13 research outputs found
Phase I-II study of docetaxel and ifosfamide combination in patients with anthracycline pretreated advanced breast cancer
Given the established individual activity of docetaxel and ifosfamide in
anthracycline pretreated advanced breast cancer, the present phase I-II
study aimed to define the maximum tolerated dose (MTD), the
dose-limiting toxicities (DLTs), and activity of the
docetaxel-ifosfamide combination in this setting. Cohorts of three to
six patients with histologically confirmed metastatic breast cancer
after prior anthracycline-based chemotherapy were treated at successive
dose levels (DLs) with escalated doses of docetaxel 70-100 mg m(-2) over
1 h on day 1 followed by ifosfamide 5-6 g m(-2) divided over days I and
2 (2.5-3.0 g m(-2) day(-1) over 1 h), and recycled every 21 days. G-CSF
was added once dose-limiting neutropenia was encountered at a certain DL
and planned to be incorporated prophylactically in subsequent higher
DLs. In total, 56 patients with a median age of 54.5 (range, 32-72)
years and performance status (WHO) of I (range, 0-2) were treated at
five DLs as follows: 21 in phase I DLs (DL I : 3, DL2: 6, DL3: 3, DL4:
6, and DL5: 3) and the remaining 35 were treated at DL4 (total of 41
patients at DL4), which was defined as the level for phase II testing.
All patients were assessable for toxicity and 53 for response.
Dose-limiting toxicity (with the addition of G-CSF after DL2) was
reached at DL5 with two out of three initial patients developing febrile
neutropenia (FN). Clinical response rates, on an intention-to-treat
basis, in phase II were: 53.6% (95% CI, 38.3-68.9%); three complete
remissions, 19 partial remissions, seven stable disease, and 12
progressive disease. The median response duration was 7 months (3-24
months), median time to progression 6.5 month (0.1-26 month), and median
overall survival 13 months (0.1-33 months). Grade 3/4 toxicities
included time to progression neutropenia in 78% of patients-with 63%
developing grade 4 neutropenia (less than or equal to7 days) and in 12%
of these FN, while no grade 3/4 thrombocytopenia was observed. Other
toxicities included peripheral neuropathy grade 2 only in 12%, grade
1/2 reversible CNS toxicity in 17%, no renal toxicity, grade 2 myalgias
in 10%, grade 3 diarrhoea in 10%, skin/nail toxicity in 17%, and
grade 2 fluid retention in 2% of patients. One patient in the study
treated at phase II died as a result of acute liver failure after the
first cycle. In conclusion, the present phase I-II study determined the
feasibility of the docetaxel-ifosfamide combination, defined the MTD and
demonstrated the encouraging activity of the regimen in phase II, thus
warranting further randomised phase III comparisons to single-agent
docetaxel or combinations of the latter with other active agents. (C)
2003 Cancer Research UK
Amifostine, in a reduced dose, protects against severe diarrhea associated with weekly fluorouracil and folinic acid chemotherapy in advanced colorectal cancer: A pilot study
Fifty-two consecutive patients with advanced colorectal cancer who developed persistent diarrhea following chemotherapy with 5-fluorouracil despite dose reduction were treated with amifostine 800, 500 or 150 mg/m 2. The administered dose of 5-fluorouracil was significantly greater during amifostine treatment. Amifostine 800 mg/m2 was associated with complete elimination of diarrhea, but 76.3% of patients developed infusion-related hypotension. At a dose of 500 mg/m2, diarrhea was significantly reduced and milder compared with baseline and the incidence of hypotension was 54.2%. At the lowest dose of amifostine, 17.1% of patients developed Grade 1 diarrhea, a significant reduction over baseline, and hypotension occurred in 25.2% of patients. Treatment with amifostine also improved mucositis but had no effect on the relatively mild nausea and vomiting due to 5-fluorouracil. In this study, amifostine reduced the incidence and severity of diarrhea associated with 5-fluorouracil in patients with advanced colorectal cancer, with acceptable efficacy at a reduced dose that offered better tolerability. © 2003 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved
Gemcitabine and docetaxel as second-line chemotherapy for patients with nonsmall cell lung carcinoma who fail prior paclitaxel plus platinum-based regimens
Background. Treatment options for patients with recurrent nonsmall cell
lung carcinoma (NSCLC) remain limited as a result of poor activity of
older agents after platinum-based therapy. In the current Phase II
study, the authors evaluated the combination of gemcitabine and
docetaxel in patients with recurrent NSCLC.
Methods. Patients with advanced NSCLC (Stage IIIB-IV) a World Health
Organization performance status (PS)less than or equal to2, prior
paclitaxel plus platinum-based chemotherapy, and unimpaired
hematopoietic and organ function were eligible. Chemotherapy was
administered as follows: gemcitabine 1000 mg/m(2) was administered on
Days 1 and 8 followed by docetaxel 100 mg/m(2) on Day 8, and this
regimen was recycled every 21 days. Prophylactic granulocyte-colony
stimulating factor was administer ed on Days 10-14 or until the patient
achieved a white blood cell count greater than or equal to 5000/muL.
Results. Of 43 patients who were entered on the study, 41 patients were
evaluable for response, and all were evaluable for toxicity. The median
patient age was 63 years (range, 47-70 years), the median PS was 1
(range, 0-2), there were 38 male patients, and there were 5 female
patients. Four patients had Stage IIIA disease, 17 patients had Stage
IIIB disease, and 22 patients had Stage IV disease. Histologies included
19 patients with adenocarcinoma, 18 patients with squamous cell
carcinoma, and 3 patients with large cell carcinoma. Metastatic sites
included lymph nodes in 28 patients, bone in 6 patients, liver in 5
patients, brain in 5 patients, lung nodules in 8 patients, adrenals in 7
patients, and other sites in 3 patients. All patients had received prior
paclitaxel plus platinum-based treatment; 28 patients had received prior
paclitaxel, ifosfamide, and cisplatin. Objective responses were partial
response (PR) in 14 of 43 patients [33%; 95% confidence interval
[95%CI], 18.5-46.6%], stable disease (SD) in 16 of 43 patients
(37%; 95% CI, 22.8-51.6%), and progressive disease (PD) in 13 of 43
patients (30%; 95% CI, 16.3-43.7%). The median time to disease
progression was 6 months (range, 1.0-20.0+ months), and the median
survival was 8.5 months (range, 1.5-20.0+ months). The 1-year survival
rate was 28%. Grade 3-4 neutropenia was experienced by 53% of patients
(30% Grade 4), with 14% of patients experiencing febrile neutropenia.
Grade 3 thrombocytopenia was experienced by 7% of patients (no Grade
4), whereas other Grade 3 nonhematologic toxicities were never
encountered.
Conclusions. The combination of gemcitabine and docetaxel is active and
is well tolerated in patients with advanced NSCLC who have failed prior
taxane plus platinum chemotherapy. This regimen represents a tolerable
and effective combination to apply in the palliative treatment of
patients with recurrent NSCLC. Cancer 2001;92:2902-10. (C) 2001 American
Cancer Society
A phase II study of the docetaxel-carboplatin chemotherapy regimen in advanced non-small-cell lung cancer
The efficacy of the docetaxel-carboplatin combination chemotherapy was
studied in various phase II studies. Based on these data we aimed to
test the regimen in previously untreated patients with advanced advanced
non-stroking lung cancer (NSCLC) with docetaxel 80 mg/m(2) a standard
dose of carboplatin at AUC = 5, in an attempt to define the efficacy and
tolerability of the combination in an open-label phase II study.
Patients with histologically confirmed advanced NSCLC stage IIIB and IV
were candidates for the present study. Docetaxel was administered at 80
mg/m(2) over 1 h by intravenous (IV) infusion followed by carboplatin
AUC = 5 in 30 min IV infusion, both on day 1, and recycled every 21
days. Sixty patients received 263 courses of therapy in total; 231/263
(88%) were administered according to the planned doses, and 48/60
(80%) patients received chemotherapy without decrement of the dose;
32/263 (12%) of the courses were administered with a 10%-30% dose
reduction. Complete responses (CR) were seen in 5 patients (8.3%) and
partial responses (PR) in 16 patients (26.7%) for an overall response
rate of 35%. Median duration of response was 7.5 months [95%
confidence interval (CI)-7.1-7.9], time to progression (TIP) 11.5 months
(95% CI-8.2-14.8), median overall survival (OS) 15.0 months (95%
CI-10.8-19.2). One-year survival was 61.7%. Toxicity was acceptable; it
was calculated according to the administered cycles and was mainly
neutropenia: grade 3, 9% and grade 4, 2%; anemia: grade 3, 8%; nausea
and vomiting: grade 3, 8%. The outpatient regimen of
docetaxel-carboplatin is effective with acceptable toxicity in patients
with advanced NSCLC
Gastrointestinal stress as innate defence against microbial attack.
A comparison of the metabolic response of Escherichia coli BL21 (DE3) towards the production of human basic fibroblast growth factor (hFGF-2) or towards carbon overfeeding revealed similarities which point to constraints in anabolic pathways. Contrary to expectations, neither energy generation (e.g., ATP) nor provision of precursor molecules for nucleotides (e.g., uracil) and amino acids (e.g., pyruvate, glutamate) limit host cell and plasmid-encoded functions. Growth inhibition is assumed to occur when hampered anabolic capacities do not match with the ongoing and overwhelming carbon catabolism. Excessive carbon uptake leads to by-product secretion, for example, pyruvate, acetate, glutamate, and energy spillage, for example, accumulation and degradation of adenine nucleotides with concomitant accumulation of extracellular hypoxanthine. The cellular response towards compromised anabolic capacities involves downregulation of cAMP formation, presumably responsible for subsequently better-controlled glucose uptake and resultant accumulation of glucose in the culture medium. Growth inhibition is neglectable under conditions of reduced carbon availability when hampered anabolic capacities also match with catabolic carbon processing. The growth inhibitory effect with accompanying energy spillage, respectively, hypoxanthine secretion and cessation of cAMP formation is not unique to the production of hFGF-2 but observed during the production of other proteins and also during overexpression of genes without transcript translation
A phase I-II study of docetaxel-ifosfamide-cisplatin (DIP) combination chemotherapy regimen in advanced nonsmall cell lung cancer
In an attempt to develop more effective chemotherapy regimens in
advanced nonsmall cell lung cancer (NSCLC), we evaluated
docetaxel-ifosfamide-cisplatin (DIP) based on our previous experience
with paclitaxel-ifosfamide-cisplatin. Patients with advanced NSCLC
(stages III-IV), WHO-PSless than or equal to2, no prior chemotherapy and
unimpaired hematopoietic and organ function were eligible. Chemotherapy
was administered in successive dose levels (DLs) and included docetaxel
(80100 rng/m(2) day 1), ifosfamide (4-5 g/m(2)) and cisplatin (80100
mg/m(2)), both divided over days I and 2 every 21 days. G-CSF
(lenograstin) was administered from days 4-13. Fifty-five patients were
accrued (phase 1: IS; phase II: 40) and all are evaluable for response
and toxicity: median age = 58 (40-72); PS = 1 (0-2); gender = 48 males,
7 females; stages IIIA = 8, 11113 = 19, IV = 28; and histologies were
adenocarcinoma (29), squamous (20), large cell (6). Metastatic sites at
diagnosis included lymph nodes (33), bone (8), liver (6) brain (6), lung
nodules (9), adrenals (7) and soft tissue (1). The dose-limiting
toxicity (DLT) was reached at DL4 (Docetaxel: 100 mg/m(2)-Ifosfamide: 5
g/m(2)-Cisplatin: 100 mg/m(2)) consisting of 2 cases of febrile
neutropenia (FN), and DL3 (Docetaxel: 100 mg/m(2)-Ifosfamide: S
g/m(2)-Cisplatin: 80 mg/m2) was considered as the maximum tolerated dose
(MTD) and recommended for further phase 11 testing. Among evaluable
patients in phase 11, 31146 (67%; Cl = 54-81%) responded; 4 were
complete responses, 27 partial responses, 12 with stable disease and 3
with progressive disease. The median response duration was 7 months
(2-21 +), median time to progression (TTP) 8 months (1-23 +) and median
overall survival (OS) 13 months (2-23 +). The 1-year survival was 57%.
Grade (Gr) 314 toxicities included neutropenia 39146 with 27 developing
Gr4 ( less than or equal to7 days) and 20% FN managed successfully with
broad-spectrum antibiotics, thrombacytopenia Gr3 3/46-Gr4 1/46, no Gr3
neuropathy, Gr1-2 CNS toxicity in 12, no renal toxicity, IS Gr2
myalgias, 17 Gr2 diarrhea and 10 Gr3 vomiting. In the present phase I-II
study, DIP appears highly active and tolerable in advanced NSCLC in the
outpatient setting. Randomized comparisons to current standard 2-drug
regimens will be warranted. (C) 2002 Wiley-Liss, Inc
Leucovorin+5-fluorouracil plus dipyridamole in leucovorin+5-fluorouracil-pretreated patients with advanced colorectal cancer: A pilot study of three different dipyridamole regimens
Dipyridamole, an inhibitor of nucleoside transport, increases the
activity of 5-fluorouracil in a dose-dependent manner. The purpose of
the present study was to determine whether dipyridamole with
5-fluorouracil and leucovorin gave an improved therapeutic outcome.
Sixty patients entered in the present pilot study had previously
received 5-ftuorouracil (450 mg/m(2)) and leucovorin (100 mg/m(2)),
every week, and relapsed during this treatment, which ended at least 6
weeks prior to study entry. Dipyridamole was administered at three
different dosing schedules (DS) and methods of administration in three
groups of patients. DS I: dipyridamole, 30 mg/m(2) in normal saline
solution, in 90 min iv infusion, followed by leucovorin, 100 mg/m(2) iv
push, followed by 5-fluorouracil, 450 mg/m(2) in normal saline solution,
in 60 min iv infusion, dipyridamole tablets (75 mg) every 12 hrs,
continuously during the time of chemotherapy. DS II: dipyridamole, 50
mg/m(2) in normal saline solution, in 90 min iv infusion, and the rest
was the same as DS I. DS III: without oral dipyridamole, patients
received dipyridamole (50 mg/m(2)) iv in the same manner as in DS I and
II. Treatment was continued until tumor progression or unacceptable
toxicity. All patients (n = 60) entered in the present study were
assessable for response and toxicity. No complete response was observed.
No patient at DS I responded, whereas 2 patients at DS II and 3 at DS
III had a partial response (P <0.1). Stable disease was found with DS I
(n = 1), DS II (n = 8) and DS III (n = 9) (P <0.01). More patients
progressed at DS I (n = 19) than at DS (n =10) and DS III (n = 8) (P
<0.0007). The median duration of response was 11 weeks (range, 8-16).
Time to progression was 17 weeks for DS I, 15 weeks (range, 10-19) for
DS II, and 14 weeks (range, 11-21) for DS III (P = 0.43). Median
survival did not differ significantly between DS I (29 weeks; range,
14-48), DS II (31.5 weeks; range, 17-63) and DS III (36 weeks; range,
16-58) (P = 0.2). Neutropenia was most severe with DS I (grade 2, P
<0.01) and DS II (grade 1, P <0.05) and nausea/vomiting with DS I (grade
0, P <0.0005, grade 1, P <0.0002, grade 2, P <0.02) and DS III (grade 3,
P <0.0009). Diarrhea was most severe in DS 11 (grade 3, P <0.005).
Mucositis was increased in DS II (grade 0, P <0.008), anorexia in DS II
(grade 0, P <0.032) and fatigue in DS I (grade 0, P <0.003). More
patients in DS I than with the other two DS experienced headache (P
<0.044). According to the response achieved at DS III (15% partial
response and 45% stable disease) and the toxicity which was well
tolerated mainly in this DS (except for nausea and vomiting grade 3, P
<0.009), it can be stated that DS III is the appropriate dose and the
simplest schedule of administration (administration of dipyridamole
during therapy only). In conclusion, it appears that dipyridamole might
still have a role in enhancing the clinical activity of drugs involved
in the inhibition of the thymidylate synthetase biochemical pathway and
its activity in combination with these agents (5-fluorouracil +
leucovorin) as frontline treatment should therefore be explored in
future phase II studies
Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study
Purpose. To evaluate the efficacy and safety of irinotecan as
second-line treatment in patients with advanced colorectal cancer (ACC)
failing or relapsing after 5-fluorouracil (5-FU) plus leucovorin (LV)
standard chemotherapy. <LF>Patients and methods. Irinotecan was randomly
administered in two different schedules (once every 3 weeks, and every
10 days) in patients failing prior 5-FU plus LV. Patients were
randomized to two treatment groups: group A received irinotecan 350
mg/m(2) every 21 days and group B received irinotecan 175 mg/m(2) days 1
and 10 every 21 days. Results. Group A comprised 60 patients: 34 male/26
female, median age 64 years (range 48-70 years), and median Karnofsky
performance status (PS) 90. Their metastatic sites included liver
(n=47), lymph nodes (n=27), lung (n=14), abdomen (n=14), pelvis (n=8),
‘other’ (n=2), and local recurrence (n=12). Group B comprised 60
patients: 36 male/24 female, median age 62 years (46-70 years), and
median PS 90. Their metastatic sites included liver (n=49), lymph nodes
(n=29), lung (n=17), abdomen (n=16), pelvis (n=11), ‘other’ (n=2), and
local recurrence (n=13). Group A showed the following responses:
complete response (CR) 2, partial response (PR) 12, stable disease (SD)
21, progressive disease (PD) 26, overall response rate (ORR) 23%, tumor
growth control 58%. Group B showed the following responses: CR 1, PR
14, SD 22, PD 23; ORR 25%; tumor growth control 62%. Toxicities
included acute cholinergic syndrome (group A 53%, group B 19%;
P<0.0001), late-onset diarrhea grade 1/2 (group A 21%, group B 46%)
and grade 3/4 (group A 41%, group B 66%; P<0.0001), nausea and
vomiting grade 1/2 (group A 34%, group B 59%) and grade 3/4 (group A
30%, group B 12%; P<0.0001), neutropenia grade 3/4 (group A 27%,
group B 28%; P<0.03), with febrile neutropenia seen in only four
patients in group A, anemia grade more than 2 (group A 28%, group B
12%; P<0.05), asthenia grade more than 3 (group A 24%, group B 18%;
P<0.001), and alopecia grade more than 3 (group A 40%, group B 34%;
P<0.2). Conclusions. The present study indicates that, in patients with
ACC who have relapsed after 5-FU plus LV, the administration of
irinotecan fractionated into two doses every 21 days yields a similar
efficacy to, but a much lower incidence of toxicity than, the same total
dose of irinotecan administered once every 21 days