Bladder cancer is the fourth most common cancer in the US. Due to its easily accessible location and relatively early diagnosis, bladder cancer is one of the least lethal cancers and there are ~540,000 survivors in the US. At presentation, >80% of bladder tumors are organ-confined, separated clinically into two groups. The most common group is the nonmuscle-invading tumors, accounting for about 70-80% of cases. This group is managed by surgery, plus neo- or adjuvant intravesical immunotherapy or chemotherapy. Intravesical therapy involves instilling a drug solution into the bladder through an indwelling catheter. Recurrence is common and occurs in 40 to 80% of patients. Between 10 to 20% of recurrences are accompanied by grade and/or stage progression (including the more fatal metastatic disease). The second group, the muscle-invading tumors, is managed by partial or complete cystectomy (removal of bladder), which presents significant risks and is not well-tolerated by older patients. The most commonly used chemotherapeutic agents for intravescial therapy are mitomycin C (MMC) and doxorubicin. Through a series of preclinical and clinical studies, our group has established that the efficacy of these agents is limited by two factors: inadequate drug delivery to tumors and low chemosensitivity (especially for the more aggressive tumors). Next, we identified a method that uses pharmacokinetic (PK) interventions to maximize the MMC delivery to nonmuscle-invading bladder tumors. This method was tested in a multi-center, randomized phase III trial;the results confirm our hypothesis that improving the drug delivery significantly improves the 5-yr recurrence-free rate (from 23.5% to 42.6%). These data also indicate that a new drug delivery approach is needed for the remaining patients, those with muscle-invading tumors, who are not adequately managed by intravesical therapy. This R43 application proposes a new drug delivery approach via an alternative administration route: intra-bladder injection of controlled release formulations (CRF) of MMC and suramin, such that therapeutic active drug levels are delivered to deeper tissues. Suramin is used to enhance the sensitivity of human tumors to MMC by 2- to 3-fold. The two aims are to (a) develop biocompatible polymeric CRF of MMC and suramin and (b) conduct in vivo evaluation of the drug-loaded CRF to determine the feasibility of using intra-bladder CRF to treat deeper tumors. Upon demonstration of feasibility, we will investigate, in the later R44 project, the therapeutic efficacy of the combination in tumor-bearing animals (e.g., dogs with naturally occurring bladder tumors), in preparation for the eventual clinical evaluation. This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.
Public Health Relevance: This R43 project has the potential to lead to a new treatment modality and significantly improve the management of bladder cancer while the disease is still localized in the bladder. Given the extremely high lifetime health care costs for these patients (over $10 billion in 2003 dollars), an additional potential benefit is cost containment.
Thesaurus Terms: 1,3,5-Naphthalenetrisulfonic Acid, 8,8'-(Carbonylbis(Imino-3,1-Phenylenecarbonylimino(4-Methyl-3,1-Phenylene)Carbonylimino))Bis-;14-Hydroxydaunomycin;Abscission;Accounting;Adjuvant;Adriamycine;Animals;Apoplexy;Biocompatible;Bladder;Bladder Cancer;Bladder Control;Bladder Neoplasm;Bladder Tissue;Bladder Transitional Cell Epithelium;Bladder Tumors;Bladder Urinary System;Bladder Urothelium;Blood Plasma;Body Tissues;Botox;Brain Vascular Accident;Bypass;Cancers;Canine Species;Canis Familiaris;Carcinoma In Situ;Cardiac Infarction;Cerebral Stroke;Cerebrovascular Apoplexy;Cerebrovascular Stroke;Clinical Evaluation;Clinical Research;Clinical Study;Clinical Testing;Communities;Cost Containment;Cost Control;Cystectomy;Data;Disease;Disorder;Dogs;Dogs Mammals;Dose;Doxorubicin;Doxorubicina;Drug Delivery;Drug Delivery Systems;Drug Evaluation;Drug Evaluation Studies;Drug Exposure;Drug Formulations;Drug Kinetics;Drug Targeting;Drugs;Early Diagnosis;Electrocautery;Electrocoagulation;Embolism;Embolus;Endocavitary Fulguration;Evaluation;Excision;Extirpation;Fda Approved;Formulation;Fulguration;Galvanocautery;Gelatin;Health Care Costs;Health Costs;Healthcare Costs;Human;Hydroxyl Daunorubicin;Hydroxyldaunorubicin;Ileus;Immunologically Directed Therapy;Immunotherapy;Implantable Catheters;In-Dwelling Catheters;Indwelling Catheter;Injection Of Therapeutic Agent;Injections;Intervention;Intervention Strategies;Intraepithelial Carcinoma;Invaded;Lamina Propria;Lead;Location;Lung;Lung Respiratory System;Malignant Bladder Neoplasm;Malignant Neoplasms;Malignant Tumor;Malignant Tumor Of The Bladder;Malignant Neoplasm Of Urinary Bladder;Man (Taxonomy);Medication;Methods;Mice;Mice Mammals;Mitomycin Antibiotic;Mitomycin C;Mitomycins;Modality;Modern Man;Morbidity;Morbidity - Disease Rate;Mortality;Mortality Vital Statistics;Murine;Mus;Muscle;Muscle Tissue;Myocardial Infarct;Myocardial Infarction;Operative Procedures;Operative Surgical Procedures;Organ;Patients;Pb Element;Pharmaceutic Preparations;Pharmaceutical Preparations;Pharmacokinetics;Phase 3 Clinical Trials;Phase Iii Clinical Trials;Plasma;Plasma Serum;Polymers;Post-Operative;Postoperative;Postoperative Period;Preinvasive Carcinoma;Preparation;Randomized;Recurrence;Recurrent;Removal;Reticuloendothelial System, Serum, Plasma;Risk;Route;Series;Solutions;Staging;Suramin;Surgical;Surgical Diathermy;Surgical Interventions;Surgical Procedure;Surgical Removal;Survivors;Testing;Therapeutic;Thermocoagulation;Time;Tissues;Toxic Effect;Toxicities;Treatment Efficacy;Urinary Bladder Cancer;Urinary Bladder Malignant Tumor;Urinary Bladder Neoplasm;Urinary Bladder Tumor;Urine;Urine Urinary System;Urology;Urothelium;Venous Reservoirs;Base;Biocompatibility;Biomaterial Compatibility;Bladder Continence;Brain Attack;Canine;Cardiac Infarct;Cerebral Vascular Accident;Cerebrovascular Accident;Chemotherapeutic Agent;Chemotherapy;Clinical Test;Controlled Release;Coronary Attack;Coronary Infarct;Coronary Infarction;Cytotoxic;Disease/Disorder;Domestic Dog;Drug/Agent;Early Detection;Elderly Patient;Heart Attack;Heart Infarct;Heart Infarction;Heavy Metal Pb;Heavy Metal Lead;Immune Therapy;Improved;In Situ Cancer;In Vivo;Intervention Efficacy;Interventional Strategy;Intravesical;Malignancy;Micturition Control;Muscular;Neoplasm/Cancer;Older Patient;Phase 3 Trial;Phase Iii Protocol;Phase Iii Trial;Poly(Lactide);Polylactide;Pre-Clinical Study;Pre-Clinical Trial;Preclinical Study;Preclinical Trial;Pulmonary;Randomisation;Randomization;Randomly Assigned;Research Clinical Testing;Resection;Residence;Stroke;Surgery;Therapeutic Efficacy;Therapeutically Effective;Therapy Efficacy;Tumor;Tumor Xenograft;Urinary Bladder;Urinary Continence;Urinary Control;Urination Control