RESUMEN
Antibody-directed cancer chemotherapy in the form of antibody-drug conjugates (ADCs) may improve the therapeutic index with the potential to enhance efficacy and decrease systemic toxicity. ADCs consist of three key components including an antibody that specifically binds to the target, a toxic agent and a linker which releases the toxic agent inside tumor cells. A novel ADC, MLN0264 (TAK-264) was recently investigated in patients with gastrointestinal (GI) malignancies. TAK-264 is an anti- guanylyl cyclase C (GCC) antibody conjugated via a protease-cleavable linker to the potent anti-microtubule agent monomethyl auristatin E (MMAE) (linker and toxin licensed from Seattle Genetics). Following binding to GCC, the ADC is internalized and transported to lysosomes where MMAE is released to bind to tubulin, leading to cell cycle arrest and apoptosis. This GCC targeting ADC has been evaluated in clinical studies in patients with advanced gastrointestinal malignancies. The early findings from Phase 1 study have shown preliminary activity signals in gastric, gastroesophageal, and pancreatic cancer. Results from two phase II studies in pancreatic and gastoesophageal adenocarcinoma showed only limited activity. Antibody-drug-conjugates offer a promising therapeutic modality aimed at providing target-directed cancer chemotherapy. Herein we discuss the GCC target and gastrointestinal malignancies where GCC based targeted therapies could further evolve and offer a significant clinical benefit.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias Gastrointestinales/tratamiento farmacológico , Inmunoconjugados/administración & dosificación , Animales , Anticuerpos/administración & dosificación , Apoptosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Diseño de Fármacos , Neoplasias Gastrointestinales/inmunología , Neoplasias Gastrointestinales/patología , Guanilato Ciclasa/inmunología , Humanos , Terapia Molecular DirigidaRESUMEN
OBJECTIVES: To identify patient characteristics associated with polypharmacy and inappropriate medication (PIM) use among older patients with newly diagnosed cancer. DESIGN: Cross-Sectional Study. SETTING: Ambulatory oncology clinics at an academic medical center. PARTICIPANTS: 117 patients aged ≥ 65 years with newly diagnosed histologically confirmed stage I-IV cancer were enrolled between April 2008 and September 2009. MEASUREMENTS: Medication review, included patient self-report and medical records. Polypharmacy was defined as the concurrent use of ≥ five medications, (Yes/No). PIM use was defined as use of ≥ one medication included in the 2003 update of Beers Criteria, (Yes/No). RESULTS: The prevalence of polypharmacy and PIM use were 80% and 41%, respectively. Three independent correlates of medication use were identified. An increase in comorbidity count by one, ECOG-PS score by one, and PIM use by one, was associated with an increase in medication use by 0.48 (P=0.0002), 0.79 (P=0.01) and 1.22 (P=0.006), respectively. Two independent correlates of PIM use were identified. The odds of using PIMs decreased by 10% for one unit increase in Body Mass Index [Odds Ratio (OR) 0.90, 95% CI = (0.84, 0.97)], and increased by 18% for each increase in medication count by one [OR 1.18, 95% CI = (1.04, 1.34)]. CONCLUSION: There was a high prevalence of polypharmacy and PIM use in older patients with newly diagnosed cancer. Given the co-occurrence of polypharmacy with poor performance status and multi-morbidity, multi-dimensional interventions are needed in the geriatric-oncology population to improve health and cancer outcomes.