Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to determine the maximally tolerated dose of doxorubicin administered during two cycles of intensive chemotherapy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac toxicity of the regimen by noninvasive radionuclide imaging and by pre-and postchemotherapy endomyocardial biopsies. Thirty-eight patients (thirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4.2 g/m2) administered over 2 h on day 5 and escalating doses of doxorubicin (50-175 mg/m2) given as a 96-h continuous i.v. infusion on days 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretreatment, and 28 patients underwent postchemotherapy endomyocardial biopsies. Twenty-nine of 38 patients received two cycles of treatment (median number of days between cycles, 44; range, 34-62). Twenty-one patients had received doxorubicin previously at cumulative dose levels </=150 mg/m2; all patients had pretreatment endomyocardial biopsy scores less than 1. One patient treated at the highest dose level of doxorubicin (175 mg/m2) developed symptoms of mild congestive heart failure following two cycles of chemotherapy. Pre- and posttreatment radionuclide ejection fractions were 65 and 45%, respectively; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose level had an asymptomatic biopsy score of 1, with a decrease in ejection fraction from 62 to 43%; this recovered to 58% 5 months after completion of chemotherapy. Six additional patients treated at lower dose levels had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycle of chemotherapy: five patients due to decreased cardiac ejection fraction following cycle 1 (two of these patients had normal endomyocardial biopsies, and two patients had biopsy scores of 1); one patient secondary to tumor progression following cycle one; one patient due to persistently detectable Clostridium difficile toxin in the stool; one patient refused cycle two; and one patient died following cycle one of complications related to sepsis. A single patient experienced a grand mal seizure associated with orthostatic hypotension, which was considered the dose-limiting toxicity. The median duration (over two cycles) of granulocytopenia (absolute granulocyte count <500/microliter) at the maximally tolerated dose level of 150 mg/m2 was 8.5 days (range, 5-13 days), and the median duration of thrombocytopenia (platelets <20,000/microliter) was 2.5 days (range, 0-9 days). The median duration of hospitalization including chemotherapy administration was 23 days (range, 19-36 days). Other toxicities included stomatitis, fever, diarrhea, and emesis. One patient developed acute leukemia 54 months posttreatment. We conclude that two courses of high-dose cyclophosphamide and doxorubicin using granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial biopsies. The dose-limiting toxicity encountered was a grand mal seizure. The recommended Phase II dose is doxorubicin 150 mg/m2 administered as a 96-h infusion on days 1-4, with cyclophosphamide 4. 2 g/m2 on day 5 and G-CSF 5 microgram/kg/day started on day 6 and administered until the total WBC is above 10,000/microliter for three consecutive days.
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PMID:High-dose infusional doxorubicin and cyclophosphamide: a feasibility study of tandem high-dose chemotherapy cycles without stem cell support. 981 32

We evaluated the pharmacokinetics of 5-fluorouracil (5-FU) combined with recombinant human interferon (IFN)-alpha 2a in 10 previously untreated patients with advanced colorectal carcinoma. 5-FU was administered as a continuous i.v. infusion, 750 mg/m2/day for 5 days during week 1. One s.c. injection of IFN-alpha 2a, 9 x 10(6) IU, was administered during week 2. Beginning with week 3, a continuous i.v. infusion of 5-FU 750 mg/m2/day for 5 days was administered in combination with IFN-alpha 2a, 9 x 10(6) IU s.c. three times per week. The combination of 5-FU and IFN-alpha 2a was continued every other week until either 3 months after complete remission or tumor progression. No grade 4 toxicity was observed. Granulocytopenia (two patients), leukopenia (one patient), thrombocytopenia (one patient), stomatitis (two patients), fatigue (one patient) and hand-foot syndrome (one patient) were the major (grade 3) toxic reactions encountered. Overall, one complete and six partial responses were noted. The results of the paired t-test showed no statistically significant differences between the means of the two treatments, 5-FU and 5-FU plus IFN-alpha 2a, with respect to the steady-state plasma concentration, area under the concentration-time curve, total body clearance, or steady-state volume of distribution of 5-FU, or the serum concentration of IFN. We conclude that 5-FU and IFN-alpha 2a do not interact pharmacokinetically at the doses and schedules in the regimen studied.
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PMID:Pharmacokinetics of recombinant human interferon-alpha 2a combined with 5-fluorouracil in patients with advanced colorectal carcinoma. 982 27

Hemostatic disorders are frequently observed in patients with malignancy with a significant proportion developing thrombotic and/or hemorrhagic complications including disseminated intravascular coagulation (DIC), deep venous thrombosis (DVT), and thrombocytopenia. Together, these abnormalities are the second most common cause of mortality in cancer patients, which has led many investigators to try to unravel the pathogenesis of thromboembolic disease, in the eventuality that this will lead to novel therapeutic treatments. The plasminogen activation system is one pathway that has been consistently implicated in cancer. Its relevance to cancer extends from being responsible for many of the hemorrhagic episodes that occur in cancer patients to being fundamental to many, if not all of the molecular mechanisms that define tumor progression. Recent developments of clinical significance shall be reviewed with respect to the role of the plasminogen activation system in tumor growth and metastasis dissemination and in the thrombophilic state in the cancer patient.
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PMID:The role of the plasminogen activation system in cancer. 1035 86

A phase II trial was conducted with mitoxantrone (12 mg/m2, day 1), vinorelbine (30 mg/m2, day 1), and carboplatin (250 mg/m2, day 2) every 21 days. Fifty eligible women who had not received prior chemotherapy for metastatic breast cancer (MBC) entered the study. Objective responses were observed in 28 patients (56%; 95% confidence interval: 42.4-69.74%), with 4 complete (8%) and 24 partial responses (48%). Stable disease was observed in 12 patients (24%) and disease progression in 10 (20%). Responses were documented in all involved sites. The median duration of response was 6 months and the median time to tumor progression 8 months. The median survival was 26 months and the estimated 2-year survival was 52%. Grade 3/4 neutropenia was observed in 29 patients (58%) with four neutropenic episodes. Grade 3/4 anemia and thrombocytopenia was observed in 7 (14%) and 11 (22%) patients, respectively. Other toxicities included grade 2/3 nausea and vomiting in 26 patients (52%) and grade 1/2 alopecia in 38 (76%). Grade 1/2 neurosensory toxicity occurred in four patients (8%). In conclusion, this three-drug regimen is effective and well tolerated for the treatment of MBC.
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PMID:First-line treatment of metastatic breast cancer with mitoxantrone, vinorelbine, and carboplatin. 1059 40

Efficiency of chemotherapy (CT) on non removable HGG has not been proven and neoadjuvant brain irradiation (RT) following biopsy is the standard treatment. We aimed to define whether combination of polychemotherapy and radiotherapy is synergistic in non removable HGG. It has been proven that F, CDDP and VP16 can reach therapeutic levels in brain after intravenous standard dose injections. The aim of this study was to assess that (i) neoadjuvant CT is safe; (ii) feasibility and efficacions of F (100 mg/m2.d1)/CDDP (100 mg/m2.d1-3 TD)/VP16 (75 mg/m2.d1-3) q21-28d regimen; (iii) Delayed RT is not unsafe: RT was performed when tumor progression or toxicity appeared. This study included 16 patients with symptomatic non removable HGG. Two of them had anaplastic gliomas and 14 glioblastomas multiforme. None of them had a prior chemotherapy regimen. Objective response was evaluated with CT scan or MRI during chemotherapy. Toxicity was moderate and mainly hematological (grade III-IV thrombopenia = 10/67 cycles; leukopenia = 13/67). Objective response rates were 5/16 (31 p. 100) (CR = 1; PR = 4; Median duration of response: 20 weeks). Median survival was 55 weeks in the 14 grade IV patients. Three/16 patients are still alived with respectively 22, 30, 40 months survival: These results confirm the neoadjuvant chemotherapy efficacy. It may be a useful tool before RT for non removable HGG.
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PMID:[Chemotherapy of malignant inoperable gliomas. The association of fotemustine-cisplatine-etoposide as neoadjuvants]. 1069 59

The efficacy of autologous peripheral stem cells given as mobilized whole blood or leukapheresis product for hematopoietic rescue after intensive chemotherapy was studied in 34 consecutive female patients with high-risk breast cancer. All patients received six cycles of chemotherapy regimen EC (epirubicin 150 mg/m2 and cyclophosphamide 1250 mg/m2) at 14-day intervals. In the first cycle, chemotherapy was given on day 1, and 24 h later mobilization of PBPC was started with G-CSF at a dose of 5 microg/kg/day for 13 days. In all other cycles, G-CSF was given at the same dose from day 7. On days 11, 12, and 13, leukaphereses were performed, and whole blood was collected on day 14 (the peak incidence of colony-forming units-granulocyte-macrophage [CFU-GM] burst-forming units-erythrocyte [BFU-E], and colony-forming unit-granulocyte-erythrocyte-macrophage-megakaryocyte [CFU-GEMM]). The second cycle of chemotherapy was started on day 15, and 24 h later, whole blood (collected in the first cycle) was reinfused, and the same was done in the third cycle. In the fourth to sixth chemotherapy cycles, leukapheresis product was used for hematopoietic rescue. The median increment of absolute values in both whole blood and leukapheresis product was as follows: CD34+ cells over baseline was approximately 17.4-fold, CFU-GM was 85.3-fold, BFU-E was 95.9-fold, and CFU-GEMM was 44.2-fold. In the cycles with whole blood support, the mean values of applied progenitors per cycle were CD34+ cells 1.52 x 10(6)/kg, CFU-GM, 1.18 x 10(5)/kg, BFU-E 2.54 x 10(5)/kg, CFU-GEMM 0.31 x 10(5)/kg. In the courses with PBPC support, the mean values of progenitors were CD34+ 2.04 x 10(6)/kg, CFU-GM 1.59 x 10(5)/kg, BFU-E 2.87 x 10(5)/kg, and CFU-GEMM 0.34 x 10(5)/kg. Leukopenia in patients supported with whole blood versus leukapheresed PBPC was as follows: grade 4, 13/6 (38.2%/17.6%), grade 3, 19/23 (55.9%/70.6%), and grade 2, 1/4 (2.9%/11.8%), respectively. Thrombocytopenia was grade 4, 11/6 (32.4%/17.6%), grade 3, 10/7 (29.4%/20.6%), grade 2, 7/13 (20.6%/38.2%), and grade 1, 6/6 (17.6%/17.6%), respectively. The median follow-up analysis was at 24.6 (7-36) months. High-risk patients previously treated with surgery and adjuvant chemotherapy (n = 5) were not evaluated for response. In 21 patients with locally advanced or inflammatory breast carcinoma the response rate (RR) was 94%, CR was 90%, and PR was 15%. No response to therapy was observed in 1 patient. In 8 patients with metastatic disease, RR was 75%, there was no CR, and PR was 75%. Two patients died during therapy. Relapse-free survival (RFS) in the adjuvant group was 23.7 (range 12-36) months and in the group with locally advanced disease was 18.2 (range 7-27) months. In the group with metastatic disease, time to tumor progression (TTP) was 12.1 (range 1-16) months. Mean duration of hospital stay for whole blood reinfusion in the second and third chemotherapy cycles was 6.7 (range 5-8) days and for PBPC in the fourth to sixth cycles was 6.2 (range 4-8) days, which at p < 0.001 was not statistically significant.
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PMID:Application of whole blood and peripheral blood progenitor cells (PBPC) and new strategies for rescue after intensive cyclic chemotherapy in high-risk breast cancer. 1073 69

In antibody-directed enzyme prodrug therapy, an enzyme conjugated to an antitumor antibody is given i.v. and localizes in the tumor. A prodrug is then given, which is converted to a cytotoxic drug selectively in the tumor. Ten patients with colorectal carcinoma expressing carcinoembryonic antigen received antibody-directed enzyme prodrug therapy with A5B7 F(ab')2 antibody to carcinoembryonic antigen conjugated to carboxypeptidase G2 (CPG2). A galactosylated antibody directed against the active site of CPG2 (SB43-gal) was given to clear and inactivate circulating enzyme. A benzoic acid mustard-glutamate prodrug was given when plasma enzyme levels had fallen to a predetermined safe level, and this was converted by CPG2 in the tumor into a cytotoxic form. Enzyme levels derived from quantitative gamma camera imaging and from direct measurements in plasma and tumor biopsies showed that the median tumor:plasma ratio of enzyme exceeded 10000:1 at the time of prodrug administration. Enzyme concentrations in the tumor (median, 0.47 units g(-1)) were sufficient to generate cytotoxic levels of active drug. The concentration of prodrug needed for optimal conversion (Km) of 3 microM was achieved. Prodrug conversion to drug was shown by finding detectable levels of drug in plasma. There was evidence of tumor response; one patient had a partial response, and six patients had stable disease for a median of 4 months after previous tumor progression (one of these six had a tumor marker response). Manageable neutropenia and thrombocytopenia occurred. Conditions for effective antitumor therapy were met, and there was evidence of tumor response in colorectal cancer.
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PMID:Antibody-directed enzyme prodrug therapy: efficacy and mechanism of action in colorectal carcinoma. 1074 95

The combination of weekly irinotecan (CPT-11) and monthly cisplatin has shown promising activity in advanced non-small cell lung cancer (NSCLC) in previous Phase I and II studies. However, same-day administration of these agents may better exploit their therapeutic synergy and minimize toxicities. This multicenter Phase II study was undertaken to evaluate the efficacy and safety of a combination of weekly CPT-11 and weekly cisplatin in patients with advanced NSCLC. Patients with chemotherapy-naive stage IIIB or IV NSCLC were treated with repeated cycles of therapy comprising weekly treatment with both cisplatin and CPT-11 for 4 weeks, followed by a 2-week rest. The starting doses of CPT-11 and cisplatin were 65 and 30 mg/m2, respectively. Treatment was continued until the occurrence of disease progression, unacceptable toxicity, or a maximum of six cycles. Fifty patients were enrolled. The median age was 59 years (range, 44-79 years). Eastern Cooperative Oncology Group performance status was 0 in 22 patients, 1 in 19 patients, and 2 in 9 patients. Seven and 43 patients had stages IIIB and IV disease, respectively. Five patients had brain metastasis. Patients received a median of three 6-week cycles (range, 1-6). The objective response rate was 36% (18 of 50; 95% confidence interval, 24-54%) and included 18 partial responses. Median time to tumor progression was 6.9 months (range, 0.6-15.2). The median survival was 11.6 months (range, 0.16-21.9 months), and the 1-year survival rate was 46%. Grade 3/4 nonhematological toxicities included vomiting (12%) and diarrhea (26%). Grade 3/4 hematological toxicities included anemia (14%), neutropenia (26%), and thrombocytopenia (14%). Relative dose intensities for CPT-11 and cisplatin were 89 and 62%, respectively. Weekly combined administration of CPT-11 and cisplatin achieved a promising overall response rate, median time to tumor progression, and median survival in patients with stage IIIB/IV NSCLC. The regimen was well tolerated, and the planned dose intensity was well maintained. Further evaluation of this combination in NSCLC is warranted.
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PMID:Weekly irinotecan and cisplatin in advanced non-small cell lung cancer: a multicenter phase II study. 1120 20

Thirty-nine patients with advanced non-small cell lung cancer, refractory or resistant to platinum or taxanes derivatives were treated on an out-patient basis with vinorelbine 25 mg/m2 intravenous (I.V.) on days 1 and 8 followed by gemcitabine 800 mg/m2 l.V. on days 1 and 8. Chemotherapy was repeated every 3 weeks. The patients were evaluated for response every two cycles of treatment. All 39 patients were assessable for toxicity and 35 were assessable for response. On an intent to treat analysis, only 1 (2.6%) patient achieved a partial response (PR) (95% CI 0.09% to 17.6%); fourteen patients (35.9%, 95% CI 29.45% to 67.4%) had stable disease (SD) and 24 (61.5%) had progressive disease (PD). The median time to tumor progression (TTP) was 4.7 months (range 0.13 to 18.9 months), the median survival time was 7.3 months (range 0.6 to 18.9 months) and the 1-year survival rate was 35%. Clinical benefit response including improvement of PS, dyspnea and anorexia, pain and cough reduction and cessation of hemoptysis and fever was observed in 10% to 50% of patients. Grade 3/4 neutropenia occurred only in 2 (5.2%) patients. Five patients experienced febrile neutropenia, which was successfully treated with G-CSF and broad-spectrum antibiotics. No patient experienced grade 3/4 anaemia or thrombocytopenia. One patient experienced grade 4 fatigue and stopped the treatment. Nausea / vomiting, fatigue, neurotoxicity, diarrhea and fever were mild in the majority of patients and did not result in any clinically significant problem. There were no treatment-related deaths. In conclusion, the combination of gemcitabine and vinorelbine showed low objective response rate in patients previously treated with CDDP/taxanes-containing regimens. This regimen was relatively well-tolerated and was associated with prolonged 1-year survival and improvement in cancer related symptoms. To validate these findings a randomized trial of gemcitabine and vinorelbine versus taxotere or best supportive care is required.
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PMID:An out-patient second-line chemotherapy with gemcitabine and vinorelbine in patients with non-small cell lung cancer previously treated with cisplatin-based chemotherapy. A phase II study of the Hellenic co-operative Oncology Group. 1171 2

The study compares docetaxel plus cisplatin (DC) and docetaxel plus gemcitabine (DG) regimens for the treatment of advanced non-small cell lung cancer (NSCLC). Patients were randomized to receive either the DC or the DG combination. They were stratified according to age, performance status (PS) and stage of disease. Three hundred seventeen patients entered the study. Of them, 162 received the DC regimen and 155 the DG regimen. There were no differences in the patients' characteristics between the two study arms. Preliminary analysis included 132 evaluable patients in the DC arm and 114 in the DG arm. Three complete responses (CR) (2.3%) and 39 partial responses (PR) (30%) were documented in the DC arm (response rate (RR) 32.3%; 95% CI 23.87-39.76%), whereas 1 CR (0.9%) and 38 PR (33%) were documented in the DG arm (RR: 33.9%; 95% CI 25.5-42.92%). No differences in the RR, response duration, time to tumor progression, overall survival and 1-year survival were observed between the two groups. Regarding toxicity, there were no significant differences in grade 3-4 anaemia and thrombocytopenia between the two arms. However, grade 3-4 neutropenia occurred in 40 patients (33%) treated with the DC regimen and in 31 patients (22%) treated with the DG regimen (P=0.01). Twenty-four (16%) patients in the DC arm and 20 (14%) in the DG arm developed febrile neutropenia. There was one death due to sepsis in each arm. Non-haematological toxicity was mild and equal in the two arms, with the exception of grade 3-4 nausea and diarrhoea, which were more frequent in the DC arm. In conclusion, preliminary results showed that the DG regimen was as effective as the DC regimen. The toxicity profile of the DG combination was relatively milder. Hence, cisplatin cannot be considered longer as a mandatory component of chemotherapy against NSCLC.
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PMID:Comparison of docetaxel/cisplatin to docetaxel/gemcitabine as first-line treatment of advanced non-small cell lung cancer: early results of a randomized trial. 1174 2


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