Treatment Of Advanced Bladder Cancer Research Articles

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.

Neo-adjuvant and adjuvant treatment of locally invasive bladder cancer.

Since Sternberg et al. in 1985 first published preliminary results of polychemotherapy in patients with metastatic bladder cancer, it became apparent that transitional carcinoma of the bladder is highly responsive to chemotherapy. Response rates up to 70% with combination therapy regimens like methotrexate, vinblastine, doxorubicin or adriamycin and cisplatin promised that transitional carcinoma might be able to cure even in advanced stages. Chemotherapy has either been applied prior to the local treatment (such as radical cystectomy or radiotherapy) in a neo-adjuvant regimen, or after local therapy in an adjuvant regimen. Although a large number of studies have been published in the past 20 years, the role of the different chemotherapeutic approaches has not been clearly defined. Therefore, neither neo-adjuvant nor adjuvant chemotherapy can be recommended as 'gold standard' treatment for advanced bladder cancer.

Treatment of Advanced Bladder Cancer With Combined Preoperative Irradiation and Radical Cystectomy Versus Radical Cystectomy Alone: A Phase III Intergroup Study

Our study was designed to compare the effects of preoperative irradiation and cystectomy to surgery alone in patients with transitional cell carcinoma of the bladder. A total of 140 patients with documented invasive bladder cancer or rapidly recurring superficial high grade tumors was randomized to receive 2,000 rad of pelvic irradiation followed by cystectomy within 1 week or surgery alone. The 5-year survival rate was 53% (95 confidence intervals 41 to 65%) in the surgery only group and 43% (95% confidence intervals 30 to 56%) in the irradiation plus surgery group. The p value for the log rank statistic comparing the survival distributions was 0.23. Although this trial showed no benefit for preoperative irradiation and cystectomy, the confidence intervals were wide. This finding does not exclude the possibility of a favorable effect of radiation in a subset of patients with high stage tumors. Overall, however, the dominant effect of distant disease as a cause of treatment failure diminishes any potential impact of radiation on results.

Treatment of Advanced Bladder Cancer With Combined Preoperative Irradiation and Radical Cystectomy Versus Radical Cystectomy Alone

Treatment of Advanced Bladder Cancer With Combined Preoperative Irradiation and Radical Cystectomy Versus Radical Cystectomy Alone

10-year survival rate in 92 patients with invasive bladder carcinoma treated by bladder sparing methods.

The 10-year survival rate was evaluated in 92 patients with invasive bladder cancer (stages T 2 to 4) who were treated between 1966 and 1985 using bladder-sparing methods such as intravesical instillation of antineoplastic agents, transurethral resection, partial cystectomy, arterial infusion chemotherapy, radiation and embolization of the internal iliac artery. The overall 5-year and 10-year survival rates were 68.1% and 53.9% respectively at a median follow-up period of 60 months. The 10-year survival rate for patients with clinical stage T 2, T3a, T3b and T 4 were 83.7%, 58.9%, 50.8% and 0%, respectively. Our data were comparable or superior to those following radical cystectomy combined with pre- and post-operative radiation or chemotherapy. In conclusion, our bladder-sparing conservative method is thought to be an alternative treatment for advanced bladder cancer and provides a favorable survival rate as well as an improved quality of life with preservation of bladder function.

1157 CMV and CaMV in the treatment of advanced bladder cancer

From June 1992 to March 1995,28 patients (pts) with advanced bladder cancer were treated with CMV cytostatic regimen (14 pts; day 1: methotrexate 40 mg/m2 e.v., vinblastine 4 mg/m2 e.v.; day 2: cisplatin 90 mg/m2 e.v.; day 8 =day 1; every 21 days) or with CaMV schedule, if serum creatinine was > 1. 5 mg/dl (14 pts; cisplatin substituted by carboplatin, according to renal function, following Calvert formula; every 28 days). Pts’ characteristics were: 23 males, 5 females; median age: 62.5 (range 49–76) median performance status (ECOG): 1 (range 0–2). Sites of disease involvement: locoregional spreading in 13 pts; nodal metastases (mts) in 15 pts; pulmonary mts in 4 pts; hepatic mts in 3 pts; bone mts in 1 patient (pt). Total number of administered cycles was 107 (median number of cycles per pt: 4; range 1–8). Grade 3 toxicity was: nausea and vomiting in 2 pts; anemia in 5 pts; leukopenia in 3 pts; thrombocytopenia in 2 pts; stomatitis in 3 pts. No grade 4 toxicity was reported. 25 pts were evaluable for the response; we observed: 3 (12%) complete remissions (CR), 8 (32%) partial remissions (PR), 4 (16%) stable diseases and 10 (40%) prog ressive diseases. Overall response rate was good (CR + PR = 44%) and toxicity was manageable and reversible.

Organ-sparing treatment of advanced bladder cancer: A 10-year experience

Purpose : Radical cystectomy is considered as standard therapy for muscle-invasive bladder cancer. We present 10-year results of bladder-sparing treatment by conservative surgery and radiotherapy ± chemotherapy. Methods and Materials : From 1982 through 1991, 245 consecutive patients, mean age 66 years, with invasive bladder cancer (T2-3 or poor prognostic T1, no distant metastases) entered a prospective protocol with the objective of bladder preservation. Treatment consisted of transurethral resection (complete, if possible) and definitive radiotherapy with 56 Gy maximum dose (50.4 Gy minimum target dose) in 28 fractions. Since 1985, 139 patients received a simultaneous chemotherapy on 5 days in the first and fifth treatment week with either 25 mg/m 2 cisplatin daily (79 patients) or 65 mg/m 2 carboplatin (60 patients). Cystectomy was performed as salvage treatment for residual or recurrent invasive disease. The median follow-up at the date of analysis (12-31-92) was 5.9 years. Results : The overall survival was 47% after 5 years and 26% after 10 years. The 5-year survival according to the initial T-category was 60% for T1 (44 patients), 64% for T2 (47 patients), 43% for T3 (127 patients), and 16% for T4 (23 patients). The most important single prognostic factor was the amount of residual tumor after TUR (5-year survival 80% after R0, 53% after R1, and 31% after R2 resection, p < 0.01). Chemotherapy increased the rate of complete remission, but had no impact on 5-year survival (52% vs. 50%). Fifty-three salvage cystectomies were performed, all without severe complications, and 192 patients (79%) maintained a normal functioning bladder. The bladder preservation rate in 5-year survivors was 83%. Conclusions : Organ-sparing treatment of advanced bladder cancer by transurethral surgery and definitive radiotherapy or radiochemotherapy is feasible and effective. The survival in this series is as good as in any comparable cystectomy series. Eighty-three percent of long-term survivors maintained their functioning bladders.

COMBINED TREATMENT APPROACHES IN REGIONALLY ADVANCED BLADDER CANCER

Multimodal therapy for locally advanced bladder carcinoma is being pursued in a wide diversity of protocols at this same time. While a number of innovative approaches are being explored, neoadjuvant and adjuvant chemotherapy in conjunction with cystectomy remains the dominant approach. The M-VAC regimen has become the dominant combination for the treatment of advanced bladder cancer; its use in an adjunctive setting is a logical progression. Although it is capable of effecting a response in the primary bladder lesion in a high percentage of cases, it is still not known whether survival will be enhanced. The use of radiosensitizing cytotoxics in conjunction with neoadjuvant chemotherapy, when combined with external-beam radiotherapy, is a provocative new approach that attempts to achieve both bladder salvage and enhanced patient survival. Completion of well-designed randomized studies will be necessary to determine whether these therapeutic innovations will yield any clinical benefit.

Treatment of advanced bladder cancer by submucosal injection of methotrexate in the anorectal area.

In 1988, Shafik et al. presented their first attempt to apply cytostatics in the treatment of pelvic malignancies. Experimentally and clinically, they studied the anal route for administration of methotrexate, and their first results showed that higher concentration of drugs can be achieved in the bladder wall compared to that in serum. Since December 1988, we have been engaged in experimental and clinical investigations of the possibilities this method might reveal. Experiments with animals have proven that submucosal injection of the cytostatic agent does not induce local changes. The clinical trial on 20 patients with tumors of stage T2-T4 has not shown side effects, either local or systemic. The treatment was well tolerated by the patients. Anorexia has been reported in 3, elevated temperature in 2 and leukopenia in 4 of 20 patients. Complete response has been documented in 3 (15%), partial response in 3 (15%), stabilization in 5 (25%) and progression of the disease in 9 (45%) of the patients. Mean duration of remissions was 10.3 months (range 9-12). The distribution of submucously injected contrast medium into the anorectal area has been studied by computerized tomography in 4 of the patients. Although our results do not support the original estimates of the inventors of the method, its ease of application, the possibility of out-patient administration and negligible side effects are sufficient arguments for performing further experimental and clinical studies.

Granulocyte-colony stimulating factor enhances the cytotoxic effects of methotrexate to bladder cancer cells in vitro.

It is possible that a strategy designed to stimulate cancer cells in the active cell cycle may increase the effectiveness of S-phase specific anti-cancer agents such as methotrexate. In this study, the effects of granulocyte-colony stimulating factor (G-CSF) on the proliferation of cultured human bladder cancer cells and on the cytotoxicity of anti-cancer drugs to bladder cancer cells were studied in vitro. The 3H-thymidine uptake of cultured human bladder cancer cells, KU-1 and NBT-2, was significantly higher when the cells were treated with 10 ng/ml G-CSF than without G-CSF after 24- and 48-hour incubation. However, the cell numbers of KU-1 and NBT-2 were not significantly affected by 72-hour treatment with 10 ng/ml G-CSF. The binding of 125I-labeled KW-2228, a muteins of G-CSF, to KU-1 and NBT-2 was inhibited by unlabeled KW-2228 in a concentration dependent manner, which demonstrated the presence of G-CSF receptors on both cells. Scatchard analysis showed that the receptor densities of KU-1 and NBT-2 were 1770 and 3070 per cell, respectively. The combination treatment with methotrexate and G-CSF resulted in a significant increase in cytotoxic effects, when compared with methotrexate treatment alone. This study supports the possibility that the combination therapy of methotrexate and G-CSF increases clinical response in the treatment of advanced bladder cancer.

Recombinant human tumor necrosis factor alone and with chemotherapeutic agents. Effect on nude mouse-supported human bladder cancer heterografts.

Although studies done in tissue culture (in vitro) have shown synergism between recombinant human tumor necrosis factor (rhTNF) and chemotherapeutic agents, whether such synergism exists in a complex in vivo environment with acceptable toxic side effects has not been determined, to our knowledge. The effect of rhTNF alone and in combination with cisplatin, etoposide, doxorubicin, or dactinomycin on the growth of heterotransplants of human bladder transitional cell carcinoma was studied using a modified subrenal capsule assay in athymic nude mice. Only etoposide potentiated rhTNF cytotoxicity; no increase in host toxicity was noted. Variably enhanced toxic side effects were seen with other combinations. It is concluded that rhTNF combined with etoposide may have potential clinically exploitable therapeutic "synergism" in the treatment of advanced bladder cancer.

Anal submucosal Injection: A New Route for Drug Administration in Pelvic Malignancies. II. Methotrexate Anal Injection in the Treatment of Advanced Bladder Cancer. Preliminary Study

The clinical efficacy of submucosal anal injections of methotrexate in advanced bladder cancer is investigated. An experimental study on 20 mice has shown that methotrexate injected into the anal submucosa has no clinicopathological effect on the anorectum. The clinical study comprised 18 patients with advanced bladder cancer (13 with stage T3 and 5 with stage T4 disease) as a test group in whom methotrexate was injected into the anal submucosa and 8 (6 with stage T3 and 2 with stage T4 cancer) treated concurrently with intravenous methotrexate. The dose in both groups was 50mg. every 5 days for 5 consecutive doses. The course was repeated at 3-week intervals. Most patients received methotrexate as outpatients. Methotrexate blood levels were measured 4 and 24hours after administration in both groups.In the test group 10 of the 18 patients showed complete tumor regression and were alive 21 to 50 months after the start of treatment. Partial regression was observed in 8 patients. Hematological reserve remained unchanged. Mild toxicity occurred in 3 patients. Of the 8 patients treated intravenously the tumor showed partial regression in 1, was stable in 3 and progressed in 4. Side effects were severe in 5 patients.Our results show that methotrexate injection is highly effective in the treatment of advanced bladder cancer. It is safe, well tolerated and can be used on an outpatient basis.

The treatment of advanced bladder cancer with methotrexate and cis-platinum—a pharmacokinetic study

As part of a phase III study in advanced bladder cancer, 5 patients received methotrexate (MTX) 50 mg/m 2 as a single agent every 2 weeks, and with every alternate dose of MTX (i.e. every 4 weeks) cis-platinum (CDDP) 50 mg/m 2 was given simultaneously, together with saline hydration and diuresis. The clearance of MTX was measured in a total of 12 courses by serial serum sampling for up to 72 hr following injection. In 4 patients (with a mean pretreatment creatinine clearance of 97 ml/min) there was no significant difference between the clearance of MTX when given alone [mean t 1 2 (β)) 3.2 hr] and when given 2 weeks later with concurrent CDDP [mean t 1 2 (β) 2.9 hr]. In 1 patient with a pretreatment creatinine clearance of 52 ml/min the clearance of MTX when given alone (without hydration) was significantly delayed compared with the clearance of MTX when given 2 weeks later concurrently with CDDP and saline hydration [ t 1 2 (β) 19 and 4.5 hr respectively]. Of the 5 patients so far treated with MTX-CDDP, 2 have had a partial objective response and 3 have had stable disease (including 2 with a marked subjective response). These data indicate that in patients with satisfactory renal function, low-dose MTX and CDDP may be given concurrently without risk of enhanced drug toxicity.

Methotrexate treatment for advanced bladder cancer. A review after 6 years.

British Journal of UrologyVolume 52, Issue 5 p. 403-403 Methotrexate Treatment for Advanced Bladder Cancer. A Review after 6 Years R. R. HALL, R. R. HALL Department of Urology, Freeman Hospital, Newcastle upon Tyne NE7 7DNSearch for more papers by this authorA. G. TURNER, A. G. TURNER Department of Urology, Peterborough and Stamford HospitalsSearch for more papers by this author R. R. HALL, R. R. HALL Department of Urology, Freeman Hospital, Newcastle upon Tyne NE7 7DNSearch for more papers by this authorA. G. TURNER, A. G. TURNER Department of Urology, Peterborough and Stamford HospitalsSearch for more papers by this author First published: October 1980 https://doi.org/10.1111/j.1464-410X.1980.tb03073.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume52, Issue5October 1980Pages 403-403 RelatedInformation

The treatment of advanced bladder cancer with methotrexate.

61 patients with advanced bladder cancer were treated with methotrexate. 3 different regimes were used, 2 given on an out-patient and 1 on an in-patient basis. A response rate of 56% was found in patients who received 100 mg of methotrexate intravenously every 2 weeks as an out-patient. Provided that renal function is checked before therapy and is normal, then methotrexate can be used safely; it being well tolerated and having few serious side-effects.

Treatment of advanced bladder cancer with adriamycin and 5-fluorouracil.

The cytotoxic drug combination of adriamycin and 5-fluorouracil has resulted in a 35% objective response in 20 patients with advanced bladder cancer. This has been achieved with minimal toxicity and on an out-patient basis. If the survival rate of patients with invasive bladder cancer is to be improved it seems likely that some form of systemic treatment will need to be added to the local measures currently in use. Further studies of different chemotherapeutic agents should help to define an effective and safe form of adjunvant therapy.

THE TREATMENT OF ADVANCED CARCINOMA OF THE BLADDER.

SUMMARYA five‐year experience of the treatment of advanced bladder cancer in a small Australian base hospital is presented. In the light of dissatisfaction with present treatment methods other avenues are being explored although the comfort of the patient must remain the prime consideration.