Treatment Of Advanced Bladder Cancer Research Articles

Accelerated Radiotherapy, Carbogen, and Nicotinamide (ARCON) in the Treatment of Advanced Bladder Cancer: Mature Results of a Phase II Nonrandomized Study

We previously showed that accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) was an effective approach to use in the radical treatment of patients with advanced bladder carcinoma. Interim analysis from this Phase II study showed that it achieved a high level of locoregional control and overall survival (OS) and an acceptable level of adverse events. From 1994 to 2000, a total of 105 consecutive patients with high-grade superficial or muscle-invasive bladder carcinoma were given accelerated radiotherapy (50-55 Gy in 4 weeks) with carbogen alone or ARCON. End points of the study were OS, disease-specific, and local regional relapse-free survival, and for late adverse events, urinary (altered urination frequency, incontinence, hematuria, and urgency) and bowel dysfunction (stool frequency and blood loss). At 5 and 10 years, local regional relapse-free survival rates were 44% after ARCON excluding the effect of salvage treatment and 62% after ARCON including the effect of salvage treatment (p = 0.04). Five- and 10-year rates were 35% and 27% for OS and 47% and 46% for disease-specific survival. The highest actuarial rate for Grade 3 or worse late urinary or bowel dysfunction was observed for altered urinary frequency (44% of patients had urinary events every 1 hour or less) and stool frequency of four or more events (26% at 5 years). Historic comparisons with other studies indicate no evidence of an increase in severe or worse adverse events and good permanent control of bladder disease after ARCON radiotherapy.

Emerging Agents for the Treatment of Advanced Bladder Cancer

To review the treatment options for advanced or metastatic bladder cancer, including novel agents. Research literature and clinical trial data. Knowledge of current and novel therapies for the treatment of advanced or metastatic bladder cancer is essential in caring for patients in this stage of disease, for whom options are relatively limited. Oncology nurses can play an important role in assessing patients for appropriate treatments, including enrollment in clinical trials of new agents.

Organ-Sparing Treatment of Advanced Bladder Cancer

Transurethral resection of bladder tumor (TUR-BT) and radiochemotherapy with cisplatin achieve high rates of bladder preservation and survival figures identical to radical cystectomy in muscle-invasive bladder cancers. The authors have investigated the potential use of paclitaxel in a radiochemotherapy protocol for patients with inoperable bladder carcinomas and mainly contraindications to cisplatin. Between October 1997 to August 2004, 42 patients (median age 71 years) suffering from muscle-invasive (n = 32) or recurrent (n = 10) bladder cancers were treated with a paclitaxel-containing radiochemotherapy (paclitaxel 25–35 mg/m2 twice weekly) after TUR-BT (R0/1/2/x in n = 18/4/14/3) or cystectomy with residual tumor (n = 3). Five patients received additional cisplatin. Radiation treatment was administered to a total dose of 45–60 Gy. 76.2% completed the planned regimen. Adaptations of treatment were mainly required due to diarrhea. Grade 3/4 toxicities occurred in 15/1 patients. Severe renal toxicities did not occur. 28 patients underwent restaging TUR-BT 6 weeks after radiochemotherapy (complete remission/partial remission/progressive disease: n = 24/3/1). Three patients developed a local recurrence and four distant metastases. Seven patients died from tumor, six of other reasons. Radiochemotherapy with paclitaxel was feasible and this bladder approach needs further investigation to evaluate whether paclitaxel could become a substitute for cisplatin.

Onkologische Therapie des Harnblasenkarzinoms

M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) and Cisplatin/Gemzar are potent therapies in the treatment of advanced bladder cancer. C/G provides similar efficacy in terms of overall survival compared with M-VAC, but does so with a superior safety profile. Therefore C/G is widely accepted as standard of care in locally advanced and metastatic bladder cancer. Despite potentially curative surgery almost half of the patients with muscle-invasive bladder cancer will have recurrence of disease. Based on a recent meta-analysis with data from 3005 patients, and 2 randomised studies, neoadjuvant cisplatin-containing therapy has shown to improve overall survival. Thus, the use of neoadjuvant systemic treatment should be considered state-of-the-art. The question whether adjuvant treatment will improve the outcome is still not sufficiently answered.

Sunitinib malate and sorafenib may be beneficial at the treatment of advanced bladder cancer due to their anti-angiogenic effects

Due to the poor prognosis of advanced bladder carcinoma and the insufficient affects of the chemotherapy agents for this disease, the investigation of the novel genetic and pharmacologic agents including anti-angiogenic agents that can target pathway-specific molecules has been the subject of several publications especially for the last 2 years. Although the clinical trials of these agents are still lacking, the experimental and the preliminary studies are giving hope for the future treatment of advanced bladder carcinoma. Sunitinib malate and sorafenib are the novel food and drug administration (FDA) approved anti-angiogenic agents, which have recently been demonstrated to improve the progression-free survival in patients with metastatic renal cell carcinoma. The main mechanism of these two drugs are defined as preventing the tumor growth by the inhibition of angiogenesis and the induction of apoptosis and necrosis via acting on different types of vascular endothelial growth factor (VEGF) such as the several agents which have been demonstrated to be beneficial for bladder carcinoma. According to this knowledge we suggest that these two new agents may also increase the progression-free survival of the patients with advanced bladder carcinoma due to their anti-angiogenic and tumor cell apoptotic effects. We believe that the evaluation of the effects of these agents on bladder cancer population by clinical, prospective and placebo controlled studies may prove our hypothesis and add critical findings to the literature which is still lacking.

Feasibilty study of gemcitabine and cisplatin administered every two weeks in patients with advanced urothelial tumors and impaired renal function

Cisplatin-based combination chemotherapy is the mainstay of treatment for advanced bladder cancer. However, full doses of cisplatin cannot be delivered in patients with impaired renal function. Our aim was to prove the feasibility of a gemcitabine and low-dose cisplatin regimen, delivered every two weeks in patients with impaired renal function. Patients with locally advanced or metastatic bladder cancer with creatinine clearance between 35-60 ml/min received gemcitabine 2500 mg/m2 and cisplatin 35 mg/m2 on day 1, every 14 days. Between January 2004 and March 2005, 17 patients were treated. Mean creatinine clearance was 47.8 ml/min (range: 37-59 ml/min). Four patients had previously received chemotherapy with gemcitabine and/ or platinum. Median number of cycles per patient was 5 (1-13). No patient developed renal toxicity or worsening of renal function. Main toxicities were (grade 3/4): Anemia 2/1; leucopenia: 1/2; trombopenia 1/1. There was one toxic death related to metabolic acidosis, secondary to vomiting. Among 16 patients evaluable for response, we observed one complete response, 7 partial responses (ORR: 53.3%; IC 95%: 28.1-78.5%), 6 stabilizations (37.5%) and 2 progressions (12.5%). Gemcitabine and low-dose cisplatin is a safe and feasible combination in patients with poor renal function. Response rates seem similar to those previously described with standard schedules of this combination.

The treatment of advanced bladder cancer with sensitized pig lymphocytes

Abstract Twenty-five patients with transitional cell carcinoma of the urinary bladder have been treated by infusion of sensitized pig lymph node cells into the arterial blood supply of the tumour. In 7 cases pig cell infusion was the only treatment, in a further 7 patients pig cells were given in the treatment of a major tumour recurrence following radiotherapy and in 11 patients pig cell infusion was followed after 4-8 weeks by an attenuated course of radiotherapy. In these three treatment groups 2, 3 and 9 patients respectively obtained clinical benefit and biopsy showed histological change.

Gemcitabine plus cisplatin therapy, a safety regimen in advanced bladder cancer

4799 Background: We evaluated the efficacy and toxicity of gemcitabine plus cisplatin (GC) therapy compared with methotrexate, vinblastin, doxorubicin puls cisplastin (MVAC) therapy in patients with advanced bladder cancer. Methods: Thirty-eight patients with measurable bladder cancer who had received no prior chemotherapy for metastatic disease were scheduled to receive gemcitabine 1,000mg/m2 intravenously over 30 minutes on days 1, 8, and 15 and cisplatin 75mg/m2 over 1 hour on day 2 of a 28-day cycle. Patients were treated with six cycles, unless disease progression or severe toxicity. Primary end point was overall survival. All toxicities were compared with previous our MVAC therapy results. Thirty-five patients were scheduled to receive MVAC therapy (methotrexate 30mg/m2, vinblastin 3mg/m2, doxorubicin 30mg/m2 puls cisplastin 70mg/m2). Results: There were six complete responses and 17 partial responses in 38 assessable patients, for an overall response rate of 23 of 38 (60.5%). The median survival was similar on both threatment group and 26 patients who had received GC therapy still alive at this time. Toxicity was primarily hematologic, with 3 of 38 patients (7.9%) having grade 3 anemia, with 6 of 38 patients (15.7%) having grade 3 granulocytopenia and 2 of 38 (5.2%) having grade 3 thrombocytopenia. Three patients had severe gastro-intestinal symptom and one patient had severe low performance status. More GC than MVAC had high grade granulocytopenia(15.7% v 33.3%, p<0.05). All patients required a dose modification of gemcitabine at some point in their therapy; the primary reason was thrombocytopenia and/or neutropenia. Conclusions: Gemcitabine plus cisplatin therapy is an active regimen for the treatment of advanced bladder cancer and better safety profile and tolerability than MVAC therapy. No significant financial relationships to disclose.

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer

Determining patient preferences for improved chemotoxicity during treatment for advanced bladder cancer Conventional treatment for advanced bladder cancer is methotrexate, vinblastine, doxorubicin plus cisplatin (MVAC), with a median survival of 1 year but significant toxicity. The newer combination of gemcitabine plus cisplatin (GC) has demonstrated comparable survival and an improved toxicity profile (Von der Maase et al. 2000). At present, the importance to patients of the toxicity of chemotherapy has not been widely studied. An earlier study in bladder cancer indicated that toxicity was an important determinant of treatment preference (Davey et al. 2000). A study of preferences for advanced bladder cancer therapy in the UK was proposed.

FOLFOX-4 in Pre-treated Patients with Advanced Transitional Cell Carcinoma of the Bladder

Despite recent progress in the treatment of advanced urothelial cancer, there continues to be a need to identify new active agents and their toxicity spectra. We conducted a study using FOLFOX-4 (oxaliplatin, fluorouracil, folinic acid) in pre-treated advanced bladder cancer patients. Sixteen eligible patients with advanced disease were treated with oxaliplatin (85 mg/m(3)) on day 1 followed by fluorouracil and folinic acid (De Gramont schedule) on days 1 and 2 every 14 days until disease progression. All patients received nutritional support to increase their caloric intake. Objective responses and toxicity were evaluated. Biochemical responses (reduction of markers) and nutritional parameters (increase in body weight and albumin, and reduction in ferritin and C-reactive protein) were also considered. Three patients obtained an objective response (overall response rate 19%). Hematological toxicity and stomatitis were the most commonly noted side effects, but we observed only low (3-4) grade toxicity. In four patients (25%), we observed a reduction in tumoral markers (carcinoembryonic antigen and tissutal polypeptide antigen) and modified nutritional parameters. Using these doses and schedules of FOLFOX-4 appears to be a promising therapy in patients pre-treated with platinum compounds. More studies are required to assess the possible role of this regimen in the treatment of advanced bladder cancer.

Organ-sparing treatment of advanced bladder cancer: First experience with paclitaxel as alternative to cisplatin

Transurethral resection (TUR-BT) and radiochemotherapy with cisplatin achieve high rates of bladder preservation and survival figures identical to radical cystectomy. Cisplatin, if administered concurrently with radiation, improves local control. However, a minority of patients has contraindications to cisplatin. We have used paclitaxel as substitute for cisplatin in these poor-risk patients. From October 1997 through March 2004, 36 patients (35 males, 1 female) with muscle-invasive (N = 27) or recurrent (N = 9) urothelial bladder cancer were treated with radiotherapy plus simultaneous paclitaxel. The median age was 69 years (range 42–80 years). T-category was Ta/1 in 3 patients (8%), T2 in 14 (39%), T3 in 9 (25%) and T4 in 10 (28%). One patient had enlarged regional nodes on imaging studies, the others were cN0. Grading was G1-2 in 6 tumors (17%) and G3 in 30 (83%). 33 patients had undergone TUR-BT prior to radiotherapy and the radicality of the TUR-BT was R0 in 12 pats. (33%), R1 in 3 (8%), R2 in 13 (36%) and RX in 5 (14%); the remaining 3 patients (8%) were treated after unradical cystectomy. 10 patients had severe hydronephrosis requiring unilateral (N = 8) or bilateral (N = 2) percutaneous nephrostomy. 33 patients were treated with curative intent and 3 (including two with distant mets) with palliative intent. Patients were treated with a conventional radiation regimen (5 fractions per week with 1.8Gy up to 56.0 ± 3.7 Gy, range 45-61.2Gy). Paclitaxel was administered twice weekly in a dose of 30mg/m2 as 1h-infusion after standard premedication; 4 pats. were treated with a reduced dose of paclitaxel (25 or 20mg/m2) and 3 pats with a higher dose (35mg/m2). 3 patients received additional cisplatin. The median treatment time was 46 days (range 31–71 days). Feasibility and toxicity: 29 pats. completed the scheduled chemotherapy. In seven patients, reductions in chemotherapy or earlier termination were necessary due to diarrhea (N = 6), cardiac problems (N = 1) or patients’ desire (N = 2). Hematological toxicity was mild to moderate in all cases; 6 anemic patients (hb<11g/dl) received transfusions (N = 2), erythropoietin (N = 3) or both (N = 1). 14 patients (39%) developed grade 1–2 and 9 (25%) grade 3 enteritis. The serum creatinine remained stable in 19 pats (53%), slightly increased in 8 (22%) and improved in 9 patients. Severe renal toxicities requiring dialysis or unplanned hospitalisation did not occur. 2 pats. experienced nausea and emesis grade 2. Other toxicities which are frequently associated with the administration of paclitaxel (neurological toxicity, alopecia, and allergy) were not observed. Response: 2 patients had early progressive disease. Further 8 patients did not undergo restaging-TUR because they were no candidates for cystectomy or treated with palliative intent. 26 patients underwent restaging TUR-BT six weeks after radiochemotherapy and 22 achieved a histologically proven complete remission and 4 a partial remission. 3 patients developed a local recurrence and 4 distant metastases. 11 patients have died from tumor (N = 7), intercurrent disease (N = 3) or unknown causes (N = 1). The 3-year overall survival was 40 ± 13%. Radiochemotherapy with paclitaxel was feasible in this high-risk group with adverse prognostic factors. The toxicity profile, especially with regard to renal toxicity, suggests that paclitaxel is an alternative in patients with contraindications to cisplatinum. The pathological response rate was encouraging in this series but requires further investigation

Organ-sparing treatment of advanced bladder cancer: First experience with paclitaxel as alternative to cisplatin

Organ-sparing treatment of advanced bladder cancer: First experience with paclitaxel as alternative to cisplatin

Gemcitabine and oxaliplatin combination: A multicenter phase II trial in unfit patients with locally advanced or metastatic urothelial cancer

4544 Background: Although cisplatin is considered the cornerstone for the treatment of advanced bladder cancer, up to 50% of the patients (pts) cannot receive it because they are considered unfit m...

Gemcitabine and oxaliplatin combination: A multicenter phase II trial in unfit patients with locally advanced or metastatic urothelial cancer

4544 Background: Although cisplatin is considered the cornerstone for the treatment of advanced bladder cancer, up to 50% of the patients (pts) cannot receive it because they are considered unfit mainly due to poor renal function. New non nephrotoxic regimens are needed. Gemcitabine and oxaliplatin are active, non-nephrotoxic and with non-overlapping toxicity and therefore being attractive to be studied in combination for unfit bladder cancer patients. Methods: Thirty-six pts unfit (mainly due to renal function,creatinine clearance < 60 mL/min) to receive standard cisplatin-based treatment were included in this multicentric phase II. We describe here the first 27 patients and give response data from the first 12 evaluable pts. Median age was 69 years (range 60–81), 24 male and 3 female, median ECOG was 1 (range 0–2). Three pts had received previous adjuvant chemotherapy and 2 were previously treated with radiotherapy. Fifteen pts had one or two metastatic sites and 12 pts had more than two metastatic sites. Calculated median creatinine clearance was 48 mL/min (range 30–76). Patients were treated with gemcitabine 1200 mg/m2 d 1 and 8 and oxaliplatin 100 mg/m2 on day 8 every 21 days. Results: Median number of cycles was 3 (range 1–6). A total of 74 cycles are evaluable for toxicity. Grade 3–4 hematological toxicity was mild. Grade 3 anemia was reported in 19% of the cycles Grade 3 thrombopenia in 11.5% and Grade 3–4 neutropenia in 4.6% of the cycles. Hospitalization due to neutropenia and fever was required for 2 pts. So far 12 pts are evaluable for efficacy for an overall response rate of 50% (6 partial responses, 5 stabilizations and 1 progression).Conclusion: Gemcitabine-oxaliplatin is an active and tolerable combination in unfit patients with locally advanced or metastatic urothelial cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co.; Sanofi-Synthelabo

Role of gemcitabine/cisplatin in the treatment of advanced and metastatic bladder cancer

M-VAC combination chemotherapy was considered as the "gold standard" of the treatment of advanced and metastatic bladder cancers. Arrival of gemcitabine or taxanes in the 90s attracted attention since their efficacy was combined with low toxicity profiles. Gemcitabine/cisplatin combination became the most frequently studied treatment modality in the past 3 years. Multicentric, multinational randomized phase-III study indicated that in bladder cancer the gemcitabine/cisplatin combination is equal to M-VAC while in the case of the former the risk to benefit ratio is lower. Accordingly, gemcitabine/cisplatin combination is a safer treatment option in advanced and metastatic bladder cancer and is a real alternative to M-VAC. In the case of patients where cisplatin cannot be administered due to poor renal function, the new drugs with better toxicity profiles provide further treatment options.

323 Treatment of advanced bladder cancer

323 Treatment of advanced bladder cancer

Combination with CD/5-FC gene therapy enhances killing of human bladder-cancer cells by radiation.

Resistance to radiation and chemotherapy is a significant obstacle to the treatment of advanced bladder cancer. Gene therapy combined with radiation represents a new approach to cancer treatment. In the present study, we investigated whether adenovirally directed, cytosine deaminase (CD)/5-fluorocytosine (5-FC) gene therapy could induce cell toxicity and radiosensitization through the intracellular production of 5-fluorouracil (5-FU) in bladder-cancer cells. Three human bladder-cancer cell lines, KK47 (wild-type p53+), T24 (p53 mutated) and 5637 (p53 mutated), were investigated. A recombinant adenovirus vector containing the CD gene (Ad-RSV-CD) was used. Cells were infected with Ad-RSV-CD and treated with 5-FC. Forty-eight hours after infection, the cells were irradiated and cytotoxicity assays performed to determine the extent of increase in in vitro cytotoxicity. A KK47 subcutaneous tumor-xenografts model was used in an animal study to examine the tumor growth inhibitory effect of this combination therapy. Ad-RSV-CD was directly injected into the tumor and daily 5-FC was intraperitoneally injected. Forty-eight hours after injection of Ad-RSV-CD, the tumor was irradiated. The tumor volume was measured every day. In all three cell lines, the combination treatment enhanced the cell killing of human bladder-cancer cells in vitro. It also enhanced the tumor-growth inhibition in the KK47 tumor model. In the present study, we demonstrated that CD/5-FC gene therapy combined with radiation therapy enhances cell killing of human bladder-cancer cells in in vitro and in vivo animal models.

BCL2 expression predicts survival in patients receiving synchronous chemoradiotherapy in advanced transitional cell carcinoma of the bladder.

It has been reported previously that BCL2 expression predicted a poor response to neo adjuvant chemotherapy but had no prognostic significance in patients receiving radiotherapy alone. We therefore investigated its role in patients receiving synchronous chemoradiotherapy as treatment for advanced bladder cancer. We examined expression of BCL2 and P53 by immunohistochemical analysis using archival tissue samples taken from patients included in the phase I/II trial of synchronous chemoradiotherapy for advanced transitional cell carcinoma (TCC) of the bladder. Data were collected on 24 patients who presented with invasive bladder cancer to the Queen Elizabeth Hospital between March 1998 and January 2001. Eleven patients had died at the time of analysis, with median follow-up of 34 months for the 13 surviving patients. Median survival for patients with strongly BCL2 positive tumours was 12.8 months while, for BCL2 weak or negative patients, the median is yet to be reached (p=0.03). The hazard ratio was 3.37 in favour of BCL2 negative tumours having longer survival. This study shows that over-expression of BCL2 in patients receiving synchronous chemoradiotherapy is an independent indicator of poor survival in muscle invasive TCC of the bladder.

Gallium nitrate in the treatment of bladder cancer.

For over 15 years, the MVAC regimen (methotrexate/vinblastine/doxorubicin/cisplatin) has been standard chemotherapy for patients with unresectable or metastatic bladder cancer. The taxanes and gemcitabine have provided new treatment options, but development of more effective regimens is needed. Gallium nitrate has significant activity as a single agent in the treatment of advanced bladder cancer, including activity in heavily pretreated patients and patients previously treated with MVAC or single-agent cisplatin. At a dosage of 300 mg/m(2) daily by continuous infusion for 5 to 7 days every 3 weeks, toxicity has been acceptable in the treatment of patients with refractory disease. Gallium nitrate is also active in combination regimens for advanced bladder cancer. Because it has a different mechanism of action, minimal myelosuppression, and activity in previously treated patients, gallium nitrate may be useful as a single agent in patients with advanced bladder cancer who fail front-line chemotherapy regimens. Evaluation of gallium nitrate in combination with newer agents such as the taxanes or gemcitabine may also be warranted given its activity, different mechanism of action, and non-overlapping toxicity profile.

MURINE IL-2 SECRETING RECOMBINANT BACILLUS CALMETTE-GUÉRIN AUGMENTS MACROPHAGE-MEDIATED CYTOTOXICITY AGAINST MURINE BLADDER CANCER MBT-2

This study was to establish a more effective anti-cancer immunomodulating agent by constructing recombinant (r) Bacillus Calmette-Guérin (BCG) secreting alpha-antigen (alpha-Ag) fused murine (m) interleukin (IL)-2, and to study its biological activity on cell-mediated cytotoxicity against murine bladder cancer cell, MBT-2, in vitro. pSO246 plasmid vector ligated with mIL-2 gene was introduced into BCG by electroporation. Thioglycollate-elicited murine peritoneal exudate cells (PEC) were stimulated in vitro with parental BCG or rBCG and their cytotoxic activity and the cytokine production was studied. Cytokines were assayed by an enzyme-linked immunosorbent assay (ELISA) and L929 bioassay. Cytotoxicity was measured by 51Cr releasing assay. rBCG (alpha-Ag-IL-2) secreted functional IL-2 and augmented more efficient cytotoxicity to MBT-2 and cytokines such as IL-12, tumor necrosis factor and interferon (IFN)-gamma in PEC than parental BCG did. rBCG (alpha-Ag) had the same activity as BCG. Anti-IL-2 antibody reduced rBCG (alpha-Ag-IL-2)-mediated cytotoxicity and IFN-gamma production. Exogenous IL-2 also enhanced BCG-mediated cytotoxicity, but 100 times more IL-2 was required to express the same activity as rBCG (alpha-Ag-IL-2). Anti-IL-12 neutralizing antibody and the depletion of T cells and NK cells reduced IFN-gamma production by PEC stimulated with rBCG (alpha-Ag-IL-2), suggesting that T cells, NK cells and IL-12 participate in the enhancement of IFN-gamma production. rBCG secreting IL-2 showed significant antitumor activity and cytokine production and this will be a promising agent for bladder cancer patient to reduce both clinical dose and side effects of BCG for immunotherapy.