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.

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.

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.

Long-term results of antegrade endoureterotomy using the holmium laser in patients with ureterointestinal strictures.

OBJECTIVES: To investigate the effectiveness and morbidity of percutaneous laser endoureterotomy in the management of ureterointestinal anastomotic strictures after radical cystectomy and urinary diversion. METHODS: Between May 1997 and August 2000, 19 percutaneous endoureterotomy incisions, including 3 repeated incisions, were performed on 15 patients with a mean age of 61 years (range 41 to 80) to treat ureterointestinal strictures. A total of 16 renal units were treated (9 left, 7 right), including one bilateral procedure. All procedures were performed using a 200-micrometer holmium laser fiber in antegrade fashion with a 7.5F flexible ureteroscope. A nephroureteral stent was left in place for 4 to 6 weeks postoperatively. Success was defined as radiologic improvement and/or the ability to return to full activity in the absence of flank pain, infection, or the need for ureteral stents or nephrostomy tubes. RESULTS: With a median follow-up of 20.5 months (range 9 to 41), the overall success rate was 57% (8 of 14 renal units). Two patients were lost to follow-up. The mean operative time was 91 minutes, and no perioperative complications occurred. Three patients required repeated endoureterotomies, with two requiring open reimplantation. Overall, the endoureterotomy failed in 6 patients in the series, with five of the six failures involving left-sided strictures. CONCLUSIONS: Percutaneous endoureterotomy is an effective, minimally invasive treatment option for patients with ureterointestinal strictures after urinary diversion. Better visualization and a more precise incision may make the holmium laser a safer cutting modality than alternative methods in patients with ureteroenteric strictures. Patients with left-sided ureterointestinal strictures should be cautioned that endourologic management might have a lower success rate.

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.

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.

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.

Correlation between biopsy and radical cystectomy in assessing grade and depth of invasion in bladder urothelial carcinoma.

OBJECTIVES: To assess the degree of correlation between the pathologic characteristics of the specimens obtained from biopsy and radical cystoprostatectomy. The stage and grade of bladder urothelial (transitional cell) carcinoma are important predictors of prognosis. METHODS: We retrospectively identified 169 cases of urothelial carcinoma from 222 radical cystectomies performed at University of Chicago Hospitals from 1992 to 1999. RESULTS: For all the cases in this study, the histologic grade, using the 1998 World Health Organization and International Society of Urological Pathologists (WHO/ISUP) classification, was identical when the biopsy specimen and radical cystectomy specimen were compared. However, when the same cases were assessed using the traditional three-grade system, the histologic grade increased or decreased by one grade in 19 (11%) and 8 (5%) of 169 cases, respectively. Patients with invasion of the lamina propria on biopsy had tumor extending outside the bladder in 15 (27%) of 55 cases. Patients with invasion of the muscularis propria on biopsy had tumor extending outside the bladder in 47 (49%) of 96 cases, including nodal metastasis in 22 (23%) of 96 cases. Overall, bladder biopsy underestimated the true extent of the disease in 78 (46%) of 169 cases. CONCLUSIONS: Using either the WHO/ISUP (1998) classification or the traditional three-grade system, the histologic grade of the biopsy specimen is a fairly good predictor of the final histologic grade. The preoperative biopsy tends to understage bladder cancer. Patients with muscularis propria invasion demonstrated by biopsy have a significantly higher risk of non-organ-confined disease than those with lamina propria invasion.

Dual stent placement for the treatment of a persistent urine leak after partial nephrectomy.

Persistent urine leak is a known complication after partial nephrectomy. In the present case, a partial nephrectomy was performed to remove a large, centrally located, renal mass in an elderly man with a solitary functioning kidney. A persistent urine leak refractory to single stent drainage was successfully treated after two stents were placed in the ipsilateral renal unit such that the upper and lower calices were drained by separate stents.

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.

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.

Comparison of artificial urinary sphincter and collagen for the treatment of postprostatectomy incontinence.

OBJECTIVES: To compare how urinary symptoms affect the quality of life in groups of men with postprostatectomy incontinence treated with collagen versus artificial urinary sphincter implantation. METHODS: Two cohorts of men, one which received urethral collagen injection and one artificial urinary sphincter (AUS) implantation, were surveyed with a validated quality-of-life questionnaire to assess how their urinary dysfunction impacted their daily activities. The mean impact score and bother score for the two groups were compared. In addition, the overall degree of continence between the groups was assessed. RESULTS: At a mean follow-up of 19 months, 8 (20%) of 41 patients treated with collagen injections were at least socially continent, requiring one pad daily or less. In comparison, 27 (75%) of 36 men treated with an AUS were at least socially continent (P <0.001). Both the impact score and the bother score from the quality-of-life questionnaire were significantly lower in the group treated with the AUS than in the group treated with collagen. CONCLUSIONS: Patients receiving an AUS achieved significantly higher continence rates. Also, the quality of life of men treated with an AUS was improved compared with that of the men treated with collagen injection.

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.

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.

New insights and candidate genes and their implications for care of patients with hereditary prostate cancer.

A positive family history is a risk factor for prostate cancer. Most studies based on segregation analysis suggest autosomal dominant transmission of susceptibility genes. Multiple loci on chromosome 1 and chromosome X have been associated with prostate cancer by linkage analysis. The candidate gene approach has also revealed multiple genetic markers that are associated with increased risk for the disease. The genetic studies in prostate cancer suggest there are multiple genes involved in the development and progression of prostate cancer.

Technique of Hautmann ileal neobladder with chimney modification: interim results in 50 patients.

PURPOSE: We report our 4-year experience with the chimney modification of the Hautmann ileal neobladder. This modification involves use of an 8 to 12 cm. tubularized isoperistaltic ileal chimney for the ureterointestinal anastomosis. MATERIALS AND METHODS: Between April 1995 and March 1998, 50 men and women with invasive bladder cancer underwent radical cystectomy and creation of a Hautmann neobladder with chimney modification. Complications were assessed, divided as early and late, and subdivided as those related or unrelated to the neobladder. Continence was evaluated using a detailed patient questionnaire. RESULTS: There were no intraoperative deaths. Early complications in 11 of the 50 patients were neobladder related in 5 (10%) and unrelated to the neobladder in 6 (12%). The early reoperation rate was 6%. Late postoperative complications in 10 patients (20%) were neobladder related in 8 (16%) and unrelated to the neobladder in 2 (4%). After 1 year 93% and 86% of patients achieved good day and nighttime continence, respectively. In 2 patients (4%) clean intermittent catheterization is performed and 1 required placement of an artificial urinary sphincter. Ureterointestinal anastomotic strictures were detected in 6 of 100 ureteral units (6%), including 2 with failed initial endoscopic management. Open surgical revision of the ureterointestinal anastomotic site was easier due to the anterior position of the ureters, and identification and mobilization of the isoperistaltic limb. CONCLUSIONS: Our experience with the chimney modification of the Hautmann neobladder compares favorably to other forms of orthotopic urinary diversion in regard to ureteral stenosis, early and late postoperative complications, urinary continence and simplification of the ureterointestinal anastomosis.

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.

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.