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Current Urology Reports Apr 2013The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is... (Review)
Review
The definitive treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) who fail to respond to intravesical bacillus Calmette-Guérin (BCG) is cystectomy. However, many patients who experience recurrence after BCG are either poor operative candidates or refuse surgery due to the long-term impact on their quality of life. In the last decade, there has been an increased interest in alternative intravesical therapies, and several novel chemotherapeutics have emerged as promising agents for high-risk NMIBC patients unable or unwilling to undergo cystectomy. Additionally, extended treatment regimens with combined induction and maintenance therapy have been investigated, and may increase the durability of response to these new agents, as has been shown for conventional intravesical therapy.
Topics: Administration, Intravesical; Antineoplastic Agents; BCG Vaccine; Carcinoma, Transitional Cell; Deoxycytidine; Docetaxel; Doxorubicin; Humans; Mitomycin; Paclitaxel; Taxoids; Thiotepa; Treatment Failure; Urinary Bladder Neoplasms; Gemcitabine
PubMed: 23378162
DOI: 10.1007/s11934-013-0312-2 -
Urologic Oncology Nov 2013Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal...
OBJECTIVES
Evaluate the efficacy and safety of valrubicin for bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder based on updated phase III pivotal trial efficacy data together with efficacy and safety data from a supportive phase II/III study.
MATERIALS AND METHODS
In a phase II/III open-label study (A9303), BCG refractory/intolerant adults with CIS (≥ 1 previous course of BCG or could not complete a BCG course owing to toxicity or contraindication) were randomized to receive 6 or 9 weekly intravesical valrubicin (800 mg) instillations. In the pivotal phase III open-label study, BCG-refractory/recurrent adults with CIS (≥ 2 previous courses of intravesical therapy, including ≥ 1 BCG course) received 6 weekly intravesical valrubicin (800 mg) instillations. Patients with muscle-invasive disease were excluded. Patients underwent a primary disease evaluation (PDE) at 3 months (≈ 6 weeks after last dose) that included cytoscopy, biopsy, and cytology. Disease recurrence was monitored at 3-month intervals. Complete response (CR) was defined as no evidence of disease at the PDE (month 3) and follow-up (month 6). Efficacy data from the pivotal trial reflect updated information based on US Food and Drug Administration review. Safety assessments in A9303 included local bladder adverse events (LBAEs) and other adverse events (AEs).
RESULTS
Eighty patients enrolled and 78 completed treatment and underwent the PDE in study A9303; in the pivotal trial, the respective numbers were 90 and 87 patients. In study A9303, 39% of patients had received ≥ 2 previous courses of BCG and 11% had received ≥ 3 courses vs. 70% and 28%, respectively, in the pivotal trial. In both studies, the CR rate was 18%. In A9303, LBAEs were the most common AEs, reported by 86% of patients during treatment and 45% during follow-up; most treatment-related LBAEs were mild to moderate. 2 serious AEs in 1 patient (azotemia/reflux nephropathy) were judged as definitely or possibly treatment related; none of the patient deaths were judged to be related to valrubicin.
CONCLUSIONS
Two trials of valrubicin in patients with CIS demonstrate a consistent degree of efficacy in highly pretreated patients (pivotal trial; BCG-refractory patients) and those with fewer previous therapies (A9303; BCG-refractory/intolerant patients).
Topics: Abdominal Pain; Administration, Intravesical; Adult; Aged; Aged, 80 and over; BCG Vaccine; Carcinoma in Situ; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Contraindications; Doxorubicin; Dysuria; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Outcome Assessment, Health Care; Randomized Controlled Trials as Topic; Treatment Failure; Urinary Bladder Neoplasms; Urinary Tract Infections
PubMed: 22575238
DOI: 10.1016/j.urolonc.2012.04.010 -
The British Journal of Dermatology Aug 2012Valrubicin is a cytostatic anthracycline analogue, lacking toxicity by skin and tissue contact, and represents a new drug with potential for topical treatment of...
BACKGROUND
Valrubicin is a cytostatic anthracycline analogue, lacking toxicity by skin and tissue contact, and represents a new drug with potential for topical treatment of psoriasis and nonmelanoma skin cancer (NMSC); the beneficial effects have been partly explained by its antiproliferative and proapoptotic characteristics.
OBJECTIVES
To assess the effect of valrubicin on skin inflammation as inflammation also plays a key role in psoriasis and NMSC.
METHODS
The effect of topical valrubicin treatment on skin inflammation in vivo was addressed in skin inflammation mouse models, where 12-O-tetradecanoylphorbol 13-acetate was used to induce irritant contact dermatitis. An acute and a chronic model were included, to investigate the effect of valrubicin in short-term inflammation and in more persistent inflammation. Inflammation-associated ear oedema was evaluated by measuring ear thickness, infiltration of neutrophil cells, and expression of inflammatory cytokines, interleukin (IL)-1β and IL-6.
RESULTS
Topical valrubicin treatment effectively reduced the inflammatory response in the acute and the chronic models.
CONCLUSIONS
The present data document an anti-inflammatory effect of valrubicin, and may suggest an interesting new role for valrubicin in other debilitating skin diseases in which inflammation is a significant factor.
Topics: Acute Disease; Administration, Cutaneous; Animals; Anti-Inflammatory Agents; Chronic Disease; Cytokines; Dermatitis, Irritant; Disease Models, Animal; Doxorubicin; Irritants; Mice; Mice, Inbred C57BL; Neutrophil Infiltration; Tetradecanoylphorbol Acetate
PubMed: 22458650
DOI: 10.1111/j.1365-2133.2012.10964.x -
International Journal of Nanomedicine 2012Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic...
Among numerous drug-delivery approaches, reconstituted high-density lipoprotein (rHDL) nanocarriers have proven particularly applicable for delivering highly hydrophobic drugs. In this study, we have investigated the enhancement of the therapeutic impact of valrubicin (AD-32), an antineoplastic agent that has been limited to intravesicular application against bladder cancer, despite the encouraging original preclinical data. Earlier studies validated the superior therapeutic efficacy of AD-32 over doxorubicin. In the present study, rHDL/AD-32 nanoparticles were formulated and characterized with regard to encapsulation efficiency, physicochemical properties, selective toxicity, and receptor-mediated uptake. The half maximal inhibitory concentration values (IC(50)) for rHDL/AD-32 nanoparticles were 1.8 and 2.6 times lower than the free AD-32 for prostate (PC-3) and ovarian (SKOV-3) cancer cell lines, respectively, whereas nonmalignant cell lines demonstrated 5 and 1.48 times higher IC(50) doses with rHDL/AD-32 formulations. The data obtained demonstrated effective receptor- mediated uptake of AD-32 from the rHDL nanocarriers by PC-3 and SKOV-3 cancer cells via a targeted drug-delivery process. The rHDL/AD-32 formulation was stable for 6 months when stored at 4°C or at -20°C, as 92% of the AD-32 was retained in the nanoparticles. The findings from this study show that the rHDL/AD-32 formulation can overcome the solubility barriers of AD-32 and thus serve as an effective systemically administered chemotherapeutic agent.
Topics: Cell Line; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Stability; Humans; Inhibitory Concentration 50; Lipoproteins, HDL; Nanocapsules; Nanoparticles; Particle Size; Solubility; Temperature
PubMed: 22393294
DOI: 10.2147/IJN.S28029 -
Best Practice & Research. Clinical... Aug 2011Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a... (Review)
Review
Our current understanding of tumourigenesis suggests that cancer develops as a series of cumulative genetic and epigenetic derangements across time culminating in a clone of cells differing from its population of origin in terms of cellular identity, growth control, and its contextual relationship to its environment. Our increasing knowledge of the timing, sequence, frequency, and specific implications of these changes provides unique opportunities for earlier identification of aberrations and preventive interventions. Here we discuss the fundamentals of cancer prevention including the targets, cohorts, agents, endpoints, mechanistic biomarkers, designs, and strategies employed in preventive drug development. There have been many notable successes in this field such as the identification and development of tamoxifen and raloxifene for breast cancer risk reduction, instillational BCG and valrubicin for treatment of preinvasive bladder cancer, and a variety of topical and systemic agents that effectively treat preinvasive neoplastic lesions of the skin. A variety of null or negative developmental endeavours have occurred as well, including trials of beta-carotene for lung cancer prevention, nutritional modifications for colorectal adenoma prevention, and most recently, selenium and alpha-tocopherol for prostate cancer prevention. A third category of prevention trials can be summarized as investigationally successful, but not achieving regulatory success. The development of finasteride and dutasteride for prostate cancer prevention, and celecoxib for colorectal neoplasia prevention fall into this category. In less than four decades, cancer chemoprevention has transformed from a concept to an achievable reality.
Topics: Animals; Anticarcinogenic Agents; Cancer Vaccines; Chemoprevention; History, 20th Century; History, 21st Century; Humans; Neoplasms
PubMed: 22122762
DOI: 10.1016/j.bpg.2011.10.012 -
Postgraduate Medicine May 2011Patients with bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder are candidates for intravesical (IVe) valrubicin. This post-hoc analysis...
OBJECTIVE
Patients with bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ (CIS) of the bladder are candidates for intravesical (IVe) valrubicin. This post-hoc analysis of data from the pivotal phase 3, prospective, open-label study of valrubicin evaluated the effects of patient characteristics and past treatments on the response to valrubicin.
METHODS
Enrolled patients had non-muscle-invasive CIS with or without concurrent papillary disease stage Ta and/or T1 for which papillary tumors had been resected before treatment, and had previously received ≥ 2 courses of IVe therapy (≥ 1 BCG course). Patients received a course of valrubicin, which consisted of 6 weekly IVe treatments of valrubicin (800 mg). Complete response was defined as no evidence of disease by urine cytology, cystoscopy, and biopsy at 3 and 6 months posttreatment. Patient characteristics, baseline urinary symptoms, and number and type of previous treatment courses and instillations were compared for complete versus nonresponders (including partial responders) to valrubicin.
RESULTS
Ninety patients enrolled; 87 patients with positive biopsy at initiation completed a valrubicin course and underwent the 3-month assessment. Five had missing data at 6 months. Of the remaining 82 patients, 18 demonstrated a complete response; 64 demonstrated partial or no response. For complete responders versus partial or nonresponders, differences in patient characteristics, baseline urinary symptoms, and number of previous courses or instillations of BCG or other types of treatment were not significant (P > 0.05). More complete responders had evidence of inflammation before or during valrubicin treatment (P = 0.005 vs nonresponders).
CONCLUSIONS
In these patients with BCG-refractory CIS, complete responders to valrubicin did not differ significantly from partial or nonresponders in the number of prior courses or instillations. The results suggest that therapy with valrubicin may be considered in appropriate candidates who have not responded to prior therapies. Cystectomy should be reconsidered when valrubicin treatment fails.
Topics: Aged; Antineoplastic Agents; BCG Vaccine; Carcinoma in Situ; Clinical Trials, Phase III as Topic; Doxorubicin; Female; Humans; Male; Middle Aged; Time Factors; Urinary Bladder Neoplasms
PubMed: 21566413
DOI: 10.3810/pgm.2011.05.2281 -
Carcinogenesis Aug 2010Valrubicin is a second generation anthracycline characterized by an excellent safety profile presenting no skin toxicity or necrosis upon contact. In its current liquid...
Valrubicin is a second generation anthracycline characterized by an excellent safety profile presenting no skin toxicity or necrosis upon contact. In its current liquid formulation (Valstar; Indevus Pharmaceuticals, Lexington, MA), it is approved solely for the treatment of bladder cancer. Recently, valrubicin was incorporated in a cream formulation rendering this drug available for topical application. The cytostatic property of valrubicin can, thus, be employed for treating hyperproliferative skin diseases as was recently described for psoriasis. In the present study, the effect of topical application of valrubicin was investigated in skin tumor development; we hypothesized that valrubicin may be employed in treating actinic keratosis, a hyperproliferative skin condition that may transform into malignancy. A two-stage chemical mouse skin carcinogenesis model that represents the multistage etiology of human skin cancer-from developing papillomas to squamous cell carcinoma (SCC) was used. Moreover, two human skin SCC cell lines: DJM-1 and HSC-1 were cultured, to further investigate the effect of valrubicin in vitro. Cell viability was assessed by adenosine triphosphate presence, proliferation as proliferative cell nuclear antigen expression and apoptosis as cytokeratin 18 cleavage, caspase activation, poly-adenosine diphosphate-ribose-polymerase cleavage and bax and bcl-2 regulation. Valrubicin significantly inhibited tumor formation in the mouse skin carcinogenesis model and significantly decreased cell viability of the cultured human skin SCC cells. In both mouse skin and SCC cells, proliferation was significantly decreased. Apoptosis was significantly increased in SCC cells but unchanged in the treated mouse skin at study completion. This study demonstrated that topical application of valrubicin has a beneficial effect in treating developing skin tumors.
Topics: Administration, Topical; Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Squamous Cell; Cell Division; Cell Survival; Cells, Cultured; Doxorubicin; Humans; Keratinocytes; Keratosis, Actinic; Mice; Papilloma; Skin; Skin Neoplasms
PubMed: 20554745
DOI: 10.1093/carcin/bgq122 -
The Journal of Urology May 2010In marker lesion experiments a single bladder tumor is deliberately left unresected for later ablation by intravesical instillation of a novel agent. While the benefits... (Review)
Review
PURPOSE
In marker lesion experiments a single bladder tumor is deliberately left unresected for later ablation by intravesical instillation of a novel agent. While the benefits are clear, eg the opportunity to examine the effect of therapy on measurable disease, the safety and medical ethics of these experiments are less obvious. We review the goals, inclusion criteria, definition of success, agents used, effectiveness, safety and ethics of marker lesion studies, and suggest a framework for future experiments.
MATERIALS AND METHODS
Published bladder cancer studies using the marker lesion concept were identified with a MEDLINE search through March 2009.
RESULTS
A total of 23 well documented marker lesion studies were identified involving more than 1,200 patients. Most agents studied were cytotoxins (mitomycin-C, epirubicin, gemcitabine, valrubicin, apaziquone) or immune response modifiers (bacillus Calmette-Guerin, tumor necrosis factor-alpha, interferon-alpha, granulocyte-macrophage colony-stimulating factor). The highest complete response rate in intermediate risk patients (67%) was attained with apaziquone. Patients who achieved a complete response with this agent also had a prophylactic benefit with a 2-year recurrence-free rate of 45.2% compared to 26.7% in those who did not achieve a complete response. The complete response rate in bacillus Calmette-Guerin trials ranged from 32% to 61%. Marker lesion experiments were deemed safe with progression to T2 disease in only 7 patients (0.6%) and only when high risk patients were selected.
CONCLUSIONS
Marker lesion studies are most appropriate for the evaluation of novel anticancer therapeutics. Only patients with multiple recurrent, noninvasive, low grade tumors (intermediate risk) should be recruited. Primary end points should be complete response and recurrence rates after 2 to 3 years.
Topics: Administration, Intravesical; Antineoplastic Agents; Catheter Ablation; Humans; Urinary Bladder Neoplasms
PubMed: 20299042
DOI: 10.1016/j.juro.2009.12.104 -
Open Access Journal of Urology May 2010Transitional cell carcinoma (TCC) is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer... (Review)
Review
Transitional cell carcinoma (TCC) is the second most common urologic malignancy, and 70% of patients present with superficial or nonmuscle invasive bladder cancer (NMIBC). Intravesical bacillus Calmette-Guerin (BCG) is the most effective agent for preventing disease recurrence, and the only therapy able to inhibit disease progression. However, recurrence rates as high as 30% and significant local and systemic toxicity have led to increased interest in alternative intravesical therapies. In patients refractory or intolerant to BCG, BCG-interferon α2b, gemcitabine, and anthracyclines (doxorubicin, epirubicin, valrubicin) have demonstrated durable clinical responses. Phase I trials investigating alternative cytotoxic agents, such as apaziquone, taxanes (docetaxel, paclitaxel), and suramin are reporting promising data. Novel immunomodulating agents have demonstrated promise as efficacious alternatives in patients refractory to BCG. Optimization of existing chemotherapeutic regimens using hyperthermia, photodynamic therapy, magnetically-targeted carriers, and liposomes remains an area of active investigation. Despite enthusiasm for new intravesical agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy and selected patients with naïve T1 tumors and aggressive features. This report provides a comprehensive review of contemporary intravesical therapy for NMIBC and refractory NMIBC, with an emphasis on emerging agents and novel treatment modalities.
PubMed: 24198616
DOI: No ID Found -
The Journal of Investigative Dermatology Feb 2010Valrubicin is a cytostatic drug currently approved by the American Federal Drug Administration as a trademarked Valstar sterile solution for the treatment of bladder...
Valrubicin is a cytostatic drug currently approved by the American Federal Drug Administration as a trademarked Valstar sterile solution for the treatment of bladder cancer. Valrubicin has shown an excellent therapeutic potential with minimal toxicity. This study investigated the effect in vivo of treating psoriasis with a daily topical application of valrubicin cream in a psoriasis xenograft transplantation model. Psoriasis is characterized by an accelerated keratinocyte proliferation, resulting in increased epidermal thickness. We thus studied the cytostatic potential of valrubicin on epidermal keratinocytes. In vivo, valrubicin treatment resulted in a normalization of epidermal morphology and a reduction in epidermal thickness after 12 days. In addition, the dermal vessel pattern was reduced and the stratum granulosum was regained. Staining for a regenerative proliferation marker showed a decrease in keratinocyte proliferation, and scattered epidermal cells showed apoptosis. In vitro, valrubicin was shown to localize solely to the cell cytoplasm in cultured keratinocytes and to reduce keratinocyte proliferation as well as increase apoptosis by activation of caspases 3, 7, and 9. Our results indicated that valrubicin successfully treats psoriasis in a xenograft transplantation model, suggesting that topical valrubicin may become an upcoming treatment for psoriasis.
Topics: Administration, Topical; Adult; Aged; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Epidermis; Humans; Keratinocytes; Mice; Mice, SCID; Middle Aged; Neoplasm Transplantation; Psoriasis; Urinary Bladder Neoplasms
PubMed: 19741712
DOI: 10.1038/jid.2009.277