UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
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Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and etoposide are two chemotherapy agents with broad cytotoxic activity but different mechanisms of action and resistance. Previous in vitro studies of their combined cytotoxicity have yielded conflicting results. We evaluated the effects of drug scheduling in cell growth inhibition in lung and breast human cancer cell lines. A clonogenic assay with either simultaneous or sequential 24-hour incubation of paclitaxel and etoposide was used to assess growth inhibition, and the combination index was used to evaluate drug interactions. In these studies, including the A549 human lung cancer cell line, mild antagonism (combination index, > 1) was observed with concurrent exposure of paclitaxel and etoposide, but synergism (combination index, < 1) was observed when the drugs were incubated sequentially. In view of the wide range of antitumor activity of both paclitaxel and etoposide, and the potential importance and clinical impact of optimizing drug doses and schedules, we recently completed a phase I study with the following objectives: (1) to determine the maximum tolerated dose of paclitaxel given intravenously on day 10 after 10 days of oral etoposide and (2) to investigate the toxicity profile of this combination of agents. Three consecutive cohorts consisting of a total of 29 patients with various measurable or assessable tumors were treated with paclitaxel by intravenous infusion over 3 hours after receiving 10 days of etoposide 50 mg orally twice daily. Conclusions for this clinical study were that the combination was feasible and tolerable and had demonstrated antitumor activity in a group of mostly pretreated patients. The recommended doses for phase II studies were etoposide 50 mg twice daily for 10 days followed by paclitaxel 150 mg/m2 intravenously over 3 hours. A phase II study in patients with extensive small cell lung cancer, with appropriate translational studies, has been initiated.
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PMID:Combinations of paclitaxel and etoposide in the treatment of lung cancer. 899 93

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a new cytotoxic chemotherapeutic agent with a novel mechanism of action. Single-agent paclitaxel studies have shown promising activity in both small cell and non-small cell lung cancers. In non-small cell lung cancer, response rates of 22% to 26% and 1-year survival rates of 40% were reported with both 3-hour and 24-hour infusions of paclitaxel. In small cell lung cancer, 24-hour infusions produced response rates of 61%. These data indicate that paclitaxel is one of the most active agents for all lung cancer patients. Combination studies demonstrated that paclitaxel could be combined with either cisplatin or carboplatin at full doses using either a 3-hour or a 24-hour infusion schedule. Response rates with these combinations have been high, usually 40% to 50%, which are higher than with any of the drugs used alone. Neutropenia is the most frequent toxicity and occurs less frequently with the 3-hour infusion. Thrombocytopenia occurred less frequently than expected. One completed randomized study showed that the paclitaxel/cisplatin regimen was superior to the etoposide/cisplatin regimen with respect to response rate and survival. Additional randomized studies are necessary to determine whether the combinations are superior to single-agent paclitaxel, to define the optimal dose with the 3-hour infusion schedule, to define the optimal schedule (3 hours v 24 hours), and to determine whether paclitaxel can be combined with other new agents.
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PMID:The North American experience with paclitaxel combined with cisplatin or carboplatin in lung cancer. 900 16

In preparation for the design of phase II studies in lung cancer, low-dose carboplatin, fixed at a target area under the concentration-time curve (AUC) of 4.0 or 4.5 mg x min/mL, has been combined with escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in a series of studies to establish the maximum tolerated dose of the combination. In patients who had received prior chemotherapy, the maximum tolerated paclitaxel dose was 135 mg/m2 (carboplatin target AUC 4.0); the dose-limiting toxicity was febrile neutropenia. Without granulocyte colony-stimulating factor support in chemotherapy-naive patients (carboplatin target AUC 4.5), and with granulocyte colony-stimulating factor in chemotherapy-pretreated patients, the current paclitaxel dose is 290 mg/m2. The maximum tolerated dose has not been defined. In a study in which paclitaxel was given by 1-hour infusion with carboplatin (target AUC 4.5), a 205 mg/m2 dose was poorly tolerated. No evidence of pharmacokinetic interactions between paclitaxel and carboplatin was found. Twenty-one evaluable patients with lung cancer have been treated to date. There have been two partial responses, one minor response, and 10 patients with stable disease at paclitaxel doses of 100 to 270 mg/m2.
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PMID:Early phase studies with paclitaxel/low-dose carboplatin in patients with solid tumors. 900 17

In 1995, a randomized intergroup study of neoadjuvant chemotherapy followed by either surgery or radiotherapy in the treatment of non-small cell lung cancer was started under the auspices of the European Organization for Research and Treatment of Cancer (EORTC 08941). The objective of this study is to investigate whether surgery or radiotherapy represents superior locoregional treatment, in terms of survival and quality of life, for patients with stage IIIA(N2) non-small cell lung cancer who have achieved a response after three courses of neoadjuvant chemotherapy. A phase II side study will investigate the clinical and pathologic response rate (if applicable), as well as acute and late side effects during or after consecutive surgery and/or radiotherapy of combination paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and carboplatin. It is planned that paclitaxel 175 mg/m2 will be given as a 3-hour infusion, followed by a 30-minute infusion of carboplatin at a dose based on a target area under the concentration-time curve of 6 mg x min/mL. This phase II study was started in October 1996. Depending on the response rate and early and late side effects observed in this well-defined, prognostically favorable group of patients, it will be decided whether and how to use the same combination chemotherapy in an ongoing randomized trial currently being conducted by the Dutch Lung Cancer Study Group (DLCSG 94-2). In the latter trial, patients with stage I and II non-small cell lung cancer are randomized to immediate surgery or two courses of neoadjuvant chemotherapy. Responding patients will receive another two courses of chemotherapy before surgery; nonresponders will go directly to surgery.
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PMID:Paclitaxel and carboplatin as neoadjuvant chemotherapy in operable (stage I and II) and locally advanced (stage IIIA-N2) non-small cell lung cancer. 900 24

Lung cancer remains a major epidemic problem worldwide. The majority of cases are associated with cigarette smoking and the number of people who smoke continues to increase. As a result, the number of lung cancer cases and deaths is expected to increase proportionately over the next decade. The majority of patients who develop lung cancer die of this disease. Non-small cell lung cancer (NSCLC) accounts for 75% of all new cases. The only hope for significant survival depends on surgical resection. At the time of initial presentation, unfortunately, the vast majority of patients are inoperable, either because of advanced disease or because of the presence of comorbid medical conditions such as coronary artery disease. For these reasons, the overall survival rates for patients with NSCLC range from 10% to 15%, figures that have not improved substantially for 20 years. The role of systemic chemotherapy in this population remains debatable for many physicians. Nevertheless, recent studies clearly demonstrate that effective systemic chemotherapy in selected patients can improve survival, quality of life, and performance status. Recently, newer cytotoxic agents, such as vinorelbine, gemcitabine, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), docetaxel, and the camptothecins, have demonstrated their activity in treating patients with NSCLC. When combined with other effective agents, response rates exceeding 50% have been achieved, with median survivals of more than 1 year. The use of these newer agents in combination with well-established agents holds promise for the role of systemic chemotherapy in the future management of patients with early or late-stage NSCLC.
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PMID:Chemotherapy in the management of patients with inoperable non-small cell lung cancer. 900 27

The acquisition of drug-resistant tumour cells is the main problem in the medical treatment of a range of malignant diseases. In recent years, three new classes of anti-cancer agents, each with a novel mechanism of action, have been brought forward to clinical trials. These are the topoisomerase I (topo I) poisons topotecan and irinotecan, which are both camptothecin derivatives, the taxane tubulin stabilizers taxol and taxotere and, finally, the antimetabolite gemcitabin, which is active in solid tumours. The process of optimizing their use in a combination with established agents is very complex, with numerous possible drug and schedule regimens. We describe here how a broad panel of drug-resistant small-cell lung cancer (SCLC) cell lines can be used as a model of tumour heterogeneity to aid in the selection of non-cross-resistant regimens. We have selected low-fold (3-10x) drug-resistant sublines from a classic (NCI-H69) and a variant (OC-NYH) SCLC cell line. The resistant cell lines include two sublines with different phenotypes towards alkylating agents (H69/BCNU and NYH/CIS), two sublines with different phenotypes against topo I poisons (NYH/CAM and NYH/TPT) and three multidrug resistant (MDR) sublines (H69/DAU, NYH/VM, and H69/VP) with combinations of mdr1 and MRP overexpression as well as topoisomerase II (topo II) down-regulation or mutation. Sensitivity to 20 established and new agents was measured in a standardized clonogenic assay. Resistance was highly drug specific. Thus, none of the cell lines was resistant to all drugs. In fact, all resistant cell lines exhibited patterns of collateral sensitivity to various different classes of drugs. The most intriguing pattern was collateral sensitivity to gemcitabin in two cell lines and to ara-C in five drug-resistant cell lines, i.e. in all lines except the lines resistant to topo I poisons. Next, all sensitivity patterns in the nine cell lines were compared by correlation analysis. A high correlation coefficient (CC) for a given pair of compounds indicates a similar pattern in response in the set of cell lines. Such data corroborate the view that there is cross-resistance among the drugs. A numerically low coefficient indicates that the two drugs are acting in different ways, suggesting a lack of cross-resistance between the drugs, and a negative correlation coefficient implies that two drugs exhibit collateral sensitivity. The most negative CCs (%) to the new drug leads were: taxotere-carmustine (BCNU) (-75), taxol-cisplatin (-58), ara-C-taxol (-25), gemcitabin-doxorubicin (-32), camptotecin-VM26 (-41) and topotecan-VP16 (-17). The most negative correlations to the clinically important agent VP-16 were: cisplatin (-70); BCNU (-68); camptothecin (-38); bleomycin (-33), gemcitabin (-32); ara-C (-21); topotecan (-17); melphalan (-3); and to the other main drug in SCLC treatment cisplatin were: doxorubicin (-70); VP-16 (-70); VM-26 (-69); mAMSA (-64); taxotere (-58); taxol (-58). Taxol and taxotere were highly correlated (cross-resistant) to VP-16 (0.76 and 0.81 respectively) and inversely correlated to cisplatin (both -0.58). Similarly, camptothecin and topotecan were correlated to cisplatin but inversely correlated to VP-16 and other topo II poisons. From the sensitivity data, we conclude that collateral sensitivity and lack of cross-resistance favours a cisplatin-taxane or topo I-topo II poison combination, whereas patterns of cross-resistance suggest that epipodophyllotoxin-taxane or topo I poison-cisplatin combinations may be disadvantageous.
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PMID:In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabin. 906 9

To determine the optimal combination of commonly used anticancer agents with 7-ethyl-10-hydroxy-camptothecin (SN-38), an active metabolite of 7-ethyl-10-[4(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11), for chemotherapy of lung cancer, we studied the effects of SN-38 in combination with six representative anticancer agents on the human small cell lung cancer (SCLC) cell line, NCl N417, and the non-small cell lung cancer (NSCLC) cell line, PC-9. The anticancer activity was evaluated by MTT assay and the effects of drug combinations on ID50 were analyzed by an improved isobologram method. In the SCLC cell line, supra-additive effect was observed for SN-38 in combination with cisplatin, etoposide (VP-16) and paclitaxel (Taxol). An additive effect was observed for its combination with bleomycin. Sub-additive and protective effects were found in combination with adriamycin (ADR) and 5-fluorouracil (5-FU). In the NSCLC cell line, supra-additive and marginal supra-additive effects were found for SN-38 in combination with VP-16, ADR, 5-FU and bleomycin. The others showed additive effects with SN-38. No drug showed sub-additive and protective effects with SN-38. These results suggest that all the drugs we selected can be used with SN-38 simultaneously for NSCLC, while for SCLC, cisplatin, VP-16 and Taxol are the most suitable for combination with SN-38.
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PMID:Effect of CPT-11 in combination with other anticancer agents in lung cancer cells. 909 27

The management of patients with non-small-cell lung cancer (NSCLC) is still evolving. Newer third-generation chemotherapy (paclitaxel [Taxol]-based; vinorelbine [Navelbine]/ cisplatin [Platinol]) is more effective than second-generation cisplatin-based chemotherapy for patients with stage IIIB and IV disease. The combined use of cisplatin-based chemotherapy with sequential or concurrent radiation therapy has improved the survival of patients with unresectable stage IIIA disease. Neoadjuvant cisplatin-based chemotherapy has improved the survival of patients with resectable stage IIIA disease compared to surgery alone. Combined-modality therapy is a fertile area of innovative clinical investigations for the majority of stage III resectable and potentially curable NSCLC patients, as well as those with locally advanced unresectable stage III disease. We expect therapy to substantially improve over the next few years. Cooperative groups should move quickly to incorporate third-generation chemotherapy into large randomized trials in order to redefine the standard of therapy for patients with this disease.
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PMID:Multidisciplinary approach to potentially curable non-small cell carcinoma of the lung. 911 51

A total of 332 patients with advanced non-small-cell lung cancer were randomized by the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC) to receive one of two cisplatin (Platinol)-based chemotherapy regimens: Paclitaxel (Taxol) 175 mg/m2 given by 3-hour infusion followed by cisplatin 80 mg/m2 on day 1; Or cisplatin 80 mg/m2 on day 1, followed by teniposide (Vumon) 100 mg/m2 given on days 1, 3, and 5. Cycles were repeated every 3 weeks. Preliminary analysis of the results of this phase III trial shows that hematologic toxicity was decidedly more severe in the group treated with cisplatin/teniposide than in those given paclitaxel/cisplatin. Of 264 patients evaluable so far, responses have been observed in 47% of those given paclitaxel and in 29% of those treated with teniposide. However, extramural radiologic response evaluation is still under way, so these figures are expected to change somewhat. It appears clear that the paclitaxel-based therapy affords a benefit in terms of response and toxicity, but survival results are premature and any definite conclusions await final analysis.
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PMID:Cisplatin/paclitaxel vs cisplatin/teniposide for advanced non-small-cell lung cancer. The EORTC Lung Cancer Cooperative Group. The European Organization for Research and Treatment of Cancer. 914 84

The treatment of non-small-cell lung cancer (NSCLC) has recently undergone major changes due to the availability of new drugs that demonstrate substantial activity in NSCLC patients. Although cure for the majority of stage III NSCLC and effectively all stage IV disease patients remains rare, a number of compounds, including carboplatin, paclitaxel, docetaxel, irinotecan, and vinorelbine, have proved useful in the treatment of these patients. Together with a number of phase II trials, phase I trials utilizing escalating doses of carboplatin and paclitaxel with growth factor or growth factor and blood stem-cell support have shown that substantial increases in dose intensity can be achieved. These studies in small numbers of patients have demonstrated that these regimens have encouraging activity and have formed the basis of a Cancer and Leukemia Group B (CALGB) phase II pilot study. This study will utilize two cycles of high-dose carboplatin and Taxol given at an AUC dose of 18 and a 24-h infusion dose of 250 mg/m2, respectively, with growth factor and stem-cell support to treat stage III NSCLC patients. Patients will also receive multimodality therapy, including radiation with or without surgery. It is hoped that this effort to intensify treatment in patients with limited-stage disease will improve survival and benefit the large number of patients with stage III tumors. This paper outlines the phase I results that formed the basis of the CALGB trial and reviews several recent reports of phase II or phase III trials of single-agent and combination regimens for NSCLC.
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PMID:High-dose carboplatin plus paclitaxel with granulocyte colony-stimulating factor and peripheral blood stem-cell support in non-small-cell lung cancer. 927 39

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