ABSTRACT
BACKGROUND: 13-Cis retinoic acid (13-CRA) is a synthetic vitamin A derivative. High-dose 13-CRA in patients with squamous cell cancers of the head and neck (SCCHNs) reduces the incidence of second primary tumors (SPTs). The authors report long-term results from a phase 3 randomized trial that compared treatment with low-dose 13-CRA versus placebo for patients who had early stage SCCHN, with a focus on the development of SPTs and overall survival (OS). METHODS: In total, 176 patients who received treatment for stage I/II SCCHN were randomized to receive either low-dose 13-CRA (weight-based dose of 7.5 mg or 10 mg) or placebo for 2 years. A competing-risk approach and the log-rank test were used to compare the time to SPT and OS, respectively, between groups. RESULTS: 13-CRA neither significantly reduced the cumulative incidence of SPT (P = .61) nor improved the time to SPT (hazard ratio [HR] for 13-CRA/placebo; 0.86; P = .61). Despite limited power, there was a trend toward improved OS for the 13-CRA arm (HR, 0.75; P = .14), particularly among patients whose index tumor was surgically excised (N = 26; HR, 0.50; P = .057) and among women (N = 39; HR, 0.44; P = .065) and never/former smokers (N = 129; HR, 0.61; P = .055), with a median follow-up of 16 years. The main 13-CRA related toxicities were dry skin and cheilitis. CONCLUSIONS: Treatment with low-dose 13-CRA for 2 years did not decrease the incidence of SPT; subset analysis indicates a potential survival advantage among patients who are women and never/former smokers. More targeted interventions based on clinical risk factors and molecular characterization of tumors may yield greater success in future prevention trials. Cancer 2017;123:4653-4662. © 2017 American Cancer Society.
Subject(s)
Carcinoma, Squamous Cell/prevention & control , Dermatologic Agents/therapeutic use , Head and Neck Neoplasms/pathology , Isotretinoin/therapeutic use , Neoplasms, Second Primary/prevention & control , Adult , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/secondary , Double-Blind Method , Female , Follow-Up Studies , Head and Neck Neoplasms/drug therapy , Humans , Male , Middle Aged , Neoplasm Staging , Neoplasms, Second Primary/epidemiology , Prognosis , United States/epidemiologyABSTRACT
Gefitinib (an epidermal growth factor receptor tyrosine kinase inhibitor) and bexarotene (a rexinoid) affect similar oncogenic pathways and are both metabolized through cytochrome P450 CYP3A4. We studied the combination of bexarotene and gefitinib in the third-line treatment of advanced non-small-cell lung cancer to examine pharmacokinetic interactions and establish the maximum tolerated dose. This was a single-institution, nonrandomized, open-label, phase I clinical trial with a standard 3+3 dose escalation. Three patients were enrolled at each dose level on the basis of pharmacokinetic analysis with dose level 1 including gefitinib (Iressa) 250 mg oral daily and bexarotene (Targretin) 400 mg/m oral daily and dose level +1 including gefitinib 500 mg oral daily and bexarotene 400 mg/m oral daily. Patients received gefitinib alone for 2 weeks to allow for steady state and thereafter, bexarotene was added. In dose level 1, two of three patients had undetectable gefitinib levels at day 15 for unknown reasons. However, the peak levels on day 29 for all three patients receiving 250 mg of gefitinib with bexarotene are lower than published peak levels. Among the three patients in dose level +1, â¼40% lower gefitinib plasma concentrations were noted on day 29 compared with day 15 along with a mean 44% reduction in area under the plasma concentration-time curve from 0 to 24 h (AUC0-24). Bexarotene appears to lower the C max and AUC0-24 of gefitinib through cytochrome P450 CYP3A4. Our results have pharmacokinetic implications for ongoing trials that combine bexarotene with other small molecules in the era of personalized cancer therapy.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Adult , Aged , Bexarotene , Cohort Studies , Female , Gefitinib , Humans , Male , Middle Aged , Quinazolines/administration & dosage , Quinazolines/pharmacokinetics , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/pharmacokinetics , Treatment OutcomeABSTRACT
PURPOSE: Preclinical data suggest that the synthetic retinoid bexarotene may be an effective chemopreventive agent and that it may act synergistically in combination with platinum-based chemotherapy. The primary objective of this study was to determine whether repeated doses of bexarotene capsules affect pharmacokinetic parameters of paclitaxel or carboplatin in patients with advanced non-small cell lung cancer. METHODS: Patients received treatment with paclitaxel (200 mg/m(2)) and carboplatin to provide a target AUC of 6 mg min/mL (day 1) every 3 weeks. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated on Day 4, and patients started lipid-lowering therapy prior to beginning chemotherapy. Blood sampling to characterize the pharmacokinetic profiles of the chemotherapeutic agents with or without bexarotene was performed during cycle 1 (without concomitant bexarotene) and during cycle 2 (with concomitant bexarotene). RESULTS: An analysis of drug concentration data from 16 patients indicated that bexarotene did not affect the pharmacokinetics of paclitaxel, free carboplatin, or total carboplatin concentrations. However, both maximal plasma concentrations and total exposure of bexarotene increased by 80% in the presence of paclitaxel-carboplatin by an, as of yet, unexplained mechanism. The toxicities observed resembled those of either the chemotherapy regimen or bexarotene alone, and there was no evidence for an enhancement of any drug-related toxicity with the combined treatment. CONCLUSIONS: The administration of bexarotene, paclitaxel, and carboplatin is feasible and safe; however, the increased bexarotene plasma concentrations and exposure warrant further investigation if this combination is to be utilized clinically.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Administration, Oral , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bexarotene , Carboplatin/administration & dosage , Carboplatin/adverse effects , Carboplatin/pharmacokinetics , Carboplatin/therapeutic use , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Female , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/therapeutic use , Infusions, Intravenous , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Paclitaxel/pharmacokinetics , Paclitaxel/therapeutic use , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/therapeutic useABSTRACT
PURPOSE: Bexarotene (Targretin(®) capsules) is a retinoid-X-receptor agonist and an inducer of CYP3A4-mediated metabolism. This phase I trial evaluated the pharmacokinetic (PK) and drug-drug interactions of bexarotene with chemotherapy and a lipid-lowering agent (atorvastatin or fenofibrate). This trial was run in parallel with phase III trials of the combinations to determine whether repeated doses of bexarotene capsules affect the pharmacokinetics (PK) of the chemotherapeutic or the lipid-lowering agents. METHODS: Patients (n = 48) with advanced non-small cell lung cancer were treated with repetitive cycles of either paclitaxel/carboplatin or cisplatin/vinorelbine chemotherapy, bexarotene (400 mg/m(2)/day) administered continuously starting on day 4 of chemotherapy, and a lipid-lowering drug, either atorvastatin or fenofibrate, starting at least 5 days before chemotherapy due to hypertriglyceridemia induced by bexarotene. Extensive plasma sampling to characterize the PK profiles of the lipid-lowering drugs, relevant chemotherapy agents was performed on day 1 (without bexarotene) and during chemotherapy cycles 2 or 3 (with bexarotene). RESULTS: Here, we report the drug-drug interactions between the lipid-lowering agents and bexarotene. Mean atorvastatin clearance and dose-corrected AUC values were reduced by nearly 50% with the addition of concomitant bexarotene. As fenofibrate was less effective at controlling hypertriglyceridemia, too few patients received this agent to make any meaningful conclusions about drug-drug interactions. CONCLUSIONS: A drug-drug interaction was seen in this trial with bexarotene co-administration leading to a significant reduction in the AUC of atorvastatin. The likely mechanism for this interaction is through induction of CYP3A4 by bexarotene given the role of this enzyme in the metabolism of atorvastatin. Knowledge of this interaction is important for optimizing lipid management with atorvastatin for patients receiving bexarotene.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Area Under Curve , Atorvastatin , Bexarotene , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Drug Administration Schedule , Drug Interactions , Female , Heptanoic Acids/administration & dosage , Heptanoic Acids/adverse effects , Heptanoic Acids/pharmacokinetics , Humans , Hypercholesterolemia/chemically induced , Hypertriglyceridemia/chemically induced , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , Metabolic Clearance Rate , Middle Aged , Pyrroles/administration & dosage , Pyrroles/adverse effects , Pyrroles/pharmacokinetics , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics , Treatment OutcomeABSTRACT
PURPOSE: This is a phase I study of the retinoid X receptor agonist bexarotene (Targretin(®)) in combination with the chemotherapeutic drugs cisplatin and vinorelbine and lipid-lowering therapy. This study looked for pharmacokinetic (PK) interactions between the agents in parallel with a phase III study of the combination. METHODS: Patients (n = 26) with advanced-stage non-small-cell lung cancer received intravenous cisplatin 100 mg/m(2) on day 1 and at 4-week intervals plus intravenous vinorelbine 25 mg/m(2) weekly. Continuous oral bexarotene therapy (400 mg/m(2)/day) was initiated at day 4. Lipid-lowering therapy was initiated in all patients due to hypertriglyceridemia associated with bexarotene use. PK profiles of the chemotherapeutic agents were obtained on day 1 (without bexarotene) and during cycles 2-4 (with bexarotene). Vinorelbine (n = 18) and free cisplatin (n = 17) PK parameters in evaluable patients were determined using non-compartmental methods. RESULTS: Mean vinorelbine and free cisplatin clearance and dose-corrected AUC values with bexarotene were within 20% of respective values without concomitant bexarotene. Bexarotene levels did not vary with or without co-administration of the chemotherapeutic agents. There was no evidence of increased toxicity when bexarotene was co-administered with the chemotherapeutic agents. CONCLUSIONS: Bexarotene does not substantially affect vinorelbine or cisplatin PK, and the combination is well tolerated. The results are consistent with the mechanisms of elimination of vinorelbine (high metabolic clearance) and cisplatin (non-enzymatic and renal elimination).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Administration, Oral , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bexarotene , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cisplatin/administration & dosage , Cisplatin/adverse effects , Cisplatin/pharmacokinetics , Cisplatin/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Female , Humans , Hypolipidemic Agents/administration & dosage , Hypolipidemic Agents/therapeutic use , Infusions, Intravenous , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Middle Aged , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/administration & dosage , Tetrahydronaphthalenes/adverse effects , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/therapeutic use , Vinblastine/administration & dosage , Vinblastine/adverse effects , Vinblastine/analogs & derivatives , Vinblastine/pharmacokinetics , Vinblastine/therapeutic use , VinorelbineABSTRACT
Introduction. Retroperitoneal sarcomas are uncommon large malignant tumors. Methods. Forty-one consecutive patients with localized retroperitoneal sarcoma were retrospectively studied. Results. Median age was 58 years (range 20-91 years). Median tumor size was 17.5 cm (range 4-41 cm). Only 2 tumors were <5 cm. Most were liposarcoma (44%) and high-grade (59%). 59% were stage 3 and the rest was stage 1. Median followup was 10 months (range 1-106 months). Thirty-eight patients had an initial complete resection; 15 (37%) developed recurrent sarcoma and 12 (80%) had a second complete resection. Patients with an initial complete resection had a 5-year survival of 46%. For all patients, tumor grade affected overall survival (P = .006). Complete surgical resection improved overall survival for high-grade tumors (P = .03). Conclusions. Tumor grade/stage and complete surgical resection for high-grade tumors are important prognostic variables. Radiation therapy or chemotherapy had no significant impact on overall or recurrence-free survival. Complete surgical resection is the treatment of choice for patients with initial and locally recurrent retroperitoneal sarcoma.
ABSTRACT
PURPOSE: Adenoid cystic carcinoma of the salivary gland (ACC-SG) is a slow-growing tumor that is refractory to most chemotherapeutic agents. Estrogen receptor (ER) antagonists provide a novel approach for recurrent disease. METHODS: We report two cases of ACC-SC in which Tamoxifen/Toremifene were used. RESULTS: Both patients obtained long-term stability of disease with no associated toxicity. CONCLUSIONS: Given the relatively unsuccessful treatments for ACC-SC and the low toxicity of ER antagonists, such therapy should be considered in these patients for its potential disease-stabilizing effects.
Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Carcinoma, Adenoid Cystic/drug therapy , Salivary Gland Neoplasms/drug therapy , Tamoxifen/therapeutic use , Adult , Carcinoma, Adenoid Cystic/secondary , Combined Modality Therapy , Female , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Neoplasm Recurrence, Local/drug therapy , Salivary Gland Neoplasms/pathology , Toremifene/therapeutic useABSTRACT
A primary paraspinal leiomyosarcoma invading the spine is an exceedingly rare neoplasm that may clinically mimic a schwannoma. The authors report a case involving a 45-year-old man with a primary leiomyosarcoma of the cervical paraspinal musculature that invaded the spinal canal at C1-2 and subsequently metastasized to the lungs and pancreas. Aggressive treatment consisting of resection of the primary tumor, adjunctive radiation therapy and chemotherapy, and surgical debulking of metastatic disease resulted in local tumor control at the primary site and long-term survival of the patient.