Gene/Protein Disease Symptom Drug Enzyme Compound
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Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered by a 3-hour infusion causes a rapid decline to and recovery from the hematologic white blood cell nadir. This suggests that biweekly administration of paclitaxel alone or in combination with drugs that have limited hematologic toxicity may be possible. The first study discussed in this report tried to determine the tolerability and activity of biweekly paclitaxel administered in combination with cisplatin in patients with metastatic breast cancer. Subsequently, after an impressive response rate, a second study of biweekly paclitaxel alone was initiated to attempt to discern which activity spectrum and which toxicities were due to paclitaxel and which were due to cisplatin. Patients with metastatic breast cancer who received up to one prior adjuvant chemotherapy regimen were eligible for both studies. Paclitaxel was administered intravenously by a 3-hour infusion followed by intravenous cisplatin biweekly in the ambulatory setting. In the second study, paclitaxel was administered alone. Twenty-nine patients have been entered in the combination study, of whom 27 had received prior adjuvant therapy and 23 had received prior anthracyclines. Dose-limiting toxicity for the phase I study of paclitaxel and cisplatin proved to be a failure to recover neutrophil counts greater than 750 cells/microL by day 14. The maximum tolerated dose was paclitaxel 90 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Nonhematologic toxicities were mild and included fatigue, arthralgias, and nausea and vomiting. At this time, the 27 patients evaluable for response have achieved an 85% response rate and an 11% complete response rate. Complete responses have been seen in soft tissue, lung, and nodal disease. All patients with complete responses have had previous anthracyclines. The biweekly paclitaxel-alone study is still accruing patients. The current paclitaxel dose level is 150 mg/m2. It is still too early to evaluate response; however, response rates appear to be less impressive than those seen with combined paclitaxel/cisplatin. The final results of these studies are pending.
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PMID:Biweekly paclitaxel in the treatment of patients with metastatic breast cancer. 748 53

Based on the superior response rates (21% to 24%) of patients treated with single-agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in Eastern Cooperative Oncology Group and M.D. Anderson Cancer Center trials in non-small cell lung cancer (NSCLC) and on the superior 1-year survival rates of NSCLC patients treated with carboplatin in a randomized study of cisplatin combination and analogues, we initiated a phase II trial of paclitaxel/carboplatin in patients with stage IV or effusion-positive stage III NSCLC. Eligibility stipulated chemotherapy-naive patients with measurable disease, good performance status, and adequate hematologic, hepatic, and renal function. Previous radiotherapy was restricted to < or = 30% of marrow-bearing bone. Paclitaxel was initially given at 135 mg/m2 over 24 hours followed by carboplatin dosed to a targeted area under the concentration versus time curve (AUC) of 7.5, with treatment repeated at 3-week intervals for six cycles. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, with the paclitaxel dose sequentially escalated in 40 mg/m2 increments to a maximum dose of 215 mg/m2 in patients with less than grade 4 granulocytopenia and less than grade 3 thrombocytopenia. Of 54 patients enrolled, 30 currently are evaluable for response, 23 for toxicity. Myelosuppression has been the principal toxicity, with grade 3 or 4 granulocytopenia occurring in 70% of patients after the first cycle. After the introduction of granulocyte colony-stimulating factor, granulocytopenia decreased to 37% during the second cycle and then consistently to 20% or lower during subsequent cycles. Only 22% of cycles have been delayed for 1 week or more. Neutropenic fever has occurred in five (5%) of 100 evaluable cycles. Other grade 3 or 4 toxicities include thrombocytopenia (13%), anemia (9%), fatigue (9%), and hemorrhagic cystitis (1%). The paclitaxel dose was boosted to 215 mg/m2 in 12 (70%) of 17 patients by cycle 3 or 4. At an AUC of 7.5, the median first-cycle carboplatin dose was 434 mg/m2 (range, 293 to 709 mg/m2). The objective response rate is 50%, with three complete, 12 partial, and five minor responses. We conclude that the paclitaxel/carboplatin combination is active in advanced NSCLC and, with AUC-based dosing of carboplatin, can be given at 3-week intervals. Although dose limiting at a paclitaxel dose of 135 mg/m2, granulocytopenia can be reduced substantially with granulocyte colony-stimulating factor, allowing sequential dose escalation of paclitaxel to 175 mg/m2 and 215 mg/m2 in 70% of patients receiving three or more cycles.
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PMID:Paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer. 754 Nov 56

A phase II trial of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin included 54 chemotherapy-naive patients with advanced non-small cell lung cancer. Eligibility mandated Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate hematologic, renal, and hepatic function. Paclitaxel 135 mg/m2 over 24 hours preceded carboplatin dosed to an area under the concentration-time curve of 7.5. Six planned courses were given every 3 weeks. Granulocyte colony-stimulating factor was introduced during the second and subsequent cycles, and paclitaxel increased 40 mg/m2/cycle (maximum, 215 mg/m2) in patients with absolute neutrophil and platelet nadirs exceeding 500/microL and 50,000/microL, respectively. Grade 3 or 4 neutropenia, observed in 54% of patients during cycle 1, declined to 35% during cycle 2 and to 22% or less during cycles 3 through 6. Neuropathy, myalgias/arthralgias, and thrombocytopenia were mild but cumulative. In 53 evaluable patients, the objective response rate was 62%, with 9% complete remissions and a median response duration of 6 months (range, 1 to 19+ months). At median potential follow-up of 16 months, 9% of patients remain progression free (52+ to 80+ weeks). Median survival is 12.5 months; 1-year survival is 54%. Paclitaxel/carboplatin is highly active in advanced non-small cell lung cancer; granulocyte colony-stimulating factor abrogates neutropenia as the dose-limiting toxicity, but has no effect on the cumulative incidence of thrombocytopenia or treatment delays. One-hour paclitaxel infusion is minimally myelosuppressive, logistically easier, and less costly. A follow-up study combined paclitaxel (175 mg/m2) over 1 hour followed by carboplatin (area under the concentration-time curve, 7.5). In the absence of grade 4 myelosuppression, paclitaxel was increased 35 mg/m2/cycle (maximum, 280 mg/m2). Granulocyte colony-stimulating factor was implemented only after neutropenic fever or grade 4 neutropenia. Of 17 patients entered, 13 are evaluable for toxicity and seven for response. Four patients have sustained a partial response, two a minor response, and one stable disease. The incidence of grade 3 or 4 neutropenia, thrombocytopenia, and anemia in cycle 1 was 38%, 16%, and 0%, respectively, and 72%, 28%, and 28%, respectively, during cycle 2. Major nonhematologic toxicities include myalgias and arthralgias (54%) and fatigue and neuropathy (78%), the latter cumulative and progressive over successive cycles. Preliminary data suggest comparable activity for the 1- and 24 hour paclitaxel infusions in combination with carboplatin. The more severe neuropathy of the 1-hour paclitaxel/carboplatin combination may be related to the paclitaxel dosing schema (175 mg/m2 to as high as 280 mg/m2).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Paclitaxel by 24- or 1-hour infusion n combination with carboplatin in advanced non-small cell lung cancer: the Fox Chase Cancer Center experience. 754 25

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) administered in a 3-hour infusion exhibits both a rapid decline to, and recovery from, the hematologic nadir. This suggests that a biweekly administration schedule of this agent either alone or in combination with agents that have limited hematologic toxicity may be possible. The objective of this study was to determine the tolerability and activity of biweekly administered paclitaxel in combination with cisplatin in patients with metastatic breast cancer. Patients with metastatic breast cancer who may have received up to one prior chemotherapy regimen in the adjuvant setting were eligible. Paclitaxel was administered intravenously by a 3-hour infusion followed by intravenous cisplatin every 2 weeks in the ambulatory setting. Twenty-nine patients have been entered in the study, of whom 27 had received prior adjuvant chemotherapy. Dose-limiting toxicity for the phase I study proved to be failure to recover the neutrophil count to more than 750 cells/microL by day 15; the maximum tolerated dose was therefore paclitaxel 90 mg/m2 and cisplatin 60 mg/m2 every 2 weeks. Nonhematologic toxicities were mild and included fatigue, arthralgias, peripheral neuropathy, and nausea and vomiting. At the present analysis, 234 cycles of treatment have been given. Among 27 patients evaluable for response (four of whom are still receiving therapy), three have had complete remissions and 18 partial responses, for an interim overall response rate of 78%. In summary, weekly paclitaxel and cisplatin is a safe and active combination in the treatment of metastatic breast cancer. Final determination of toxicity and activity will be published at the conclusion of this study.
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PMID:Interim results of a phase I/II study of biweekly paclitaxel and cisplatin in patients with metastatic breast cancer. 763 39

Paclitaxel is an antimicrotubule agent that was recently approved by the Food and Drug Administration (FDA). Because it is insoluble in water, it is mixed with Cremophor EL (polyoxyethylated castor oil). The addition of Cremophor requires the use of glass bottles or polyolefin or polypropylene bags and polypropylene-lined tubings for the administration of paclitaxel. In addition, 0.22 micron in-line filters are necessary. The potential side effects of paclitaxel during its infusion include hypersensitivity reaction (HSR), cardiotoxicity, infiltration, diarrhea, and nausea, whereas myelosuppression, neurotoxicity, myalgias, arthralgias, alopecia, fatigue, headache, taste changes, and minor alterations in renal and liver function tests can occur after its administration. Premedications including an H2 blocker, a corticosteroid, and an antihistamine are necessary to minimize the occurrences of HSRs. Vital signs should be monitored throughout the infusion to assess for HSRs and cardiotoxicity. Paclitaxel has been shown to be safe in both the inpatient and outpatient settings. Nursing care includes the administration of the drug, the assessment and management of side effects, and psychosocial support of patients receiving the drug.
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PMID:Nursing implications in the administration of paclitaxel (TAXOL). 790 74

We tested paclitaxel (Taxol) and low dose hydroxyurea as second line therapy in 30 patients with non-small cell lung cancer since both drugs are active against non-small cell lung cancer in other settings, and since hydroxyurea may reverse chemotherapy resistance by disrupting double minute chromosomes. Hydroxyurea 500 mg was given orally each Monday, Wednesday, Friday starting 1 week before paclitaxel, and continuing until removal from study. Paclitaxel 135 mg/m2 was given i.v. over > or = 1 h every 3 weeks with dexamethasone, diphenhydramine, and ranitidine. Patients could have paclitaxel doses escalated to 175 mg/m2 in course 2 and to 200 mg/m2 in course 3, where tolerated. Sixteen males and 14 females were treated. All patients had previously received a single cisplatin-based chemotherapy regimen and 23 had previously received radiotherapy. Twelve patients had adenocarcinomas, six had squamous cell carcinomas, and 12 had large cell carcinomas. Eight patients had Stage IIIb cancers and 22 had Stage IV. Paclitaxel doses were 135 mg/m2 in 56 courses, 175 mg/m2 in 24, and 200 mg/m2 in 15. Treatment was well tolerated. Median granulocyte nadirs were 2.5 (x 10(9)/l) for paclitaxel 135 mg/m2, 1.8 for 175 mg/m2, and 1.3 for 200 mg/m2. No patient developed febrile neutropenia, and none required a dose reduction. Two patients had reversible anaphylaxis. Other toxicities were quite tolerable. They included fatigue, myalgias, dizziness, paresthesias, diarrhea, alopecia, mucositis, flushing, headache, swollen red hands, and anxiety. One patient had a partial remission and 15 had stable disease (including six with minor responses). Median survival was 20 (95% CI, 12-34) weeks, with 19% of patients remaining alive at 1 year from initiation of treatment. This is a well-tolerated regimen with modest activity as second line chemotherapy for patients with non-small cell lung cancer previously treated with cisplatin regimens. Higher doses would be feasible and other strategies are now being explored.
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PMID:Paclitaxel plus hydroxyurea as second line therapy for non-small cell lung cancer. 886 29

The aim of this study was to evaluate the efficacy of high-dose paclitaxel in patients with previously untreated stage IV epithelial ovarian cancer. Paclitaxel was administered intravenously over 3 h at a dose of 225 mg m(-2) on a 21-day cycle for six courses. Thirty-six patients were entered into this study; all 36 were assessed for toxicity and 33 patients were evaluable for response. One patient had a complete response and 12 patients had partial responses (overall response rate 39.4%, 95% CI 23-58%). The overall median duration of response was 9 months (range 3.5-23+ months). The response rate to carboplatin following failure of paclitaxel within 1 year of stopping therapy was 57% (four out of seven patients). The median survival of patients was 17.2 months. The main toxicity encountered was neutropenia which was WHO grade 3 in 11 patients (31%) and WHO grade 4 in seven patients (19%). Granulocyte colony-stimulating factor (GCSF) was not given to any patient during the study. Other toxicities were: grade 3/4 infection (11%) and nausea and vomiting (11%); grade 3 bone pain (22%), fatigue (14%), diarrhoea (3%), myalgia/arthralgia (3%) and dry eyes (3%). Transient peripheral neuropathy occurred in 16 patients (44%), and alopecia was encountered in most patients (grade 2/3, 78%). Paclitaxel given at 225 mg m(-2) to patients with stage IV epithelial ovarian cancer is active, well tolerated and does not require GCSF support.
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PMID:Single-agent paclitaxel in patients with previously untreated stage IV epithelial ovarian cancer. London Gynaecological Oncology and North Thames Gynaecological Oncology Groups. 904 29

This study was aimed to determine the activity and toxicity of combination paclitaxel and carboplatin in stage III B and IV NSCLC. Eligibililty required performance status. Paclitaxel was administered at a dose of 200 mg/m2, 3-hour infusion, followed by carboplatin at a tartgeted area under the concentration-time curve (AUC) of 6. Treatment was repeated at 3-week intervals for 6 courses. G-CSF 5 micrograms/kg was subcutaneously injected during subsequent courses if there was grade 3-4 leukopenia or granulocytopenia in the previous course. From August 1996 through June 1997, 15 patients were enrolled. The median age was 47 years (range 20-68 years), 60 per cent were female. 73.3 per cent had adenocarcinoma, and 66.7 per cent had stage III B disease. Eighty three courses were administered; 13 patients (86.7%) completed all six cycles. The objective response rate was 53.3 per cent, with 1 (6.7%) complete response and 7 (46.7%) partial responses. Pleural effusion, lung lesion and lymph node were the three most common sites that responded to chemotherapy. The major toxicity was myelosuppression. Grade 3 or 4 granulocytopenia, anemia and thrombocytopenia were observed in 18 per cent, 7.2 per cent and 1.2 per cent, respectively, of 83 courses administered. Four episodes of febrile neutropenia (4.8%) occurred in 3 patients. There was one episode of anaphylaxis during Paclitaxel infusion. Other common toxicities were mild myalgia, paresthesias, alopecia and fatigue. Most of the toxicities showed cumulative effect. Paclitaxel plus carboplatin is a moderately active regimen in advanced NSCLC. Toxicities of this regimen are well tolerated.
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PMID:Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer (NSCLC): a preliminary study. 980 67

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most commonly used agents in treating patients with locally advanced and metastatic non-small cell lung cancer (NSCLC). It is usually given once every 3 weeks. We have evaluated paclitaxel given once per week for 3 weeks every 4 weeks for patients with recurrent or metastatic NSCLC. Two consecutive studies using weekly paclitaxel were performed. The first study was a dose-escalation study with paclitaxel beginning at 50 mg/m(2) days 1, 8, and 15 every 4 weeks. Subsequent dose escalation was performed with 10 mg/m(2) increments per week. The second phase II study used paclitaxel at 80 mg/m(2) days 1, 8, and 15 every 4 weeks. The phase I study showed that the maximum tolerated dose was 90 mg/m(2)/wk for 3 weeks with 1 week off. The efficacy and side effects of both phase I and II were quite similar; therefore, the results were combined. Seventeen patients were in the phase I and 30 patients in the phase II study. The mean age was 72 years. Twenty-three patients had Eastern Cooperative Oncology Group performance status of 2 and 16 patients had received prior chemotherapy. One complete and 13 partial responses were observed with response duration ranging from 1 to 18+ months. Overall response rate was 30% (95% confidence interval, 18.5% to 42%). Overall median survival was 184 days. Grade 3/4 neutropenia was 8.5%, grade 3/4 infections was 6.4%, and grade 2 peripheral neuropathy was also 6.4%. Hyperglycemia with random blood sugar levels greater than 250 mg/dL was 6.4% and grade 3 fatigue was 4.3%. In general, treatment was well tolerated. In the best prognostic group of 16 patients without prior chemotherapy and with performance status 0 to 1, the response rate was 37.5% with a 1-year survival rate of 44% and median survival of 305 days. Prior chemotherapy, poor performance status, age higher than 70 years, and male gender carried a worse prognosis. In both phase I and II studies we observed limited myelosuppression, peripheral neuropathy, and constitutional symptoms. Weekly paclitaxel, delivered at our schedule, is an active and well-tolerated regimen. The role of weekly paclitaxel in NSCLC should be better defined in future randomized studies.
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PMID:Weekly paclitaxel in advanced non-small cell lung cancer. 1160 77

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate. Pharmacokinetic analysis showed an approximately 2-fold reduction of DNA-adduct formation in leucocytes compared with cisplatin without paclitaxel. No pharmacokinetic interaction was found between paclitaxel and cisplatin. After (re-)induction, additional chemotherapy consisted of conventional paclitaxel/cisplatin, paclitaxel/carboplatin, paclitaxel single agent or carboplatin/cyclophosphamide. The overall response rate was 94% in 17 evaluable chemotherapy-nai;ve patients and 84% in 25 patients with recurrent disease. Median progression-free survival (PFS) was 17 months (chemotherapy-nai;ve: 23 months, recurrent: 11 months) and median overall survival was 41 months (chemotherapy-nai;ve: 48 months, recurrent: 24 months). In conclusion, both cisplatin/paclitaxel regimens showed excellent activity with manageable toxicity in patients with advanced ovarian cancer.
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PMID:Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer. 1237 5


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