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1.
Front Oncol ; 13: 1168654, 2023.
Article in English | MEDLINE | ID: mdl-37601667

ABSTRACT

Background: The incidence of irinotecan-induced diarrhea varies between 60-90%, by which the incidence of severe diarrhea is 20-40%. The objective of this phase III trial was to determine the effectiveness of the probiotic mixture containing Bifidobacterium, BB-12® and Lactobacillus rhamnosus, LGG® in the prophylaxis of irinotecan-induced diarrhea in metastatic colorectal cancer patients due to a reduction in the activity of intestinal beta-D-glucuronidase. Methods: From March 2016 to May 2022, a total of 242 patients with colorectal cancer starting a new line of irinotecan-based therapy were registered to the study in 11 cancer centers in Slovakia. Patients were randomized in a ratio 1:1 to probiotic formula vs. placebo that was administered for 6 weeks. Each capsule of Probio-Tec® BG-Vcap-6.5 contained 2.7x109 colony-forming units (CFU) of 2 lyophilized probiotic strains Bifidobacterium, BB-12® (50%) and Lactobacillus rhamnosus GG, LGG® (50%). Results: Administration of probiotics compared to placebo was not associated with a significant reduction of grade 3/4 diarrhea (placebo arm 11.8% vs. probiotic arm 7.9%, p=0.38). Neither the overall incidence of diarrhea (46.2% vs. 41.2%, p=0.51) nor the incidence of enterocolitis (3.4% vs. 0.9%, p=0.37) was different in the placebo vs. probiotic arm. Subgroup analysis revealed that patients with colostomy had higher incidence of any diarrhea and grade 3/4 diarrhea in the placebo arm compared to the probiotic arm (48.5% vs. 22.2%, p=0.06 and 15.2% vs. 0%, p=0.06, respectively). Moreover, patients on probiotic arm had significantly better diarrhea-free survival (HR = 0.41, 95%CI 0.18 - 0.95, p=0.05) and needed less loperamide (p=0.01) compared to patients on placebo arm. We did not observe any infection caused by probiotic strains used in this study. Conclusion: This study failed to achieve its primary endpoint, and results suggest a lack of benefit of administered probiotic formula for the prevention of irinotecan-induced diarrhea. However, subgroup analysis suggests a possible benefit in patients with colostomy.

2.
Pathol Oncol Res ; 18(1): 61-8, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21681601

ABSTRACT

There is a need for the selection of those breast cancers where benefit may be attained from the addition of an anthracycline to the adjuvant chemotherapy. The expression of topoisomerase II alpha (TOP2A) protein in 3 cohorts of breast cancers treated with adjuvant dose-dense anthracycline-based chemotherapy was determined retrospectively. The TOP2A status was analysed in relation with the other standard tumour features and the outcome. TOP2A IHC results were assessable in 106 patients: with a cut-off value of 15%, 48% of the tumours were classified as TOP2A-positive. The expression of TOP2A correlated with that of Ki67 (R = 0.532, p < 0.001) and a high grade (p = 0.04), but did not correlate with the proportion of ER- or PR-positive cells in the tumour. More tumors were TOP2A-negative among the ER- or PR-positive cancers than among the ER/PR-negative cancers (p = 0.021 and p = 0.002, respectively). After a median follow-up time of 64.5 months, 31 relapses (23.5%) and 23 deaths (17.4%) had occurred in 131 patients. The overall survival was longer in the TOP2A-positive cases than in the TOP2A-negative cases. The recurrence-free survival and the overall survival were significantly more favourable in the ER/PR-negative and TOP2A-positive tumours than in other subgroups. In a Cox proportional hazards model, the grade and TOP2A remained significant determinants in the ER/PR-negative subgroup. TOP2A positivity and grade 3 indicated a decrease in the risk of death with HR = 0.211 (95% CI: 0.042-1.05, p = 0.056) and HR = 0.216 (95% CI: 0.047-0.990, p = 0.048), respectively. A higher sensitivity to anthracycline-containing regimens is suggested in ER/PR-negative and TOP2A-positive cancers.


Subject(s)
Antigens, Neoplasm/biosynthesis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , DNA Topoisomerases, Type II/biosynthesis , DNA-Binding Proteins/biosynthesis , Analysis of Variance , Anthracyclines/administration & dosage , Antigens, Neoplasm/metabolism , Breast Neoplasms/metabolism , Chemotherapy, Adjuvant , DNA Topoisomerases, Type II/metabolism , DNA-Binding Proteins/metabolism , Disease-Free Survival , Female , Follow-Up Studies , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Ki-67 Antigen/metabolism , Middle Aged , Poly-ADP-Ribose Binding Proteins , Proportional Hazards Models , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Retrospective Studies , Treatment Outcome
3.
J Clin Oncol ; 27(19): 3097-103, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19451434

ABSTRACT

PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.


Subject(s)
Antineoplastic Agents/administration & dosage , Epothilones/administration & dosage , Fallopian Tube Neoplasms/drug therapy , Ovarian Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Dose-Response Relationship, Drug , Epothilones/adverse effects , Epothilones/pharmacokinetics , Female , Humans , Maximum Tolerated Dose , Middle Aged
4.
Breast Cancer Res Treat ; 112(3): 557-63, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18189160

ABSTRACT

Addition of epirubicin to adjuvant chemotherapy can provide important benefits for patients with early breast cancer, but the optimal dose remains unclear. Further improvements can be achieved with dose-dense regimens, but densification of fluorouracil/epirubicin/cyclophosphamide (FEC) has proved difficult, with FEC(60) providing little benefit over standard chemotherapy and FEC(100) associated with toxicity. We investigated the feasibility of two intermediate dose-dense FEC regimens. Patients were randomised to six cycles of FEC(75) or FEC(90), with all three drugs given on day 1 of each 14-day cycle. Patients also received pegfilgrastim 6 mg as a single subcutaneous injection on day 2 of each cycle. The primary efficacy endpoint was the proportion of subjects receiving > or =85% relative dose intensity and was achieved by 96% and 88% of patients in the FEC(75) and FEC(90) arms, respectively. Of 147 FEC(75) infusions, 4.1% were delayed, while 9.8% of 143 FEC(90) infusions were delayed. The most common reasons for delay were adverse events and personal/logistical reasons. One dose reduction occurred during the study (FEC(90)), related to diarrhoea. Grade 3-4 haematological toxicities were reported in two patients in the FEC(90) arm. There were no incidences of febrile neutropenia during the study. The most common adverse events were increases in liver enzymes and gastrointestinal events; no event resulted in discontinuation. Only one patient (FEC(90)) experienced serious adverse events (vomiting and throat oedema). In conclusion, dose-dense FEC(75 )and FEC(90) are feasible with pegfilgrastim support. These regimens are associated with a very low risk of Grade 3-4 toxicity.


Subject(s)
Breast Neoplasms/therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Adjuvant/methods , Cyclophosphamide/therapeutic use , Dose-Response Relationship, Drug , Epirubicin/therapeutic use , Female , Filgrastim , Fluorouracil/therapeutic use , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Medical Oncology/methods , Middle Aged , Polyethylene Glycols , Recombinant Proteins , Treatment Outcome
5.
Lung Cancer ; 52(2): 155-63, 2006 May.
Article in English | MEDLINE | ID: mdl-16569462

ABSTRACT

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/therapeutic use , Deoxycytidine/analogs & derivatives , Immunosuppressive Agents/therapeutic use , Lung Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Deoxycytidine/therapeutic use , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Immunosuppressive Agents/administration & dosage , Injections, Intravenous , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Male , Middle Aged , Retrospective Studies , Ribonucleotide Reductases/antagonists & inhibitors , Survival Rate , Treatment Outcome , Gemcitabine
6.
J Clin Oncol ; 23(7): 1401-8, 2005 Mar 01.
Article in English | MEDLINE | ID: mdl-15735116

ABSTRACT

BACKGROUND: The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel (GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles. RESULTS: Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm. CONCLUSION: No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Cyclophosphamide/therapeutic use , Deoxycytidine/therapeutic use , Epirubicin/therapeutic use , Fluorouracil/therapeutic use , Taxoids/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/toxicity , Breast Neoplasms/mortality , Cyclophosphamide/toxicity , Deoxycytidine/analogs & derivatives , Deoxycytidine/toxicity , Epirubicin/toxicity , Female , Fluorouracil/toxicity , Humans , Middle Aged , Paclitaxel/administration & dosage , Taxoids/toxicity
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