Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gemcitabine (Gemzar) and paclitaxel show good activity as single agents and combined in metastatic breast cancer, and the combination of paclitaxel/trastuzumab (Herceptin) has been shown to prolong time to disease progression and survival significantly in this setting. Preclinical data indicate additive or synergistic effects of gemcitabine and trastuzumab in HER2-positive human breast cancer cell lines. In a phase II trial, patients with HER2-overexpressing metastatic breast cancer who had received no prior chemotherapy for metastatic disease received gemcitabine at 1,200 mg/m2 on days 1 and 8 and paclitaxel at 175 mg/m2 on day 1 every 21 days for six cycles plus trastuzumab at an initial loading dose of 4 mg/kg followed by 2 mg/kg weekly; patients without progressive disease after six cycles continued to receive trastuzumab until disease progression. Overall, objective response was observed in 28 (67%) of 42 evaluable patients, including complete response in 4 (10%) and partial response in 24 (57%); stable disease was observed in 7 (17%) and progressive disease was observed in 6 (14%). Median time to treatment failure was 9+ months. Median overall survival has not yet been reached, but is estimated at approximately 27 months. Significant toxicities apart from neutropenia were uncommon. The triplet combination of gemcitabine, paclitaxel, and trastuzumab is highly active and well tolerated in patients with HER2-overexpressing metastatic breast cancer.
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PMID:Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer. 1476 3

In patients with advanced breast cancer, treatment with paclitaxel and doxorubicin has been shown to produce impressive overall response rates (up to 94%) and to prolong overall survival significantly over a combination of fluorouracil (5-FU), doxorubicin, and cyclophosphamide (Cytoxan, Neosar) in one prospective phase III clinical study. These results have been challenged, however, by other data demonstrating no survival advantage for taxane-based therapies. In addition, the combination of paclitaxel and doxorubicin has repeatedly been shown to be complicated by the development of treatment-related congestive heart failure, when cumulative doxorubicin doses exceed 300-360 mg/m2. Consequently, attempts have been made to increase the complete remission rate and overall survival resulting from first-line treatment of metastatic breast cancer without compromising patient safety. Gemcitabine (Gemzar)--a relatively effective, well-tolerated and partially non-cross-resistant antitumor compound with limited toxicity--represents an attractive alternative to paclitaxel/anthracycline combinations. Initial studies of combination therapy with gemcitabine and paclitaxel have produced an average response rate of 52%, with time to progression ranging between 7.0 and 14.5 months. Three-drug regimens containing gemcitabine, an anthracycline, and paclitaxel have been tested in phase II studies and have produced impressive response rates of 82.9% with gemcitabine, doxorubicin, and paclitaxel and 92% with gemcitabine, epirubicin (Ellence), and paclitaxel (GET). The Central European Cooperative Oncology Group has evaluated the GET regimen vs a regimen containing 5-FU, epirubicin, and cyclophosphamide (FEC) in a randomized, prospective phase III study. Interim toxicity analysis showed that the GET regimen was well tolerated but produced more grade 4 neutropenia (64% vs 42%, P = .084) and significantly more grade 4 thrombocytopenia (12% vs 0%; P < .001) than FEC. Anaphylactic/allergic reactions, peripheral polyneuropathy, nausea, and cardiotoxicity constituted rare events and did not exceed grade 1 or 2 in severity. Although final data from this phase III trial are not yet available, preliminary analysis suggests the GET regimen represents an attractive option for patients with advanced breast cancer.
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PMID:Gemcitabine, anthracycline, and taxane combinations for advanced breast cancer. 1476 4

Single-agent gemcitabine (Gemzar) is the standard of chemotherapy for advanced pancreatic cancer, with no phase III trials to date having shown significantly improved survival with gemcitabine-based combinations vs single-agent treatment. The multitargeted antifolate agent pemetrexed (Alimta) shows synergistic effects in vitro in combination with gemcitabine, and activity and good tolerability when used as single-agent treatment in advanced pancreatic cancer. In a phase II trial in patients with advanced pancreatic cancer, the combination of gemcitabine at 1,250 mg/m2 on days 1 and 8 plus pemetrexed at 500 mg/m2 on day 8 after gemcitabine every 21 days resulted in a median survival of 6.5 months and a 1-year survival rate of 29%. Neutropenia was the primary toxicity, with grade 4 toxicity in 51% of patients. The promising results of this trial prompted the initiation of a phase III trial comparing gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every 28 days vs the 21-day gemcitabine/pemetrexed regimen given with vitamin supplementation in patients with pancreatic cancer. The primary outcome measure was overall survival, with secondary measures including response rate, progression-free survival, and quality of life. While an increase in response and time to progression was reported for the gemcitabine/pemetrexed combination, there were no significant differences in survival between treatment arms.
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PMID:Pemetrexed in pancreatic cancer. 1565 36

Pemetrexed (Alimta) is active in a variety of solid tumors, including breast and gynecologic cancers. Phase II trials of pemetrexed at a dose of 600 mg/m2 without vitamin B12 and folic acid supplementation in largely pretreated metastatic breast cancer patients demonstrated objective response rates of 21% and 28%, with generally manageable neutropenia constituting the primary toxicity. In phase II trials using 500 mg/m2 with or without vitamin supplementation in anthracycline- and taxane-pretreated patients, response rates were lower (approximately 9%) and treatment was generally well tolerated irrespective of vitamin supplementation status. A phase II trial is currently comparing pemetrexed doses of 600 and 900 mg/m2 with vitamin B12 supplementation in patients with previously untreated advanced breast cancer. In a phase II trial in patients with advanced cervical cancer, pemetrexed at 600 mg/m2 without vitamin supplementation and 500 mg/m2 with supplementation produced similar response rates, with the frequency of neutropenia being somewhat lower among patients receiving the lower dose and vitamin supplementation. Preliminary results in an ongoing phase II trial indicate activity of the regimen of gemcitabine (Gemzar) at 1,000 mg/m2 plus pemetrexed at 500 mg/m2 with vitamin supplementation in patients with ovarian cancer. Ongoing and future studies will establish optimal dosing regimens of pemetrexed and potential benefits of vitamin supplementation in the settings of metastatic breast cancer and gynecologic malignancies.
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PMID:Phase II studies of pemetrexed in metastatic breast and gynecologic cancers. 1565 40

Gemcitabine (Gemzar) and paclitaxel are active drugs in the treatment of metastatic breast cancer. Phase I clinical trials data have suggested that the gemcitabine plus paclitaxel combination is safe in breast cancer patients. Two doses/administration schedules have been preferred in subsequent phase II and III trials: gemcitabine on days 1 and 8 plus a taxane on day 1, every 3 weeks; or gemcitabine plus a taxane on days 1 and 14, every 4 weeks. In phase II trials, 114 of 221 patients (52%) responded to gemcitabine/paclitaxel therapy. Response rates were lower among patients who received previous chemotherapy for metastatic disease (response rates: 45%, second line and 70%, first line). Toxicity of gemcitabine/paclitaxel regimens has generally been low, with few cases of neutropenia or nonhematologic toxicity. Results of the randomized phase III registration trial show a clear advantage for gemcitabine plus paclitaxel over paclitaxel alone in time to disease progression, objective response, and overall survival. Triplet combinations, in which an anthracycline is added to gemcitabine/paclitaxel, are being explored in the metastatic and neoadjuvant settings.
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PMID:Gemcitabine and paclitaxel in metastatic breast cancer: a review. 1568 19

Use of the gemcitabine (Gemzar) plus docetaxel (Taxotere) combination in metastatic breast cancer is motivated by the different mechanisms of action of the drugs, partially nonoverlapping toxicity profiles, and good single-agent activities of both drugs in treatment-naive and anthracycline-pretreated patients. In phase II trials, combinations of gemcitabine at 900 or 1,000 mg/m2 on days 1 and 8 and docetaxel at 75 to 100 mg/m2 on either day 1 or day 8 every 3 weeks, or gemcitabine at 800 mg/m2 on days 1, 8, and 15 and docetaxel at 35 mg/m2 on days 1, 8, and 15 or 100 mg/m2 on day 1 every 4 weeks, have produced response rates of 36% to 79% in patients receiving primarily second-line treatment; response rates were greater than 50% in five of six studies. In phase II trials using every-2-week regimens of gemcitabine at 1,500 or 2,000 mg/m2 on day 1 and docetaxel at 50 or 65 mg/m2 on day 1 or 55 mg/m2 on day 8, response rates were 50% in pretreated patients and 66% in treatment-naive patients. Neutropenia is the primary toxicity of the combination; in phase II studies performed with or without growth factor support, rates of grade 3/4 neutropenia ranged from 29% to 79% and rates of febrile neutropenia ranged from 0% to 18%. An ongoing phase III trial is comparing gemcitabine at 1,000 mg/m2 on days 1 and 8 plus docetaxel at 75 mg/m2 on day 1 every 21 days, vs capecitabine at 1,000 mg/m2 twice daily for 14 days plus docetaxel at 75 mg/m2 on day 1 every 21 days in patients with metastatic breast cancer. Results of this trial will help to determine optimal use of taxane-based combinations in patients with advanced disease.
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PMID:Gemcitabine and docetaxel in metastatic breast cancer. 1568 20

Primary systemic therapy (ie, preoperative or neoadjuvant) increases the possibility for breast-conserving surgery in patients with primary breast cancer. Patients with pathologic complete response to primary systemic therapy have improved survival compared with those with persistent tumors. Several phase II trials have evaluated gemcitabine-containing doublet or triplet regimens as primary systemic therapy for breast cancer, results of which have shown promising clinical and pathologic response rates with manageable toxicity. Results of a phase I/II study of gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), or GEDoc, with prophylactic filgrastim (Neupogen), as primary systemic therapy in 77 evaluable patients with primary breast cancer are reported herein. Dose-limiting toxicities were grade 3 febrile neutropenia (n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level of GEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at 90 mg/m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed by ultrasound, 92% of patients responded overall (22% complete response), and 79% of patients could undergo breast-conserving surgery. The pathologic complete response rate in resected breast tissue was 26%.
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PMID:Neoadjuvant therapy with gemcitabine in breast cancer. 1568 23

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.
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PMID:The evolving role of pemetrexed (Alimta) in lung cancer. 1581 33


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