Therapy For Transitional Cell Carcinoma Research Articles

Monoinstitutional real world experience in management of Vinflunine as second line therapy for transitional cell carcinoma of the urothelium.

Vinflunine is the only cytotoxic agent tested as a second line therapy in transitional cell carcinoma of the urothelium in a phase III trial. It is not largely employed in clinical practice because of the high incidence of grade 3–4 toxicity. We evaluated efficacy and safety of Vinflunine at the dose of 280 mg/m2 every 3 weeks associated with primary prophylaxis with granulocyte growth factors and laxatives for patients progressed after platinum + Gemcitabine. Overall survival was 8.5 months, progression-free survival 4.33 months and response rate 25%, with disease control rate 57.2%. Grade III-IV neutropenia occurred in 10.7% of the patients, grade III-IV anemia and grade III thrombocytopenia in 10.7% and 7.2%, respectively. Among non haematological toxicity, grade I-II constipation was reported in 14.2% of the patients, without grade III-IV adverse events. No discontinuation for toxicity was observed. This study underlines that Vinfluinine at a dose of 280 mg/m2 associated with primary prophylaxis for neutropenia and constipation is effective and with a favorable toxicity profile.

A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma.

BackgroundEffective therapies for transitional cell carcinoma (TCC) are limited, with objective response rates to most chemotherapeutic regimens below 20%. The purpose of this study was to investigate the biologic activity of combined toceranib phosphate and vinblastine chemotherapy for treatment of TCC. A secondary objective was to compare the utility of Computed Tomography (CT) and abdominal ultrasound (AUS) in tumor response assessments.ResultsDogs with TCC received vinblastine at 1.6 mg/m2 every 2 weeks and toceranib at 2.5–2.75 mg/kg on Monday/Wednesday/Friday. Tumor monitoring was achieved through CT and AUS. Five patients completed the 16-week study. Based on AUS assessments, 3 dogs experienced biologic response to therapy including partial responses (PR, n = 2) and stable disease (SD, n = 1). Based on CT, 5 dogs experienced a biologic response (n = 2 PR, n = 3 SD). Both imaging modalities (ultrasound and CT) were found to provide repeatable measurements between operators, however agreement between operator measurements was greater when CT images were used to assess tumor size.ConclusionsThe combination of toceranib and vinblastine did not result in improved response rates. While agreement in tumor volume assessments between both AUS and CT were excellent between operators, this did not extend to assessment of tumor response. The higher rate of concordance between operators when assessing response to treatment with CT suggests that CT should be considered for future clinical trials involving canine bladder TCC to improve the accuracy and repeatability of tumor measurement. The data suggest that response to therapy as assessed by AUS or CT do not predict duration of clinical response.

The Feasibility of BCG and Sunitinib Combination Therapy for Transitional Cell Carcinoma

Currently, intravesical bacille Calmette-Guérin (BCG) instillation is the standard treatment for patients with an intermediate to high risk of bladder cancer. Nevertheless, BCG-refractory generation is a common process during treatment. We hypothesized that sunitinib, a vascular endothelial growth factor (VEGF) receptor inhibitor, can synergistically enhance the immunotherapeutic effect of BCG on bladder tumor growth. The 50% inhibitory concentration (IC 50 ) of BCG and sunitinib in various transitional cell carcinoma (TCC) cell lines was determined by the MTT method. The therapeutic effects of BCG, sunitinib, and their combination on MBT-2 tumors were investigated in both orthotopic bladder cancer and subcutaneously inoculated tumor models in mice. Evaluated parameters included the tumor growth rate and tumor burden in the bladder, tumor volume in the subcutaneous site, survival rate, serum cytokine changes, and mean vascular density in tumor tissues. BCG and sunitinib showed in vitro cytotoxicity to tested TCC cell lines with slight variations in IC 50 . Sunitinib had an in vitro synergistic effect on BCG cytotoxicity in TCC cells. BCG and sunitinib had individual tumor suppression activities in mice MBT-2 tumors in both the orthotopic and subcutaneous models. Surprisingly, synchronous combination treatment using BCG and sunitinib did not demonstrate synergistic suppression efficacy in animal tumor models. Inhibition of tumor growth, increased survival rate, and decreased mean vascular density were observed in mice treated with BCG, sunitinib, and synchronous cotreatment. In contrast, no therapeutic efficacy was seen in mice treated with BCG and sunitinib metachronously. BCG and the VEGF receptor inhibitor sunitinib had significant suppressive effects in mice bladder cancer models when administered individually. The underlying mechanisms by which they counteract cytotoxicity and the interaction of BCG and sunitinib during cotreatment require further investigation.

Selection of optimal antisense accessible sites of uroplakin II mRNA for bladder urothelium

The optimal antisense accessible sites (AAS) of uroplakin II (UP II) mRNA, a specific gene expressed in bladder urothelium, were selected in order to provide a novel method for targeted therapy of transitional cell carcinoma (TCC) of bladder. The 20 mer random oligonucleotide library was synthesized, hybridized with in vitro transcripted total UP II cRNA, then digested by RNase H. After primer extension and autoradiography, the AAS of UP II were selected. The RNADraw software was used to analyze and choose the AAS with obvious stem-loop structures, according to which the complementary antisense oligonucleotides (AS-ODN) were synthesized. With the AS-ODN(0) designed only by RNADraw as a control, the AS-ODNs were transferred into UP II highly-expressing cell line RT(4). The cellular expression of UP II mRNA was detected by RT-PCR and Western blot. Twelve AAS of UP II mRNA were selected in vitro. Four AAS with stem-loop structures were chosen, locating at 558-577, 552-571, 217-236 and 97-116 bp of UP II mRNA respectively. After transfection with the corresponding AS-ODN (AS-ODN(1), AS-ODN(2), AS-ODN(3) and AS-ODN(4)) for 18 h, the UP II mRNA levels in RT(4) cells were reduced by 29.3%, 82.7%, 71.3% and 70.9%, while UP II protein levels were decreased by 20.2%, 78.5%, 65.2% and 64.4% respectively, which were significantly higher than those of AS-ODN(0) (14.3%, 12.1% respectively) (P<0.01). The AAS of UP II mRNA was effectively selected in vitro by random oligonucletide library/RNase H cleavage method in combination with computer software analysis, which had important reference values for further studying biological functions of UP II gene and targeted therapeutic strategy for TCC of bladder.

Long-term effects of bacille calmette-guérin perfusion therapy for treatment of transitional cell carcinoma in situ of upper urinary tract

Objectives To report our experience with bacille Calmette-Guérin (BCG) perfusion therapy for transitional cell carcinoma in situ of the upper urinary tract. BCG perfusion therapy is widely used to treat transitional cell carcinoma in situ of the upper urinary tract. However, it has not yet been established as a standard treatment. Methods Ten patients diagnosed with transitional cell carcinoma in situ of the upper urinary tract were treated with BCG perfusion therapy from January 1990 to May 2002. BCG was instilled weekly for 6 weeks, with a median dose of 65 mg at 1.17 mg/mL (Tokyo 172 strain, dissolved in normal saline). Results The mean follow-up period was 50.9 months (range 12 to 134). The initial response to therapy was excellent, and cytology became negative in all patients after one course of BCG perfusion. Five patients developed recurrence after 5, 11, 24, 26, and 45 months, and all died after 46, 12, 41, 134, and 79 months, respectively. The mortality rate was 50% and was 100% in those with recurrence. The mean recurrence-free period was 22.2 months (range 5 to 45). Complications included bladder irritation-related symptoms in all patients, fever greater than 38°C (n = 9), hematuria (n = 2), hydronephrosis (n = 2), and lumbago (n = 1) but all were transient and did not affect long-term prognosis. Conclusions BCG perfusion therapy for carcinoma in situ of the upper urinary tract is safe, and the short-term response is excellent. However, the long-term results were not satisfactory. Therefore, this therapy should be considered experimental, although it may have potential benefits in delaying progression and possibly providing local control for patients in poor condition. Long-term studies are required for additional evaluation of BCG therapy.

Immunotherapy for bladder cancer.

The primary role of immunotherapy for bladder cancer is to treat superficial transitional cell carcinomas (ie, carcinoma in situ, Ta, and T1). Immunotherapy in the form of bacille Calmette-Guérin (BCG), interferon, bropirimine, keyhole limpet hemocyanin, and gene therapy is intended to treat existing or residual tumor, to prevent recurrence of tumor, to prevent progression of disease, and to prolong survival of patients. Presently, BCG is commonly used and is the most effective immunotherapeutic agent against superficial transitional cell carcinoma. Data support that BCG has a positive impact on tumor recurrence, disease progression, and survival. Proper attention to maintenance schedules, route of administration, dosing, strains, and viability is essential to obtain the maximum benefits of BCG immunotherapy. This review highlights and summarizes the recent advances concerning immunotherapy, with special emphasis on BCG therapy for transitional cell carcinoma.

New approaches to treatment of metastatic bladder cancer.

The combination of methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) has been the standard therapy for transitional cell carcinoma for over a decade. Despite evidence that MVAC can improve outcome in comparison with single drugs or other combinations in this disease, only a small fraction of patients (less than 4%) become long-term survivors, and the regimen is quite toxic. Attempts to improve upon the MVAC regimen have partially ameliorated its toxicity, but they have not clearly improved outcome. Recently, a number of new chemotherapeutic agents have become available. This report summarizes the current experience with these agents and combinations.

Allium sativum Potentiates Suicide Gene Therapy for Murine Transitional Cell Carcinoma

This study evaluated the synergistic effect of Allium sativum (AS) with suicide gene therapy for transitional cell carcinoma (TCC) of the bladder. Subcutaneous TCCs were established in syngeneic C3H/He mice with 1 × 105 MBT-2 cells. AS liquid extract was injected at the site of tumor transplantation on Day 1 for three weeks (Experiment I) and into the established tumors weekly for five weeks (Experiment II) in combination with or without gene therapy using a replication-defective adenoviral vector containing a herpes simplex virus thymidine kinase (HSV-TK) gene under the transcriptional control of Rous sarcoma virus (RSV) promoter (Ad-RSV-TK, 5 × 108 plaque-forming units) plus ganciclovir (20 mg/kg/day ip). AS demonstrated a statistically significant reduction in incidence of TCC (cumulative dose 25 mg of AS). Combination AS-suicide gene therapy significantly inhibited the tumor growth compared with the controls, which was evidenced by apoptosis on histomorphological and immunohistochemical studies. These results suggest that AS had a definite antitumor effect in inhibiting tumorigenesis and growth of TCC in a murine model. AS treatment combined with suicide gene therapy had significant additive antitumor effects on TCC and may provide a novel and effective treatment modality for TCC of the bladder.

RECURRENCE, PROGRESSION AND SUCCESS IN STAGE TA GRADE 3 BLADDER TUMORS TREATED WITH LOW DOSE BACILLUS CALMETTE-GUERIN INSTILLATIONS

Bacillus Calmette-Guerin (BCG) therapy is considered to be an effective prophylactic and therapeutic agent for high risk superficial transitional cell carcinoma of the bladder. Nevertheless, in a select uncommon population of stage Ta grade 3 superficial lamina-free tumors the results of this treatment have not yet been well established. We evaluated recurrence and progression rates, and the success of BCG therapy in a population with stage Ta grade 3 transitional cell carcinoma of the bladder. Of the 605 patients treated at our institution from 1982 to 1996 for the histopathological diagnosis of primary bladder cancer 32 (5.3%) with stage Ta grade 3 noninvasive primary bladder tumor were treated with intravesical instillations of 75 mg. Pasteur strain BCG in 50 ml. saline weekly for 6 weeks. At a followup of 2 to 13 years (mean 58.4 months) patients were evaluated with urinary cytology, cystoscopy, transurethral resection and random mucosal biopsies. Recurrence, grade and stage progression, death and causality were analyzed. Of the 32 patients 9 (28%) responded positively to BCG without recurrence, while disease recurred as stage Ta in 8 (25%) and T1 in 7 (22%), and progressed to muscle layer infiltration in 8 (25%). Four patients (12%) died of bladder cancer. The number of tumors at primary resection, gross examination, the mitotic index or an association with carcinoma in situ did not appear to be predictive factors of progression to muscle invasion. Urine cytology (I to II versus III to IV) appeared to correlate highly with progression and BCG response (p<0.001) with excellent sensitivity (1) but low specificity (0.67). Our study demonstrates the high progression potential of stage Ta grade 3 tumors, since nearly 50% recurred and 25% progressed to invasive disease. These results may be closely compared with the results of previous trials of stage T1 grade 3 disease. We suggest that recurrence should be detected at an early stage using long-term followup with strict observance of the surveillance protocols during a minimum 5-year tumor-free period.

Enhanced Adenovirus-Mediated Gene Transfer To The Urothelium For Gene Therapy Of Transitional Cell Carcinoma

Enhanced Adenovirus-Mediated Gene Transfer To The Urothelium For Gene Therapy Of Transitional Cell Carcinoma

Intravesical therapy for transitional cell carcinoma of the bladder: the community practice

Objectives. To assess how the community urologist employs intravesical therapy in patients with transitional cell carcinoma (TCC) of the bladder because most data on intravesical therapy reflect the experience of major referral centers. Methods. The medical records of 234 consecutive patients with TCC were reviewed. Sixty-nine patients received intravesical treatment before referral. The initial pathologic findings, the indication for treatment (eg, grade and stage, initial versus recurrent tumor), the schedule of intravesical therapy, and the drug selected for each course of treatment were assessed. Results. A total of 139 courses of intravesical treatment were given to 69 patients; thus, the avarage number of courses was 2.02 per patient. The drug used was bacillus Calmette-Guérin (BCG) in 81 (58%), mitomycin C in 34 (24%), thiotepa in 16 (12%), Adriamycin in 4 (3%), and unknown in 4 (3%). Intravesical treatment was given after transurethral resection of the initial tumor in 33 patients; the initial pathologic finding was high grade (ie, grade 3 or carcinoma in situ) and/or Stage T1 in 22, TaG1-G2 in 9, and unknown in 2. One course of treatment was administered to 34 patients (49%) and two or more courses to 35 patients (51%). Eleven patients with TaG1-2 tumors were treated repetitively despite failure, with an average of 3.5 courses per patient; the drug used was BCG in 44%. Nineteen percent of patients received maintenance therapy. Intravesical therapy had to be discontinued in 10 patients because of side effects; 8 patients (12%) developed small contracted bladders and severe irritative symptoms, 3 required cystectomy despite the lack of bladder cancer. Conclusions. Intravesical therapy in community practice conforms with the generally accepted indications for high-grade and T1 disease. However, the use of BCG for low-grade TCC appears to be quite common. Repeated courses may result in significant side effects. We emphasize that excessive treatment should be avoided for low-grade, Ta lesions and BCG reserved for patients with TaG3, carcinoma in situ, or T1 TCC.

Additional bacillus calmette-guérin therapy for recurrent transitional cell carcinoma after an initial complete response

Objectives To determine the success of additional bacillus Calmette-Guérin (BCG) therapy for transitional cell carcinoma recurring after a complete response (CR) to the initial treatment course of BCG. Methods All patients treated with BCG with a minimum follow-up of 5 years were reviewed to identify complete responders who subsequently recurred and received additional BCG therapy. The duration of initial response and the incidence and duration of a second CR were recorded. Results Of 11 patients with an initial CR to a 6-week course of BCG, 9 (82%) achieved a second CR and 5 of the 9 (42%) maintained tumor-free status beyond 5 years of follow-up (median 87 months, range 64 to 110). Patients who again recurred after the second CR did not benefit from further BCG therapy. Conclusions A repeat course of BCG is a reasonable option of therapy for transitional cell carcinoma that has recurred after a CR to a prior course of BCG. Careful monitoring by cytology, cystoscopy, and biopsy is mandatory to direct nonresponders to prompt alternative therapy and to ensure continued disease-free status among responders.

Intravesical suramin in the prevention of transitional cell carcinoma

Objectives. To examine the effects of intravesical suramin on N-methyl-N-nitrosurea (MNU)-induced bladder tumors in Fischer 344 rats. Methods. Multiple cohorts of female rats received four biweekly intravesical instillations of MNU. A control group received no other treatment, the experimental group received 25 mg/kg intravesical suramin twice a week beginning at week 6. Results. After 18 weeks from the first instillation of MNU, 60% to 65% of control animals developed papillary transitional cell carcinoma, compared with only 0% to 10% of the suramin-treated animals ( P = 0.01 to P = 0.0007). There was no local or systemic toxicity observed. Conclusions. Intravesical suramin is an effective chemopreventative therapy for transitional cell carcinoma in vivo with minimal toxicity.

Psoas Abscess Following Intravesical Bacillus Calmette-Guerin for Bladder Cancer: A Case Report

An 87-year-old man with an abdominal aortic aneurysm received intravesical bacillus Calmette-Guerin therapy for transitional cell carcinoma of the bladder. He presented 9 months later with a psoas abscess that mimicked a contained retroperitoneal abdominal aortic aneurysm rupture. The abscess cultures yielded Mycobacterium bovis. Recent transurethral resection and high voiding pressures after instillations of bacillus Calmette-Guerin may have led to distant dissemination of the drug.

The impact of squamous metaplasia in transitional cell carcinoma of the bladder

The authors report a case of squamous cell carcinoma of the bladder induced by radiation therapy for transitional cell carcinoma, possibly from sites of squamous metaplasia, which were present at the time of initial diagnosis. Although data in the literature are not sufficient at the moment in terms of implication on prognosis, foci of squamous metaplasia during the initial diagnosis of transitional cell carcinoma must be carefully sought and their presence warrants caution in utilizing irradiation in the management of the disease.

Transitional Cell Carcinoma of the Prostate Following Intravesical Therapy for Transitional Cell Carcinoma of the Bladder

From 1983 to 1986, 63 male patients received various regimens of intravesical therapy for superficial transitional cell carcinoma of the bladder. Of these 63 patients 10 were subsequently diagnosed as having transitional cell carcinoma of the prostate. Five of the 10 patients had no tumor remaining in the bladder at diagnosis of transitional cell carcinoma of the prostate. In 3 patients tumor in the prostate was more invasive than tumor in the bladder. In 2 patients tumor involvement was greater in the bladder than in the prostate.Patients undergoing treatment with intravesical therapy for transitional cell carcinoma of the bladder, especially those receiving multiple courses for prolonged periods, should be monitored closely for the development of transitional cell carcinoma of the prostate.

Porphyrin photosensitization and phototherapy.

Porphyrin photosensitization and phototherapy.

Prognostic indices for bladder cancer: An analysis of patients with transitional cell carcinoma of the bladder primarily treated by radical megavoltage X-ray therapy

A group of 889 patients who completed radical X-ray therapy for transitional cell carcinoma of the bladder during a 12 year period were analysed by a multivariate technique. The patient's age, tumour category, tumour size and haemoglobin level were shown to be independent prognostic covariates. A prognostic index was derived and four prognostic subgroups were identified. The prognostic index could divide patients within each T category into those with good, moderate, fair or poor prognosis. The 5 year actuarial survival rate for patients in the poor prognosis group was 5.8% compared to 69.8% for patients in the good prognosis group. Durable local tumour control after radical radiotherapy was also analysed by a multivariate technique. Tumour category, grade, haemoglobin and urea level were found to be significant covariates. A tumour control index was derived and two groups were identified corresponding to a high probability of lasting local control after radical radiotherapy (47.8% of patients) or a low probability of control (52.2%).

Salvage cystectomy following failed definitive radiation therapy for transitional cell carcinoma of bladder

Between 1971 and 1983 we performed 18 salvage cystectomies on patients with recurrent transitional cell bladder cancer initially treated with definitive radiation therapy (5,500–6,820 R). The interval between tumor diagnosis and radiation ranged from zero to twenty-one years (mean 3.5 years), and the interval between radiation therapy and cystectomy ranged between six months and twelve years (mean 2.5 years). Early major complications occurred in 5 patients, and there was one early and one late postoperative death. The overall patient survival from the time of diagnosis to death or the present (1985) ranged from two to thirty-one years (mean 9.8 years), and from the time of radiation to the present or death ranged from one to nineteen years (mean 6.2 years). The overall crude five-year survival from the time of cystectomy excluding 2 patients operated on in 1982 and 1983 was 50 per cent, however 3 of these patients died of cancer after five years. Breakdown of survival of these patients by stage demonstrated the best survival in patients with carcinoma in situ and Stage A or no neoplasm at the time of cystectomy. This report confirms the value of salvage cystectomy after radiation failure in invasive transitional cell bladder cancer.

Whole bladder photodynamic therapy for transitional cell carcinoma of bladder

Our preliminary studies indicate that the bulb-tip technique for whole bladder photodynamic therapy (PDT) illuminates the entire bladder mucosa and is applicable to the management of superficial transitional cell carcinoma of the bladder. This treatment modality may be an option to patients who are failures to other standard treatments. A randomized clinical study is needed to decide on PDT as a primary treatment of choice for transitional cell carcinoma of the bladder.