ABSTRACT
BACKGROUND: Hyperthermia (heating to 43 °C) activates the innate immune system and improves bladder cancer chemosensitivity. OBJECTIVE: To evaluate the tissue penetration and safety of convective hyperthermia combined with intravesical mitomycin C (MMC) pharmacokinetics in live porcine bladder models using the Combat bladder recirculation system (BRS). METHODS: Forty 60 kg-female swine were anesthetized and catheterized with a 3-way, 16 F catheter. The Combat device was used to heat the bladders to a target temperature of 43 °C with recirculating intravesical MMC at doses of 40, 80, and 120 mg. Dwell-heat time varied from 30-180 min. Rapid necropsy with immediate flash freezing of tissues, blood and urine occurred. MMC concentrations were measured by liquid chromatography tandem-mass spectrometry. RESULTS: The Combat BRS system was able to achieve target range temperature (42-44 °C) in 12 mins, and this temperature was maintained as long as the device was running. Two factors increased tissue penetration of MMC in the bladder: drug concentration, and the presence of heat. In the hyperthermia arm, MMC penetration saturated at 80 mg, suggesting that with heating, drug absorption may saturate and not require higher doses to achieve the maximal biological effect. Convective hyperthermia did not increase the MMC concentration in the liver, heart, kidney, spleen, lung, and lymph node tissue even at the 120 mg dose. CONCLUSIONS: Convective bladder hyperthermia using the Combat BRS device is safe and the temperature can be maintained at 43 °C. Hyperthermia therapy may increase MMC penetration into the bladder wall but does not result in an increase of MMC levels in other organs.
Subject(s)
Hyperthermia, Induced , Urinary Bladder Neoplasms , Administration, Intravesical , Animals , Antibiotics, Antineoplastic/therapeutic use , Female , Hyperthermia , Mitomycin/therapeutic use , Swine , Urinary Bladder Neoplasms/drug therapySubject(s)
Fasciitis, Necrotizing/etiology , Gas Gangrene/etiology , Postoperative Complications/etiology , Prostatectomy/adverse effects , Prostatic Neoplasms/surgery , Aged , Anti-Bacterial Agents/therapeutic use , Clostridium perfringens/isolation & purification , Debridement , Diagnosis, Differential , Drainage , Fasciitis, Necrotizing/diagnosis , Fasciitis, Necrotizing/therapy , Fatal Outcome , Gas Gangrene/diagnosis , Gas Gangrene/therapy , Humans , Hyperbaric Oxygenation , Male , Postoperative Complications/diagnosis , Postoperative Complications/therapy , Prostate/pathology , Prostate/surgery , Prostatic Neoplasms/pathologyABSTRACT
Disease recurrence and progression remain as significant challenges for the management of non-muscle invasive bladder cancer (NMIBC). In recent years, novel drugs and delivery systems have been investigated as strategies to reduce recurrence, progression and mortality. In this review, we focus on the role of intravesical hyperthermic chemotherapy and discuss a novel approach involving a heat-activated drug delivery system (ThermoDox®) that enables local accumulation of systemic chemotherapy.
Subject(s)
Antineoplastic Agents/administration & dosage , Hyperthermia, Induced , Urinary Bladder Neoplasms/therapy , Combined Modality Therapy , Drug Delivery Systems/methods , Humans , Organ Sparing TreatmentsABSTRACT
La recurrencia y la progresión de la enfermedad siguen siendo desafíos importantes para el tratamiento del cáncer de vejiga no músculo invasivo (NMIBC). En los últimos años, se han investigado nuevos fármacos y sistemas de administración como estrategias para reducir la recurrencia, la progresión y la mortalidad. En esta revisión, nos centramos en el papel de la quimioterapia hipertérmica intravesical y discutimos un enfoque novedoso que involucra un sistema de administración de fármacos activados por calor (ThermoDox (R)) que permite la acumulación local de quimioterapia sistémica
Disease recurrence and progression remain as significant challenges for the management of non-muscle invasive bladder cancer (NMIBC). In recent years, novel drugs and delivery systems have been investigated as strategies to reduce recurrence, progression and mortality. In this review, we focus on the role of intravesical hyperthermic chemotherapy and discuss a novel approach involving a heat-activated drug delivery system (ThermoDoxR) that enables local accumulation of systemic chemotherapy
Subject(s)
Humans , Antineoplastic Agents/administration & dosage , Hyperthermia, Induced , Urinary Bladder Neoplasms/therapy , Combined Modality Therapy , Drug Delivery Systems/methods , Organ Sparing TreatmentsABSTRACT
BACKGROUND: A systematic review and meta-analysis of the use of systemic vinflunine (VIN) in the treatment of urothelial carcinoma (UC) was performed to evaluate its efficacy based on current available clinical data. METHODS: This review was prospectively registered at the International Prospective Register of Systematic Reviews, PROSPERO (registration CRD42016049294). Electronic databases including MEDLINE®, Embase®, Cochrane Central Register of Controlled Trials, and Web of Science were searched through December 2016. We performed a meta-analysis of the published data. Primary end points were progression-free survival (PFS) and overall survival (OS). Numerous secondary clinical outcomes were analyzed including response and toxicity data. RESULTS: We identified 382 publications, of which 35 met inclusion criteria for this review representing 29 unique studies. A total of 2,255 patients received VIN for the treatment of UC in the included studies. OS and PFS were analyzed in a pooled Kaplan-Meier analysis. Response data were available for 1,416 VIN-treated patients with random effects proportion of complete response in 1%, partial response in 18%, and overall response rate of 21%. Toxicity analysis revealed fatigue (40.1%), nausea (33.9%), constipation (34.1%), and alopecia (26.0%) as the most prevalent overall non-hematologic adverse events (AEs). Most prevalent grade 3-4 AEs were fatigue (10.2%), abdominal pain (8.2%), myalgias (2.5%), and nausea (2.3%). Most common hematologic AEs of all grades were anemia (56.6%), neutropenia (46.0%), thrombocytopenia (25.5%), and febrile neutropenia (6.6%). Grade 3-4 hematologic AEs had the following pooled rates: neutropenia, 24.6%; anemia, 10.2%; febrile neutropenia, 5.4%; and thrombocytopenia, 3.0%. CONCLUSION: VIN has been explored as a combination first-line treatment as well as a single-agent second-line, third-line, and maintenance therapy for advanced and metastatic UC. In first-line treatment of UC, either as a maintenance agent after cisplatin or as a primary combination therapy, VIN may be a promising alternative to current treatments. Further studies are needed to compare first-line combination VIN regimens to the current standard of care in order to assess long-term survival outcomes. Second- and third-line VIN monotherapy does provide a proven, although limited, survival benefit in platinum-refractory patients.
