Renal Transitional Cell Carcinoma Treatment & Management

Updated: Nov 05, 2019
  • Author: Bagi RP Jana, MD, MBA, MHA, FACP; Chief Editor: E Jason Abel, MD  more...
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Treatment

Approach Considerations

Once the diagnosis of upper urinary tract transitional cell carcinoma (TCC) has been made, treatment is mandatory. Surgical intervention is the main form of radical treatment for localized disease.

Local immunotherapy or chemotherapy can be attempted as an independent treatment method in cases of carcinoma in situ (CIS) or to reduce the recurrence rate after endoscopic management of upper urinary tract urothelial carcinoma (UC).

The role of radiation therapy in the management of upper urinary tract transitional cell carcinoma (TCC) is not well defined. Some studies suggest that radiation therapy may have some effect as adjuvant therapy to improve local control after radical surgical treatment for high-grade disease.

Medical therapy is usually indicated for patients with advanced disease or in whom surgical treatment is contraindicated (eg, because of poor general condition or the presence of advanced disease). Given the lack of data from randomized trials, routine use of neoadjuvant or adjuvant chemotherapy is not recommended.

 

 

 

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Topical Immunotherapy or Chemotherapy

As a rule, local treatment is administered as adjuvant therapy, after endoscopic treatment of the UC, to decrease the recurrence rate. Methods of delivery vary (eg, irrigation through a ureteroscopic catheter or intravesical instillation after vesicoureteral reflux is ensured); however, irrigation through a percutaneous nephrostomy catheter is the most reliable method.

Bacille Calmette-Guérin

Instillation of bacille Calmette-Guérin (BCG) through a percutaneous catheter resulted in conversion of urine cytology from positive to negative in 7 of 10 patients with upper urinary tract CIS. BCG sepsis was observed in 1 patient and was treated successfully.

Administration of BCG as a prophylactic agent after endoscopic treatment of superficial urothelial tumors resulted in a recurrence rate of 12.5% in 1 study. However, some studies reported a recurrence rate of up to 50%.

In contrast to the efficacy of BCG in bladder cancer, the ability of BCG to treat high-grade UC of the upper urinary tract or reduce the progression rate is not determined. Therefore, high-grade upper urinary tract UC requires radical surgical intervention.

A retrospective study by Rastinehad et al compared 50 cases in which adjuvant BCG was given after resection of upper urinary tract TCC with 39 control cases. In treated cases, BCG was started 2 weeks after endoscopic management and given for a total of 6 courses. The comparison showed no overall benefit from BCG with regard to disease recurrence, interval to recurrence, and progression of disease. [15]

Mitomycin-C

Rates of progression and recurrence of upper urinary tract UC after treatment with mitomycin-C are comparable to those after treatment with BCG. However, the possibility of complications is much less with mitomycin-C, making it more attractive as a first-line agent in the secondary prophylaxis of upper urinary tract UC. In 1 study, irrigation with mitomycin-C reduced the recurrence rate to 14.2%.

Complications

Seeding through the nephrostomy tract remains a concern during percutaneous management; at least 1 case has been reported. Other serious complications of percutaneous treatment include perforation (5.5%) and ureteropelvic-junction stricture (1.4%). The frequency of stricture is much lower after percutaneous treatment than after ureteroscopy.

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Systemic Chemotherapy

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the best-studied chemotherapy regimen for upper urinary tract TCC. Durable, complete responses were obtained in only 5-10% of patients. Serious complications were encountered in 41% of patients; treatment-related mortality was 2-4%.

Gemcitabine-based combinations (gemcitabine + cisplatin or carboplatin) have activity similar to MVAC in bladder cancer but are associated with less toxicity. [16] Some studies found the combination of gemcitabine and paclitaxel to be as effective as cisplatin-based therapies, with less nephrotoxicity. However, in a study compared the incidence of vascular thromboembolic events (VTEs) in patients with metastatic or unresectable UC who were treated with gemcitabine and carboplatin (GCb); gemcitabine, carboplatin, and bevacizumab (GCbBev), or gemcitabine and cisplatin (GCis), researchers found high incidence (>20%) of VTEs in patients treated with GCb and GCbBev. [17]

A meta-analysis by Giannatempo et al concluded that adding a taxane (paclitaxel or docetaxel) to gemcitabine and platinum as first-line therapy for advanced or metastatic UC showed a trend for improved overall survival. Median overall survival with taxanes was 15.5 mo, versus 12.5 mo without taxanes (P=0.056). However, the addition of a taxane led to an increase in grade 3 or higher neurotoxicity P=0.051), regardless of the specific platinum agent used. [18]

In a retrospective study, DiLorenzo and colleagues found that approximately half of the patients treated with second-line chemotherapy went on to receive third-line treatment. The study also found the median overall survival associated with the use of third-line chemotherapy was 31 (28–36) weeks. Significantly longer overall survival was seen in patients receiving single-agent cyclophosphamide than in patients treated with platinum-based combinations. [19]

Immunotherapy with checkpoint inhibitors is a promising development in the treatment of urothelial carcinoma. Atezolizumab, a monoclonal antibody to programmed death ligand 1 (PD-L1), was approved in May 2016 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. [20]

A phase II trial of atezolizumab as first-line treatment in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for cisplatin therapy demonstrated encouraging durable response rates, survival, and tolerability. [21]

Nivolumab, a monoclonal antibody to programmed death–1 receptor (PD-1) was approved in February 2017 for treatment of locally advanced or metastatic urothelial carcinoma of the bladder in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. [22]

Clinical trials of other immune checkpoint inhibitors, including pembrolizumab, durvalumab, avelumab, and a combination of nivolumab and ipilimumab are in advanced stages, and are expected to lead to approval of many of these agents or combinations in the near future. [23]

Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immunotherapy. In an open-label phase II study of erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, Loriot et al reported an objective tumor response in 40% of previously treated patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. [24]

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Surgical Resection

Patients with low-stage, low-grade tumors respond well to either radical or conservative surgical treatment. In a retrospective review of patients treated with renal-sparing ureteroscopic management, Pak et al reported that renal preservation approached 81%, with cancer-specific survival of 94.7% and significant cost savings over the cost of nephroureterectomy; these authors recommend conservative endoscopic management as the gold standard for low-grade and superficial-stage disease. [25] However, preoperative cytology and ureterorenoscopically-performed biopsies have limited accuracy in predicting the correct tumor grade. Additional diagnostic procedures should be done prior to definitive surgical intervention. [26]

Patients with high-stage, high-grade tumors respond poorly to either radical surgery or conservative surgery.

Patients with positive cytologic findings but normal radiographic and endoscopic examinations are not treated but are monitored closely by means of periodic intravenous urography (IVU) or retrograde pyelography (RPG).

Radical nephroureterectomy

Traditional radical surgery for renal UC consists of total nephroureterectomy with excision of a bladder cuff around the ureteral orifice. Otherwise, 30-75% of patients develop tumor recurrence in the ureteral stump or around the ipsilateral ureteral orifice. Transection of the ureter must be avoided because of the high risk of tumor spillage in the retroperitoneum.

Oncologically, laparoscopic or hand-assisted laparoscopic nephroureterectomy is as effective for localized disease as an open technique would be. [27, 28] In general, the laparoscopic approach is accompanied by less blood loss, less pain and discomfort, faster recovery, and shorter hospital stay. Trocar site recurrence is very rare; to date, 3 cases have been reported. [29]

Patients with poorly differentiated tumors or high-stage disease (especially those with microscopic lymph node involvement) may benefit from extensive retroperitoneal lymphadenectomy. However, the benefit is marginal, and appropriate candidates must be chosen carefully.

Conservative open surgical treatment

Conservative excision for upper urinary tract urothelial tumors includes segmental ureteral resection with reanastomosis or ureteroneocystostomy and partial nephrectomy. Conservative management is especially appropriate for solitary or functionally dominant kidneys, bilateral tumors, or small, low-grade ureteral tumors.

Upper ureteral and midureteral tumors may be treated with segmental resections if they are low-grade, solitary lesions.

Distal ureteral tumors may be treated with distal ureterectomy and ureteral reimplantation if no evidence of multifocality is noted. In these cases, distal ureterectomy may be as successful as total nephroureterectomy because proximal spread of UC after resection is rare.

Partial nephrectomy may be performed in patients with localized renal pelvic tumors; however, this approach should be employed only in situations requiring avoidance of renal failure.

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Endoscopic Treatment

Urothelial tumors of the upper urinary tract can be excised by means of endoscopy in much the same fashion as superficial bladder tumors are. Indications for endoscopic management are the same as those for conservative resection and include low-grade tumors, bilateral involvement, and compromised renal function that necessitates a nephron-sparing approach.

Electrocautery and fulguration are used most commonly in the endoscopic setting. Currently, lasers (Ho:YAG and Nd:YAG) are being used for management of low-grade upper urinary tract urothelial tumors.

In cases of larger low-grade tumors with low metastatic potential, which cannot be eliminated during one session, ureteroscopic management can be performed several times.

Tumor size (>1.5 cm), multifocal disease, and high-grade tumors are the main risk factors for recurrence after ureteroscopic management of upper urinary tract UC. The presence of high-grade or invasive tumors, which cannot be eradicated endoscopically, necessitates radical surgical intervention (usually involving open or laparoscopic nephroureterectomy).

Complications

Perforation (0-10%) and stricture formation (5-13%) are the major complications of ureteroscopic treatment. Use of lasers (especially the Ho:YAG laser, which has low tissue penetration) may decrease the rate of stricture formation.

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Long-Term Monitoring

Because of the high risk of local and bladder recurrences, long-term follow-up care for these patients is mandatory. Include ureteroscopy, cystoscopy, and either IVU or RPG in the routine follow-up procedures.

Urine markers are used more and more frequently in the follow-up of patients with UCs. The specificity of these tests (eg, BTA Stat [Polymedco, Cortlandt Manor, NY], ImmunoCyt [Scimedx, Denville, NJ], and fluorescence in situ hybridization [FISH]) is acceptable for follow-up, and their sensitivity is much better than that of urine cytology.

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