Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Characterization of an N-methyl-N-nitrosourea-induced autochthonous rat bladder cancer model.

Cohorts of 4- to 5-wk-old female Fischer 344 rats received four biweekly 1.5-mg doses of N-methyl-N-nitrosourea (MNU) intravesically and were sacrificed at various intervals. By 13 wk after initiation of the carcinogen, all animals have flat epithelial atypia and/or papillary transitional cell bladder carcinomas, and 67% of the lesions are histological Grade II or III. By 20 wk, 83% have gross bladder wall muscle-invasive tumors that eventually kill the host. There was no gross evidence of visceral metastases in any animal. This rat model of transitional cell carcinoma of the bladder is useful because: (a) all animals develop progressive neoplastic changes in situ within 4 mo after initiation of MNU treatment; (b) these lesions progress to grossly detectable bladder tumors which invade the bladder wall and kill the host; (c) this full progression of bladder epithelial cells from atypical hyperplasia through flat carcinoma in situ to transitional cell carcinoma occurs at discrete time points; (d) the histology of the grossly detectable tumors is that of invasive transitional cell carcinomas; and (e) no leukemias, breast cancers, lymphomas, or other non-bladder tumors are induced. Six MNU-induced bladder wall-invasive tumors were karyotyped, and all tumors were diploid with 42 chromosomes. Three of the tumors had apparently normal karyotypes, while three tumors had karyotypes containing one or more cytogenetic structural markers. One of these markers (i.e., 8p+) was observed in two of the three tumors. The level of expression of total ras p21 (N-, Ki-, and Ha-ras p21) and codon 12-mutated c-Ha-ras p21 (i.e., glycine to glutamic acid mutation in codon 12) in a series of these MNU-induced bladder tumors was determined by Western blot analysis. No increase in the total ras p21 nor any expression of codon 12-mutated c-Ha-ras p21 was detected in any of these tumors.

Basal Tumor Cell Isolation and Patient-Derived Xenograft Engraftment Identify High-Risk Clinical Bladder Cancers.

Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: To prospectively evaluate in a multicenter randomized trial the antitumor activity of CD8(+) tumor-infiltrating lymphocytes (TILs) in combination with low-dose recombinant interleukin-2 (rIL-2), compared with rIL-2 alone, after radical nephrectomy in metastatic renal cell carcinoma patients. PATIENTS AND METHODS: Between December 1994 and March 1997, 178 patients with resectable primary tumors were enrolled at 29 centers in the United States and Europe. Patients underwent total nephrectomy, recovered, and were randomized to receive either CD8(+) TILs (5 x 10(7) to 3 x 10(10) cells intravenously, day 1) plus rIL-2 (one to four cycles: 5 x 10(6) IU/m(2) by continuous infusion daily for 4 days per week for 4 weeks) (TIL/rIL-2 group) or placebo cell infusion plus rIL-2 (identical regimen) (rIL-2 control group). Primary tumor specimens were cultured at a central cell-processing center in serum-free medium containing rIL-2 to generate TILs. RESULTS: Of 178 enrolled patients, 160 were randomized (TIL/rIL-2 group, n = 81; rIL-2 control group, n = 79). Twenty randomized patients received no treatment after nephrectomy because of surgical complications (four patients), operative mortality (two patients), or ineligibility for rIL-2 therapy (14 patients). Among 72 patients eligible for TIL/rIL-2 therapy, 33 (41%) received no TIL therapy because of an insufficient number of viable cells. Intent-to-treat analysis demonstrated objective response rates of 9.9% v 11.4% and 1-year survival rates of 55% v 47% in the TIL/rIL-2 and rIL-2 control groups, respectively. The study was terminated early for lack of efficacy as determined by the Data Safety Monitoring Board. CONCLUSION: Treatment with CD8(+) TILs did not improve response rate or survival in patients treated with low-dose rIL-2 after nephrectomy.

Surgical therapy for locally advanced bladder cancer.

Radical cystectomy followed by a urinary diversion or an orthotopic neobladder remains standard treatment for patients with muscle-invasive bladder cancer. The advances in surgical technique and reconstructive options allow many patients to enjoy a high quality of life after surgical extirpation. For those unable or unwilling to undergo a radical cystectomy, several treatment alternatives exist, using aggressive TUR and combinations of chemotherapy and/or radiation. Continued investigations into the biological behavior of this malignancy, as well as the identification of more effective chemotherapeutic agents, will allow more definitive treatment approaches with improved outcomes.

An observational urodynamic evaluation of men with lower urinary tract symptoms treated with doxazosin.

OBJECTIVES: To assess the urodynamic changes in men with lower urinary tract symptoms (LUTS) suggestive of bladder outlet obstruction treated with doxazosin and to correlate these changes with voiding symptoms. METHODS: Fifty patients with LUTS were treated with doxazosin at a dose of 4 mg/day for 3 months. All men were initially evaluated by International Prostate Symptom Score (I-PSS) questionnaires, measurements of urinary flow rate, and complex urodynamic study. Those patients completing the 3-month study underwent repeat testing. RESULTS: Forty-four (88%) men underwent initial and follow-up urodynamic evaluation. The mean I-PSS improved from 20.6 to 10.5 (P < 0.001), mean peak urinary flow rate increased for 11.7 to 13.2 cc/s (P = 0.20), mean detrusor pressure at peak flow decreased from 9 3.6 to 83.0 cm H20 (P = 0.15), and mean cystometric bladder capacity increased from 266 to 304 cc (P = 0.07). Using the Abrams-Griffiths nomogram and number, more than 58% of patients remained obstructed after treatment with doxazosin for 3 months. Men with and without objective evidence of bladder outlet obstruction at the outset of the study had similar improvement in voiding symptoms. Most patients elected to continue treatment with doxazosin at the completion of the study (41/44, 93%). CONCLUSIONS: The majority of patients had objective evidence of persistent bladder outlet obstruction after treatment with doxazosin for 3 months despite significant benefit. The results of complex urodynamic evaluation did not predict treatment response in men with LUTS suggestive of bladder outlet obstruction. Urodynamic study does not appear to be helpful in the evaluation of patients with uncomplicated LUTS prior to treatment with doxazosin.

Benign adenomatous multicystic kidney tumor (Perlmann's tumor) and renal cortical carcinoma with adenomatous multicystic features: 12 cases.

OBJECTIVES: To re-examine clear cell cystic lesions of the kidney and to assess their potential clinicopathologic significance, as the long-forgotten diagnosis of benign adenomatous multicystic kidney tumor (Perlmann's tumor) has not been cited in the literature in more than 35 years. METHODS: We identified 12 patients between 1959 and 1996 who underwent a radical nephrectomy at our institution and were diagnosed with either adenomatous multicystic clear cell kidney tumor (n = 4) or with renal cell carcinoma (RCC) associated with features of adenomatous clear cell multicystic kidney tumors (n = 8). All diagnoses were reviewed histologically by a single pathologist. RESULTS: Nine of 1 2 patients had Stage T2NOMO disease, and 3 patients had Stage T1 NOMO disease. There were 8 men and 4 women. The average age at the time of surgery was 60.5 years (range 25 to 74). Six patients are still alive with a mean follow-up of 4.7 years (range 1.5 to 16.3) and have no evidence of recurrent disease. Of the 6 patients who died, mean survival time was 8.8 years (range 0 to 15.7). One patient died in the perioperative period, and the other 5 patients died of other causes, unrelated to their kidney tumor. CONCLUSIONS: Adenomatous clear cell multicystic kidney disease may represent a histologically distinct benign neoplasm, and its presence in association with RCC may confer a more favorable prognosis. Its distinction from usual solid hemorrhagic or focally necrotic RCC is important.

Doxazosin in men with lower urinary tract symptoms: urodynamic evaluation at 15 months.

OBJECTIVES: To assess the results of doxazosin treatment in men with lower urinary tract symptoms (LUTS) treated for 15 months and to correlate symptomatic changes with alterations in urodynamic measures. METHODS: After an initial 3-month treatment period with doxazosin 4 mg/day, 50 men with LUTS were given the choice of continued treatment with this agent or other therapeutic options. All patients were evaluated by International Prostate Symptom Score (IPSS) questionnaires and urodynamic evaluation initially and after 3 months of treatment. Patients were followed for an additional 12 months and those who continued doxazosin treatment underwent repeat urodynamic testing. RESULTS: Among the original 50 patients, 24 men (48%) continued doxazosin treatment for 15 months, 18 men (36%) discontinued therapy, and 8 men (16%) were either dead or lost to follow-up or had been diagnosed and treated for prostate cancer. Comparison of values at 3 and 15 months of follow-up (9.4 versus 13.4, P = 0.03) showed significant worsening of voiding symptoms, as assessed by the IPSS, in the 24 men still receiving doxazosin. This deterioration of subjective results with doxazosin occurred despite continued improvements in peak urinary flow rate (Qmax), detrusor pressure at peak flow (PdetQmax), and objective measures of obstruction (Abrams-Griffiths number) from 3 to 15 months of follow-up. CONCLUSIONS: Relief of voiding symptoms in men with LUTS treated with doxazosin over prolonged intervals of 15 months does not correlate well with changes in urodynamic measures.

Initial report on intravesical administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder.

OBJECTIVES: This study was designed to assess the pharmacokinetics, safety, and antitumor activity of intravesically administered AD 32, a novel anthracycline, in patients with transitional cell carcinoma (TCC) of the bladder. METHODS: Six weekly doses of AD 32 (200 to 900 mg) were administered to 32 patients with superficial TCC who were candidates for intravesical treatment. Serum drug levels were measured during the 6-hour period after administration of the first, third, and sixth doses. Patients underwent bladder evaluations at 3-month intervals to determine responses to treatment. RESULTS: Very low levels of unmetabolized AD 32 and its two primary metabolites were measured in serum. The lack of systemic exposure was confirmed by the finding of only a few minor systemic adverse events. Local bladder irritation, the main toxicity associated with intravesical administration of AD 32, persisted for several days after each instillation. The maximum tolerated dose was 800 mg. Thirteen patients had complete responses to treatment, including 8 who remained disease free for 12.1 to 38.5 months. CONCLUSIONS: AD 32 is an active drug for the treatment of superficial bladder cancer. Further studies of intravesical administration of AD 32 are warranted.

Metastatic bladder cancer. Natural history, clinical course, and consideration for treatment.

Patients with metastatic transitional-cell carcinoma of the bladder have a poor prognosis with brief survival. Controversy exists as to the clonality of bladder cancer, as well as the natural history of muscle-invasive disease that subsequently becomes metastatic. Newer molecular biologic techniques may help us identify and understand the molecular changes involved in transforming normal urothelium into the malignant phenotype. In addition, newer chromosomal markers may enable us to determine the prognosis and the potential for progression to invasion and metastases. Additional work to find the optimum doses and dosing schedules and combinations of chemotherapeutic agents for metastatic transitional-cell carcinoma will be necessary before we can improve survival for all patients with this disease.

Therapeutic options and treatment of muscle invasive bladder cancer.

Carcinoma of the bladder is the second most common genitourinary malignancy. Although several treatments exist, the gold standard therapy for muscle invasive bladder cancer (> or = stage T2) is cystectomy with urinary diversion. We review various surgical treatments for muscle invasive bladder cancer, focusing on the reported survival rates, complications, advantages and disadvantages of each therapeutic modality.

Medical management of patients with refractory carcinoma in situ of the bladder.

Bladder cancer is a common genitourinary malignancy and carcinoma in situ (CIS) of the bladder exists as a potentially aggressive variant of the superficial form of the disease. Treatment must reflect the unpredictable nature of this disease entity. In 1976, the use of intravesical Bacillus Calmette-Guerin (BCG) was described for the management of early stage bladder cancer. A subsequent report demonstrated efficacy in a cohort of patients with CIS of the bladder. Since this time, intravesical BCG has been recognised as the initial therapy for CIS of the bladder. Although a 6-week treatment with intravesical BCG has been established as standard therapy in patients with CIS, there has been no consensus as to the subsequent treatment for patients in the setting of failure to initial management with BCG. In addition, a number of reports have demonstrated an increased potential of adverse effects after repeated treatment with intravesical BCG. A variety of alternative immunological and chemotherapeutic agents have been developed in response to the limitations of BCG for patients with refractory CIS of the bladder. At present, valrubicin remains the only agent that is approved by the US Food and Drug Administration for the specific indication of CIS of the bladder unresponsive to intravesical BCG. Although these agents appear promising, the most efficacious therapy remains to be determined. The specific treatment protocol for refractory CIS of the bladder remains elusive. It is ultimately the combined decision of the clinician and patient to determine which course of management is most beneficial.

Intravesical valrubicin in the treatment of carcinoma in situ of the bladder.

The propensity of patients with carcinoma in situ (CIS) of the bladder to progress to invasive and metastatic disease is clearly established. Today, the standard therapy in treating patients with CIS of the bladder is intravesical bacillus Calmette-Guerin (BCG). Nevertheless, patients who fail intravesical BCG have few viable options except to undergo a radical cystectomy. Valrubicin (N-trifluoroacetyladriamycin-14-valerate) is a new semisynthetic derivative of the anthracycline antibiotic doxorubicin that has been shown to benefit patients with BCG-refractory CIS of the bladder. Intravesical instillation of valrubicin is well-tolerated, safe and can be durable. Early non-randomised studies show promise and the current utilisation of this drug is limited to patients with BCG-refractory CIS of the bladder who are not good surgical candidates. Randomised studies of intravesical valrubicin for the treatment of superficial bladder cancer are ongoing.

The dimensions and symmetry of the seminal vesicles.

The traditional anatomical description of the seminal vesicles is based on autopsy and imaging studies. Trans-peritoneal robotic-assisted laproscopic surgery, with its three-dimensional magnified view and miniature articulated working instruments, provides an opportunity to perform accurate dissections of the seminal vesicles even when extremely long and tortuous. We used specimens obtained by robotic-assisted laparoscopic radical prostatectomy (RLRP) for accurate anatomic assessment of the dimensions of the seminal vesicles. Digital photos of 78 specimens from men (mean age 59 ± 6.1 years) who underwent RLRP were analyzed using the Image Pro Plus software. Seminal vesicle dimensions were correlated with patients' age, weight, height, prostate weight, sexual function profile (SHIM) and symptom severity score of the lower urinary tract symptoms (IPSS). We found that the length of the seminal vesicles is highly variable (range of 8.5-94.6 mm). The average seminal vesicle length was 31 ± 10.3 mm and its average volume 7.1 ± 5.2 ml. The right seminal vesicle was significantly larger than the left in length, width and volume (P < 0.003). The seminal vesicles were found to be highly asymmetric with a mean difference of 17.8% in length and 24.9% in width between the sides. No correlation between seminal vesicle dimensions and any of the parameters tested was found. We concluded that the normal human seminal vesicles are characterized by marked (11-fold) variation in length and are asymmetric in most patients. The right seminal vesicle is significantly larger than the left. Seminal vesicle dimensions cannot be predicted from other morphometric or physiologic parameters.

Salvage radical prostatectomy for radio-recurrent prostate cancer: is this a viable option?

The role of salvage prostatectomy for radio-recurrent prostate cancer remains unclear. Recurrent prostate cancer after radiation therapy is in many cases biologically aggressive. It is unclear whether the biologic aggressiveness of radio-recurrent prostate cancer is due to time-dependent cancer clonal evolution (potentially induced by radiation damage), or is due to an innately aggressive tumor secondary to overexpression or mutation of apoptotic inhibitors that render these tumors resistant to radiation. Recent studies examined the role of DNA ploidy, p53 and bcl-2 expression, proliferative indices and glutathione S-transferase-pi in predicting response to radiation therapy or salvage prostatectomy. Because of the potential for significant morbidity after salvage prostatectomy, preoperative parameters that aid in the identification of the patients who are most likely to benefit from surgery are needed.

The limits of bacillus Calmette-Guerin for carcinoma in situ of the bladder.

PURPOSE: Historically carcinoma in situ of the bladder has been treated with radical cystectomy based on the aggressive and potentially invasive nature of this disease. The introduction in the late 1970s of intravesical bacillus Calmette-Guerin (BCG) has made this therapy the gold standard in the management of carcinoma in situ. Cases that are refractory or resistant to BCG therapy are a management dilemma with various available treatment options. MATERIALS AND METHODS: A comprehensive literature review of the current management of carcinoma in situ of the bladder was performed using MEDLINE, a review of current urology journals and abstracts from recent urology meetings. Data focused on BCG resistant carcinoma in situ of the bladder and current approaches in use for refractory disease. RESULTS: Complete and durable response rates have been reported in more than 70% of patients with carcinoma in situ who are treated with intravesical BCG. To our knowledge the optimal therapeutic regimen has not been established, although extended periods of treatment beyond the originally described 6-week course have not been shown to improve complete response rates. Prolonged administration of BCG is associated with adverse side effects. Various prognostic indicators of recurrence and progression exist that may identify a subset of cases unlikely to respond favorably to a conservative approach, including carcinoma in situ with associated stage T1 bladder lesions, diffuse and multifocal carcinoma in situ, multiple recurrences with intravesical therapy and extravesical involvement. Current molecular markers may also predict the response of carcinoma in situ to therapy. Treatment options available for BCG refractory carcinoma in situ of the bladder include intravesical chemotherapy, combined immuno-chemotherapy and radical cystectomy. Intravesical valrubicin and oral bropirimine have been shown to induce a complete response rate of 21% to 50%, although data on long-term followup are forthcoming. Radical cystectomy remains effective therapy for aggressive carcinoma in situ of the bladder. CONCLUSIONS: The current management of carcinoma in situ of the bladder is ill defined due to the variable natural history and unpredictable response of this disease to therapy. Controversy exists as to the optimal treatment of carcinoma in situ of the bladder since different forms of carcinoma in situ may exist that complicate therapeutic decisions for appropriate therapy. Some tumor characteristics are associated with more aggressive behavior and may be predictive of treatment outcome.

Complications of cystectomy in patients with a history of pelvic radiation.

OBJECTIVES: To compare the complications occurring during the first year of follow-up after radical cystectomy in two groups, one with and one without a history of pelvic radiation. Radical cystectomy and urinary diversion is the treatment of choice for invasive bladder cancer. METHODS: One hundred ninety-four cystectomies were performed between January 1995 and June 2000 by a single surgeon. Twenty-three patients were identified with a history of external beam radiotherapy to the pelvis (EBRT group), and 23 additional patients without a history of pelvic radiation were randomly selected to serve as the control group. RESULTS: Although the overall risk of having a complication was not statistically different in the EBRT group (48%) than in the control group (30%; P = 0.183), complications directly related to surgery were higher in the EBRT group than in the control group (48% versus 26%; P = 0.045). The patients in the EBRT group were more likely to require an invasive procedure (39% versus 9%; P = 0.018). In addition, 5 (22%) of 23 patients in the EBRT group had a symptomatic fluid collection, which was diagnosed as a urine leak (n = 2) or an abdominal abscess (n = 3). In contrast, no patient in the control group developed a symptomatic fluid collection. CONCLUSIONS: Cystectomy after pelvic radiation is associated with acceptable morbidity; however, compared with cystectomy performed in a nonirradiated pelvis, the risk of complications that will require invasive intervention is increased. A history of prior pelvic radiation significantly increases the risk of a symptomatic fluid collection.

The current status of bladder preservation in the treatment of muscle invasive bladder cancer.

PURPOSE: Bladder preserving strategies for muscle invasive bladder cancer have evolved from single modality to multimodality treatment approaches with improved results. MATERIALS AND METHODS: We review the rationale for a multimodality approach to treat invasive bladder cancer and the results of some recent multimodality bladder sparing treatments. In addition, we compare this approach to radical cystectomy. RESULTS: Multimodality bladder sparing treatment involves combined transurethral bladder resection, external beam radiation with concurrent radiosensitizers and cisplatin based chemotherapy. With this approach overall 5-year survival is 48% to 63% and overall 5-year survival with the bladder intact is 36% to 43%. Survival with this approach is comparable to that in series of patients treated with primary radical cystectomy. The primary impetus for a multimodality bladder sparing approach is the improved quality of life associated with retaining the native bladder. However, the multimodality bladder sparing approach involves a complex treatment schedule associated with significant morbidity and mortality. Cystectomy is eventually required after attempted bladder preservation in 34% to 45% of cases and the rate of superficial recurrence is approximately 28%. CONCLUSIONS: Multimodality bladder sparing treatment is a viable option at centers with a dedicated multidisciplinary team. However, primary radical surgery remains the standard of care for invasive bladder cancer.

Endourologic treatment of renal pelvic and ureteral transitional cell carcinoma.

Endoscopic treatment of patients with upper urinary tract transitional cell carcinoma is recommended in those with tumor in a solitary kidney, bilateral disease, renal dysfunction, and significant intercurrent illness that precludes a major abdominal surgical procedure. Endoscopic management also may be appropriate in selected patients with small, low-grade lesions in the presence of a normal contralateral kidney. Almost all ureteral tumors and some renal collecting system lesions can be managed using rigid and/or flexible ureteroscopy, which is associated with less bleeding and more rapid recovery than a percutaneous approach. However, larger renal malignancies can be managed effectively using percutaneous resection. Six patients with upper tract transitional cell carcinoma underwent endoscopic resection. The antegrade and retrograde surgical techniques are described. With follow-up up to 23 months, local recurrence in two patients was managed successfully by repeat endoscopic resection. No patient has experienced disease progression or developed metastases.