion over 96 hours as first line therapy for 21 patients with intermediate- or high-grade non-Hodgkin's lymphoma associated with human immunodeficiency virus (HIV) infection. Treatment was repeated every 28 or more days. The median CD4 count of the study group was 87/ul, and the median serum lactate dehydrogenase was 383 IU/L. Extranodal disease, lymphomatous marrow involvement, and lymphomatous meningitis were present at diagnosis in 90%, 33%, and 10% of patients, respectively. Complete response (CR) occurred in 13 patients (62%, 95% confidence intervals 41%, 81%) and partial response occurred in five patients (24%). The estimated median survival of the study group was 18.0 months. Hematologic toxicity required dose reduction for 47% of cycles and for 79% of patients who received at least two cycles. The mean dose intensity for C., D., and E were 73%, 70%, and 73% of the intended dose intensity, respectively. Opportunistic infection included oral/esophageal candidiasis (N = 7), herpes labialis (N = 3), pulmonary Mycobacterium avium-intracellulare (N = 1), candidemia (N = 1), pneumonitis (N = 1), and disseminated aspergillosis than resulted in a single treatment-related death (5%). Treatment resulted in a significant decrease in the CD4+ lymphocytes, as well as total lymphocytes, T lymphocytes, and CD8+ lymphocytes. Our findings suggest that infusional CDE is a highly active regimen capable of producing durable CRs in a substantial proportion of patients with HIV-related NHL and requires further study.