ABSTRACT
Drug development in oncology usually establishes efficacy in metastatic disease before advancing a therapy to the adjuvant or neoadjuvant settings. Unfortunately, too often use in adjuvant or neoadjuvant settings fails to improve overall survival. Reasons for the modest benefits include the fact that in many cases surgery cures a majority of patients making it difficult to demonstrate gains. We begin by looking at the history of adjuvant and neoadjuvant therapies and the principles guiding their development. We summarize accepted adjuvant and neoadjuvant therapies in several cancers and tabulate their outcomes. Then, extending our work on the growth and regression rate constants of tumors and the fraction of cells killed we demonstrate that therapies developed in the metastatic setting primarily delay tumor growth rather than kill more cells and argue this is a likely explanation for poor outcomes in adjuvant or neoadjuvant settings. We suggest a rational approach for enhancing success.
Subject(s)
Chemotherapy, Adjuvant/trends , Neoadjuvant Therapy/trends , Neoplasms/drug therapy , Humans , Neoplasm Metastasis , Neoplasms/epidemiologyABSTRACT
The use of hybrid materials, where a matrix sustains nanoparticles controlling the release of the chemotherapeutic drug, could be beneficial for the treatment of primary tumors prior or after surgery. This localized chemotherapy would guarantee high drug concentrations at the tumor site while precluding systemic drug exposure minimizing undesirable side effects. We combined bacterial cellulose hydrogel (BC) and nanostructured lipid carriers (NLCs) including doxorubicin (Dox) as a drug model. NLCs loaded with cationic Dox (NLCs-H) or neutral Dox (NLCs-N) were fully characterized and their cell internalization and cytotoxic efficacy were evaluated in vitro against MDA-MB-231 cells. Thereafter, a fixed combination of NLCs-H and NLCs-N loaded into BC (BC-NLCs-NH) was assayed in vivo into an orthotopic breast cancer mouse model. NLCs-H showed low encapsulation efficiency (48%) and fast release of the drug while NLCs-N showed higher encapsulation (97%) and sustained drug release. Both NLCs internalized via endocytic pathway, while allowing a sustained release of the Dox, which in turn rendered IC50 values below of those of free Dox. Taking advantage of the differential drug release, a mixture of NLCs-N and NLCs-H was encapsulated into BC matrix (BC-NLCs-NH) and assayed in vivo, showing a significant reduction of tumor growth, metastasis incidence and local drug toxicities.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Breast Neoplasms/drug therapy , Cellulose/chemistry , Doxorubicin/pharmacology , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Lipids/chemistry , Nanoparticles/chemistry , Acetobacteraceae/chemistry , Animals , Antibiotics, Antineoplastic/administration & dosage , Breast Neoplasms/pathology , Cell Proliferation/drug effects , Cell Survival/drug effects , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Drug Delivery Systems , Drug Screening Assays, Antitumor , Female , Humans , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Nude , Particle Size , Surface Properties , Tumor Cells, CulturedABSTRACT
Presentar el caso de una paciente con cáncer de cérvix en estadio IB1 mayor de dos centímetros, a quien se le administró quimioterapia neoadyuvante seguida de traquelectomía radical con linfadenectomía pélvica por laparoscopia, con el fin de preservar su fertilidad; hacer una revisión de los casos reportados en la literatura con énfasis en los resultados obstétricos y oncológicos.Materiales y métodos: presentación del caso y bésqueda en Medline vía PubMed de los artículos publicados en inglés, francés y español desde enero de 2000 hasta agosto de 2014, sobre la administración de quimioterapia neoadyuvante y cirugía conservadora de la fertilidad en pacientes con cáncer de cérvix en estadio IB.Resultados: se seleccionaron 12 artículos pertinentes, para un total de 55 pacientes. Con un seguimiento entre 14 y 69 meses, se reportaron 4 recaídas y solo una muerte por enfermedad. Resultados obstétricos: 30 embarazos, 24 nacimientos, 3 abortos, 1 embarazo ectópico y 2 embarazos en curso.Conclusión: la quimioterapia neoadyuvante, seguida de cirugía conservadora de la fertilidad, puede considerarse como una alternativa de manejo en pacientes seleccionadas con cáncer de cérvix en estadio IB, con tumores voluminosos, que deseen preservar su fertilidad...
To present the case of a patient with stage IB1 cervical cancer larger than 2 centimetres who received neo-adjuvant chemotherapy followed by laparoscopic radical cervicectomy and pelvic lymphadenectomy for fertility preservation; and to review the literature for case reports emphasizing obstetric and oncologic outcomes.Materials and methods: Case presentation and search of the literature in Medline through PubMed of articles published in English, French and Spanish between January 2000 and August 2014 on the topic of neo-adjuvant chemotherapy and fertility preservation surgery in patients with stage IB cervical cancer.Results: Overall, 12 relevant articles were selected totalling 55 patients. Over follow-up period ranging between 14 and 69 months there were 4 relapses and only one death attributable to the disease. Obstetric outcomes included 30 pregnancies, 24 births, 3 miscarriages, 1 ectopic pregnancy, and 2 on going pregnancies.Conclusion: Neo-adjuvant chemotherapy followed by conservative, fertility preservation surgery may be an option for the management of selected patients with stage IB cervical cancer involving large tumours sizes, who wish to preserve their fertility...