Treatment options for BCG failures.
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Antineoplastic Agents↗
Biomedical subjects
Michael A O'Donnell
Publications and source records attributed to Michael A O'Donnell.
Minimally invasive management of upper tract urothelial carcinoma.
Recently published studies that evaluated minimally invasive treatments for upper tract urothelial cancer (UTUC) were reviewed, including adjuvant topical therapy. Ureteroscopic management remains the initial diagnostic and possibly therapeutic procedure of choice. Percutaneous management is used to treat bulky tumors or tumors that cannot be accessed ureteroscopically. Low-grade UTUC in appropriately selected patients can be safely and effectively treated endoscopically. High-grade disease tends to fail, regardless of treatment modality, and warrants aggressive therapy. Adjuvant therapy seems to be safe, although its efficacy is debatable. Immunotherapy appears to be most effective in patients with upper tract carcinoma in situ.
Carcinoma in Situ↗
The impact of age on the response of patients with superficial bladder cancer to intravesical immunotherapy.
PURPOSE: We determined the influence of age on response to intravesical immunotherapy in patients with superficial bladder cancer. MATERIALS AND METHODS: Data from a national phase II multicenter trial for BCG plus IFN-alpha intravesical therapy for superficial bladder cancer were analyzed. Recurrence-free survival 2 years after the initiation of therapy was examined in patients by incremental age decade. BCG-N patients received 81 mg BCG and 50 MU IFN-alpha, while patients who had previously been treated with BCG received a third of the BCG dose with 50 MU IFN-alpha and those who were BCG intolerant received a tenth of the BCG dose with 100 MU IFN-alpha. Kaplan-Meier survival curves were obtained. RESULTS: In all patients the largest difference in response was between the 289 who were 61 to 70 years old and the 123 who were older than 80 years with a 22% difference in cancer-free survival at a median followup of 24 months (61% vs 39%, p = 0.0002). When we assessed BCG-N and BCG treated patients separately in the 2 age groups, patients older than 80 years had a persistently lower response rate than younger patients 61 to 70 years old. Of BCG-N patients those older than 80 and younger than 50 years had the lowest cancer-free survival at a median followup of 24 months (47% and 45%, respectively). On multivariate analysis age was an independent risk factor for response. CONCLUSIONS: Aging appears to be associated with a decreased response to intravesical immunotherapy and is particularly apparent in patients older than 80 years. A potential explanation could be their depressed baseline immune status and consequent inability to mount an immune reaction to BCG or IFN-alpha.
Adjuvants, Immunologic↗
Patient-recognition data-mining model for BCG-plus interferon immunotherapy bladder cancer treatment.
Bladder cancer is the fifth most common malignant disease in the United States with an annual incidence of around 63,210 new cases and 13,180 deaths. The cost for providing care for patients with bladder cancer disease is high. Bladder cancer treatment options such as immunotherapy, chemotherapy, radiation therapy, transurethral resection, and cystectomy, are used with varying success rates. In this research, data from a nationwide bacillus Calmette-Gue rin (BCG) plus interferon-alpha (IFN-alpha) immunotherapy clinical trial was considered. Data mining algorithms were used to analyze the effectiveness of immunotherapy treatment and to understand the prominent parameters and their interactions. The extracted knowledge was used to build a patient recognition model for prediction of treatment outcomes. The data was analyzed to understand the impact of various parameters on the treatment outcome. A list of significant parameters such as cumulative tumor size, presence of residual disease, stages of prior bladder cancer, current state of bladder cancer, and the presence of current bladder cancer (T1) is provided. The decision-making approach outlined in the paper supplemented with additional knowledge bases will lead to a comprehensive analytical road map of the BCG/IFN-alpha immunotherapy treatment. It will provide individualized guidelines for each stage of the treatment as well as measure the success of the treatment.
Adjuvants, Immunologic↗
Practical applications of intravesical chemotherapy and immunotherapy in high-risk patients with superficial bladder cancer.
The following steps are practical in the treatment of intermediate-to-high risk patients with superficial bladder cancer: Resect all visible tumor at the time of first TUR of bladder tumor. Strongly consider re-resection, especially for high-risk, large, multifocal, stage T1 tumors. Apply one dose of cytotoxic chemotherapy perioperatively within 6 hours of TUR (ideally immediately). Once histopathology is available, consider intravesical induction chemotherapy for intermediate-risk patients and BCG for intermediate- or high-risk patients and those having failed prior chemotherapy. At least 1 year of maintenance therapy should be planned for all intermediate-to-high risk BCG-treated patients. Chemotherapy maintenance may be useful if perioperative chemotherapy was omitted. For patients failing standard therapy, a thorough discussion of the risks (including progression and metastasis) and expected benefits should take place before the initiation of salvage therapy. The radical cystectomy option should be openly entertained. Consider BCG plus interferon or gemcitabine-based salvage programs if appropriate. Explore clinical trial options. Contact urologic cancer experts for guidance and advice.
Administration, Intravesical↗
Two-surgeon versus single-surgeon radical cystectomy and urinary diversion: impact on patient outcomes and costs.
OBJECTIVES: To examine the difference in charges and outcomes between patients who underwent radical cystectomy and urinary diversion by a team of two surgeons versus a single surgeon. METHODS: A total of 63 patients with bladder cancer who underwent the procedures were retrospectively analyzed. Two surgeons sequentially performed the cystectomy and ileal conduit (IC, n = 17) or neobladder (NBL, n = 18) or a single surgeon performed both the cystectomy and IC (n = 21) or NBL (n = 7). Procedure-related charges, hospital charges, operating room time, length of stay, and complications were compared between the two groups. RESULTS: For the IC patients, the two-surgeon team had 60% greater mean surgeon charges (P <0.0001), 23% lower mean anesthesia charges (P <0.0001), 121 minutes shorter operating room time (P = 0.001), and 30% lower operating room charges (P = 0.001). For the NBL patients, the two-surgeon team had 32% greater surgeon charges (P <0.0001), 22% lower anesthesia charges (P = 0.003), 149 minutes shorter operating room time (P <0.0001), and 41% less operating room charges (P <0.0001). No differences were found in total hospital charges. The NBL patients who underwent surgery by two surgeons had a longer length of stay (P = 0.008). No differences were found in complications between the groups. CONCLUSIONS: For IC patients, our data showed no differences in the average overall charges, whether a two-surgeon team or a single surgeon performed the procedure. Additional reductions in hospital charges could offset the greater physician charges in the NBL patients and allow full realization of the benefit from the shorter operative time with the two-surgeon team.
Aged↗
A novel expression of macrophage derived chemokine in human bladder cancer.
PURPOSE: Successful bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer is associated with proper induction of T helper (Th)1 immunity. Unfortunately, 30% to 40% of bladder tumors never respond to BCG. We sought evidence of antagonistic Th2 chemokine production by bladder tumors as a potential cause of BCG nonresponsiveness. MATERIALS AND METHODS: Expression of interferon-gamma inducible protein-10 (IP-10), a Th1 chemokine, and macrophage derived chemokine (MDC), a Th2 chemokine, was examined in 9 clinical bladder tumor specimens and 7 human bladder cancer lines by sandwich enzyme-linked immunosorbent assay, immunohistochemistry and immunofluorescence. Regulation of these chemokine expressions in the human RT4 bladder cancer line was also explored by reverse transcription-polymerase chain reaction and electrophoretic mobility shift assay. RESULTS: Eight of 9 clinical specimens expressed IP-10 and 5 expressed MDC. However, of 7 cancer lines only 1 low grade line (RT4) expressed IP-10 and MDC, and 1 high grade line (T24) expressed IP-10. Histological staining demonstrated MDC and IP-10 expression in human bladder tumors. Interestingly interferon-gamma and tumor necrosis factor-alpha up-regulated and synergized the expression of these 2 chemokines in RT4 cells. Such positive effects appeared to be mediated by nuclear factor-kappaB but not by the AP-1 signaling pathway. CONCLUSIONS: These results indicate that certain bladder tumors produce the Th2 chemokine MDC, which may antagonize the local Th1 environment induced by BCG. MDC production by bladder tumors appears to be mediated by signals distinct from those identified in macrophages.
Carcinoma, Transitional Cell↗
Cytokine-modified Mycobacterium smegmatis as a novel anticancer immunotherapy.
Intravesical administration of live M. bovis BCG organisms for carcinoma in situ of the urinary bladder is the most successful immunotherapy for solid malignancy. Nevertheless BCG-therapy is associated with significant toxicity and is ineffective in 30-40% of cases. Recently it has been proposed that cytokine-modified mycobacteria may give greater efficacy. As any immunotherapy involving administration of live BCG organisms (wild-type or recombinant) is likely to have associated toxicity (notably in the immunocompromised), we examined the anti-tumour potential of the closely related nonpathogenic organism, Mycobacterium smegmatis, and a TNFalpha gene-modified recombinant M. smegmatis. When wild-type M. smegmatis were delivered to immunocompetent C57Bl/6 mice bearing the transplantable MB49 bladder tumour, efficacy comparable to live BCG was observed with 10-20% long-term survival. However, this effect was lost in both Nude and Beige mice, lacking functional T and NK cells, respectively. Recombinant M. smegmatis secreting TNFalpha, however, gave a 70% durable tumour-free survival. Lymphocytes from draining lymph-nodes and spleens of these mice exhibited pronounced IFNgamma production to mycobacterial-antigen and tumour-lysate, indicating a bias towards cell-mediated immunity. This was further supported by histopathological examination of the tumour site, which revealed significantly increased numbers of CD3+ lymphocytes in animals receiving the recombinant vaccine, but not in those receiving wild-type bacteria. Importantly, tumour rejection following M. smegmatis/TNFalpha was independent of T lymphocytes, as athymic Nude mice efficiently eradicated MB49 tumours. In contrast, the therapeutic efficacy of M. smegmatis/TNFalpha was reduced in animals deficient in NK cytolytic function, suggesting a role for NK-cells in initial tumour destruction. Furthermore the absence of NK-function in Beige mice did not prevent the establishment of tumour-protective memory. No toxicity was observed with wild-type or recombinant M. smegmatis in immunocompetent, T-deficient or NK-deficient models. We demonstrate for the first time that recombinant mycobacteria expressing mammalian cytokines have markedly increased anti-tumour properties. The lack of toxicity suggests that M. smegmatis is a "safe" vehicle for use in immunocompromised patients.
Animals↗
Tumor necrosis factor-related apoptosis-inducing ligand: a novel mechanism for Bacillus Calmette-Guérin-induced antitumor activity.
Mycobacterium bovis Bacillus Calmette-Guérin (BCG) use in the treatment of bladder cancer was first reported in 1976, but the mechanism of the induced antitumor activity has still not been fully explained. BCG is a potent immunostimulant, normally producing a Th1 cytokine response, including IFN. Recent studies have shown CpG oligodeoxynucleotide induce tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression via IFN production. Given that Mycobacterial DNA contains high amounts of CpG motifs, we hypothesized that BCG's antitumor properties are akin to CpG oligodeoxynucleotide, where the cytokine response to BCG induces TRAIL up-regulation. Using ELISA, urine IFN-gamma, and TRAIL levels were initially undetectable in BCG therapy patients but were high after later induction treatments. More importantly, patients that responded to BCG therapy had significantly higher urine TRAIL levels, which killed bladder tumor cells in vitro versus nonresponders. Flow cytometry of fresh urine revealed TRAIL-expressing neutrophils. Given these data, we propose TRAIL plays a role in BCG-induced antitumor effects.
Apoptosis Regulatory Proteins↗
Second-line intravesical therapy versus cystectomy for bacille Calmette-Guérin (BCG) failures.
PURPOSE OF REVIEW: To give an update on the new modalities in treating patients with superficial bladder cancer who have failed bacille Calmette-Guérin. RECENT FINDINGS: The addition of interferon to bacille Calmette-Guérin has proven to be an effective combination therapy for bacille Calmette-Guérin failures. Electromotive intravesical mitomycin C as well as local microwave hyperthermia have been shown to improve drug delivery and increase response rates. Intravesical gemcitabine has shown some promising results in phase I studies and is being investigated in phase II trials. Photodynamic therapy is proposed as a second-line therapy for bacille Calmette-Guérin failures. SUMMARY: New treatment modalities are being introduced and existing ones improved to treat bacille Calmette-Guérin-refractory superficial bladder cancer. These agents need to be studied in large randomized trials. Until these agents prove to decrease recurrence rates and delay progression of high-risk superficial bladder cancer, cystectomy remains the standard of care for the patient who is a good surgical candidate and willing to undergo such major surgery.
Adjuvants, Immunologic↗
Intravesical colonic pseudotumor.
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Aged↗
Interleukin-12 immunotherapy of murine transitional cell carcinoma of the bladder: dose dependent tumor eradication and generation of protective immunity.
PURPOSE: The antitumor activity of interleukin (IL)-12 has been demonstrated in a number of tumor models but barely tested in bladder cancer models. We evaluated the antibladder cancer activity of this cytokine in syngeneic mice bearing subcutaneous, metastatic and orthotopic tumors. MATERIALS AND METHODS: Mice were implanted subcutaneously, intravenously or orthotopically with syngeneic transitional cell carcinoma (TCC) of the bladder. The tumor bearing mice were then treated with IL-12 locally or systemically and monitored for tumor regression and survival. RESULTS: In the subcutaneous model dose dependent suppression of tumorigenesis was observed when IL-12 was administered subcutaneously at a distal site with the MB49 line being more sensitive than MBT-2. IL-12 (10 days) above 50 ng daily was tumor inhibitory, while doses of 500 or 1000 ng daily prolonged survival and cured 70% and 75% of subjects, respectively. Upon re-challenge with parental tumor cells mice previously cured with IL-12 (1000 vs 500 ng daily) exhibited specific protection (70% vs 35% rejection) that was dependent on the earlier dose of cytokine. IL-12 administered intraperitoneally at a dose of 250 ng daily was more potent than subcutaneous administration and complete regression was observed. Metastatic TCC in the lungs and orthotopic tumors in the bladder also favorably responded to systemic or intravesical IL-12 therapy, respectively. Addition of IL-2 to IL-12 therapy increased tumor regression, long-term survival and rejection of re-challenged parental tumor. CONCLUSIONS: IL-12 is exceptionally effective for treating murine bladder TCC in subcutaneous, metastatic and orthotopic models. The antibladder cancer activity of this cytokine should be tested in human bladder cancer therapy.
Animals↗
The essential role of interferon-gamma during interleukin-12 therapy for murine transitional cell carcinoma of the bladder.
PURPOSE: Recombinant interleukin (IL)-12 and adenoviral IL-12 gene therapy have been shown to be potent therapeutic interventions for murine transitional cell carcinoma (TCC) of the bladder in vivo. We investigated the mechanisms through which IL-12 induces antibladder cancer immunity. MATERIALS AND METHODS: The ability of IL-12 to enhance interferon-gamma (IFN-gamma) expression, a major T-helper type 1 cytokine, was analyzed in murine serum, urine and splenocyte cultures. MB49, a murine TCC line, was treated with IFN-gamma and evaluated for its proliferation, surface molecule expression and sensitivity to splenocyte mediated cytotoxicity. Neutralizing antiIFN-gamma antibody was applied to test the role of IFN-gamma in the IL-12 therapy of MB49 tumor. RESULTS: IL-12 was observed to significantly increase IFN-gamma concentrations in serum and urine as well as in splenocyte cultures. While IL-12 had no direct activity against TCC in vitro, IFN-gamma showed potent dose dependent antiproliferative and pro-apoptotic activity, which was further enhanced by supplementation of tumor necrosis factor-alpha. In addition, IFN-gamma substantially up-regulated the expression of surface immune molecules on TCC cells, including MHC-I, MHC-II, ICAM-I, B7.1, B7.2 and Fas. Maximum splenocyte mediated cytotoxicity against TCC was enhanced by pretreatment of target bladder cancer cells with IFN-gamma plus tumor necrosis factor-alpha. Furthermore, IL-2 in combination with IL-12 further enhanced splenocyte mediated cytotoxicity. The in vivo antibladder cancer activity of IL-12 was abolished by concurrent treatment with antibodies to IFN-gamma. CONCLUSIONS: This study strongly suggests that IFN-gamma has an essential role in IL-12 induced antibladder tumor immunity. Activation of host effector immune cells by IL-12 is also required for induction of optimal tumor destruction in IL-12 therapy.
Animals↗
Association between volume and charges for most frequently performed ambulatory and nonambulatory surgery for bladder cancer. Is more cheaper?
PURPOSE: We investigated the relationship between provider volume and charges for transurethral bladder tumor resection (TURBT) and radical cystectomy in patients with bladder cancer. MATERIALS AND METHODS: The National Inpatient Sample (1988 to 1999) of the Health Care Utilization Project, and State Ambulatory Surgery Databases for Wisconsin and Florida (2000 data set) were used for analysis. All patients with bladder cancer who had undergone radical cystectomy or TURBT as the principal procedure were identified. Hospitals and surgeons were categorized into terciles of volume based on the average number performed per year. The average hospital charge per discharge/procedure corrected to 2000 levels was calculated. One-way ANOVA with the Bonferroni correction was used to compare charges between different volume levels. RESULTS: A total of 13,498 patients who underwent radical cystectomy and 5,954 who underwent TURBT were included in the analysis. Charges for radical cystectomy were 5,648 USD lower at high volume hospitals than at low volume hospitals (p <0.001). High volume surgeons were 2,976 USD less expensive than low volume surgeons (p =0.054). For TURBT total hospital charges at high volume hospitals were 1,013 USD more than at low volume hospitals (p <0.0001), while average total hospital charges for procedures performed by high volume surgeons were 919 USD less compared to low volume surgeons (p <0.0001). CONCLUSIONS: High risk inpatient procedures for bladder cancer such as cystectomy, which are more influenced by systems of care, are less expensive to perform at high volume centers. Lower risk ambulatory procedures for bladder cancer, such as TURBT, which are not influenced by systems of care, may be more cost efficiently performed by high volume surgeons at low volume centers.
Ambulatory Surgical Procedures↗
Interim results from a national multicenter phase II trial of combination bacillus Calmette-Guerin plus interferon alfa-2b for superficial bladder cancer.
PURPOSE: Interim results are provided from a large multicenter trial of combination bacillus Calmette-Guerin (BCG) plus interferon (IFN) alfa-2b for BCG naive (BCG-N) and previous BCG failure (BCG-F) cases of superficial bladder cancer. MATERIALS AND METHODS: A total of 490 patients enrolled from May 1999 to May 2000 with a median of 24 months of followup were analyzed. The BCG-N group (259) was treated with a 6-week induction course of standard dose BCG plus 50 million units of IFN followed by 3, 3-week maintenance cycles of reduced dose BCG (1/3 to 1/10) plus 50 million units IFN at 3, 9 and 15 months after induction. The BCG-F group (231) was treated similarly except induction therapy began at a decreased (1/3 to 1/10) BCG dose. RESULTS: The simple tumor recurrence rates for BCG-N and BCG-F groups were 40% and 52%, and the Kaplan-Meier estimates for disease freedom at 24 months were 57% and 42%, respectively. Progression to muscle invasion occurred in 5% and 4.3% while metastasis occurred in 2.3% and 2.6%, respectively. In each group 3.9% of patients underwent cystectomy and 2 patients in each group died of bladder cancer. Serious adverse events occurred in 5.5% with infection related serious adverse events being less prevalent in the BCG-F group (2.6% vs 5.4%). Toxicity related dropout, treatment delay and/or further BCG dose reduction, and need for symptomatic drugs were similar. Moderate to severe local side effects during induction were higher in the BCG-F group (6.2% vs 16.9%) but equilibrated during maintenance therapy. Systemic reactions were rare. CONCLUSIONS: This multicenter trial provides a benchmark for the efficacy and safety of combination BCG and IFN as up front and salvage therapy. The incremental value of IFN cannot be determined from this study.
Aged↗
Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect.
Induction of a T-helper-type 1 (Th1) immune response is indispensable for successful treatment of superficial bladder cancer with BCG. In this study possible involvement of various cytokines in BCG action as well as their potential roles in enhancing and mimicking BCG effect were explored. In immunocompetent cell cultures, IFN-gamma, a major Th1 cytokine, appears to be a late responsive cytokine to BCG stimulation. Its induction requires involvement of various endogenously produced Th1 and Th2 cytokines. Functional abolishment of any one of these cytokines (IL-2, IL-6, IL-12, IL-18, GMCSF, TNF-alpha, or IFN-alpha, except IL-10) by neutralizing antibodies leads to reduced IFN-gamma production (19-82% inhibition in mouse and 44-77% inhibition in human systems, respectively). In mice cytokines IL-2, IL-12, IL-18, and GMCSF are observed to synergize with BCG for IFN-gamma production, whereas in human cytokines IL-2, IL-12, TNF-alpha, and IFN-alpha exhibit similar synergistic effects. Rational combinations of these Th1-stimulating cytokines (IL-12 plus IL-18 in mice and IL-2 plus IL-12 in humans, respectively) dramatically up-regulate IFN-gamma production that is incomparably superior to BCG for induction of this cytokine. These results suggest that combined Th1-stimulating cytokines and combinations of BCG plus selected Th1-stimulating cytokines are rational candidates for further study in the treatment of bladder cancer patients.
Adjuvants, Immunologic↗
Contemporary management of superficial bladder cancer in the United States: a pattern of care analysis.
OBJECTIVES: To assess the practice preferences among urologists treating superficial bladder cancer in the United States. METHODS: We surveyed 226 urologists using a specially designed survey instrument. The type of practice, number of urologists in group practice, annual volume of patients with bladder cancer, and those treated with intravesical therapy were assessed. We also obtained information on the American Urological Association section and year of graduation from urology residency training. RESULTS: Of the 226 contacted urologists, 105 (46%) returned a completed survey instrument. Seventeen percent were practicing in academic institutions and 63% were in independent community practice. Forty-five percent had graduated from urology training in or before 1985. Thirty-six percent were in small and 37% were in moderate-size groups. Thirty-five percent were treating a moderate number of patients with bladder cancer, and 44% were treating a large number of patients annually. Thirty-two percent had a moderate number and 40% had a large number of patients receiving intravesical therapy annually. Immunotherapy was preferred in patients at high risk of recurrence. Intravesical chemotherapy was preferred by many for immunotherapy failure. The type of practice and year of graduation were the factors most frequently affecting treatment choice. CONCLUSIONS: Practice preferences for the management of superficial bladder cancer are in general agreement with the American Urological Association Bladder Cancer Guidelines Panel recommendations. However, 81% of surveyed urologists were still reluctant to refer patients with high-grade Ta-T1 disease with failure after intravesical immunotherapy twice for more aggressive therapy such as cystectomy or radiotherapy.
Administration, Intravesical↗
Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the Surveillance, Epidemiology and End Results Program data base.
PURPOSE: The benefit of pelvic lymphadenectomy in patients with bladder cancer remains controversial. We analyzed the impact of lymphadenectomy on disease specific survival in a population based sample of patients with bladder cancer who underwent radical cystectomy. MATERIALS AND METHODS: Analysis included data on 1,923 patients who underwent radical cystectomy for bladder cancer between 1988 and 1996 obtained from the Surveillance, Epidemiology and End Results program cancer registry. We analyzed the impact of the number of lymph nodes examined, number of positive lymph nodes and ratio of positive-to-total number of lymph nodes resected on disease specific and overall survival independent of patient age, gender, stage, race, radiation and chemotherapy. RESULTS: Median followup in cystectomy cases was 63.5 months (range 0 to 131). Patients with 0 to 3 lymph nodes examined were at significantly higher risk of death from bladder cancer than those with greater than 3 (HR 1 to 1.2 versus 0.41 to 0.58). Patients with stages I/in situ, III and IV disease benefited from more extensive lymphadenectomy. In stage IV cases, while the total number of positive lymph nodes removed did not correlate with increased survival, the proportion of excised lymph nodes positive for metastatic bladder cancer tended to correlate with the risk of death from the disease. CONCLUSIONS: These results indicate significantly increased survival rates after cystectomy in patients with bladder cancer diagnosed with stages III or IV disease who have relatively more lymph nodes examined, suggesting that even some with higher stage disease may benefit from extended pelvic lymphadenectomy at cystectomy.
Adult↗