Urothelial tumors of the renal pelvis and ureters (upper urinary tract) are relatively rare. Tumors of the renal pelvis account for approximately 10% of all renal tumors and only 5% of all urothelial tumors of the urinary tract. Ureteral tumors occur about one half as often as tumors located in the renal pelvis. Transitional cell carcinoma (TCC) accounts for more than 95% of urothelial tumors of the upper urinary tract.
The estimated annual incidence in Western countries is approximately two per 100,000 population.[1]
The mean age in persons who develop upper urinary tract urothelial tumors is 65 years. The incidence of transitional cell carcinoma (TCC) increases with age. The peak incidence is in those in their 70s and 80s.
Upper tract urothelial tumors are more common in men, with a male-to-female ratio of 3:1. Upper tract urothelial tumors are twice as common in white people as in people of African descent.
Unlike bladder cancer, in which 80% of tumors are noninvasive, only 40% of upper tract tumors are noninvasive.
Tobacco smoking is the factor most strongly associated with upper tract transitional cell carcinoma (TCC) and increases the risk more than 3-fold. Estimates point to smoking as the cause of 70% of upper tract tumors in men and 40% in women.
Drinking coffee slightly increases the risk of upper tract TCC; this risk factor is typically observed in people who consume more than seven cups of coffee per day.
Analgesic abuse is also a risk factor for urothelial malignancy. It is independent from and synergistic with renal papillary necrosis. Long-term exposure to analgesics, notably phenacetin, induces a nephropathy that raises the risk of upper tract TCC to as high as 70%. Capillarosclerosis, which is characterized by a thickening of the basement membrane, is the pathognomonic finding of analgesic abuse and is found in 15% of patients with upper urinary tract tumors. In contrast, Shih et al demonstrated a risk reduction in upper tract TCC with use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAID)s in those patients who quit smoking at least 10 years ago.[2]
Occupational exposure to agents used in the petrochemical, plastic, and tar industries has been linked to an increased risk of TCC.
Chronic infections, irritation, and calculi may also predispose to squamous cell carcinoma and, less commonly, adenocarcinoma of the upper urinary tract.
Cyclophosphamide has been linked to the development of urothelial tumors. More specifically, a breakdown metabolite called acrolein is thought to be the causative agent. Tumors associated with cyclophosphamide tend to be high-grade.
Upper tract TCC is associated with Balkan nephropathy, which is a degenerative interstitial nephritis linked to the consumption of aristolochic acid (contained in some plants in the Balkans). Tumors associated with Balkan nephropathy are generally low-grade, multiple, and bilateral, in contrast to TCC of other etiologies.
Finally, heredity can play a part in the development of TCC. TCC is associated with Lynch syndrome type II (hereditary nonpolyposis colorectal carcinoma), which is a syndrome characterized by an early onset of proximal colonic nonpolyposis tumors, numerous synchronous and metachronous colonic tumors, and extracolonic tumors. If patients younger than 60 years old are diagnosed with upper tract TCC, a thorough family history should be taken and they should be counseled about genetic testing and Lynch syndrome.
Transitional cell carcinoma (TCC) is the most common histology observed, accounting for greater than 95% of upper urinary tract urothelial tumors. TCCs are strongly associated with smoking.
Squamous cell carcinoma comprises 1-7% of upper tract urothelial tumors. Squamous cell carcinoma is frequently associated with longstanding infected staghorn calculi. Affected patients frequently present with moderately to poorly differentiated tumors and advanced disease.
Adenocarcinoma accounts for less than 1% of upper tract tumors. Patients with adenocarcinoma of the upper urinary tract may also have associated calculi and long-term obstruction, suggesting an etiologic origin for these processes.
Inverted papilloma is an unusual lesion that is generally considered a benign histologic lesion; however, it may harbor foci of malignant change.
Mechanisms
Several molecular mechanisms have been associated with the development of upper urinary tract TCC. Tumor suppressor genes P19, P16, RB1, and P53 have all been associated with upper urinary tract TCC. Losses of P53, P19, and P16 are associated with low-grade cancers, while a loss of RB1 has been associated with higher-grade, more aggressive tumors.[3]
Markers
Tumor microsatellite instability (MSI) has been studied as a prognostic indicator for upper urinary tract tumors. In general, high levels of MSI seem to correlate with a more favorable prognosis, particularly in younger patients with T2 or T3/N0 disease (see Staging).[4, 5]
E-cadherin, hypoxia-inducible factor-1α, Ki-67, survivin (a protein apoptosis inhibitor), epidermal growth factor receptor (EGFR), and telomerase RNA component have been identified as independent markers of advanced disease and/or prognosis. However, none has been externally validated or widely used.[6, 7, 8, 9] In a multivariate analysis, P53 was not an independent predictor of prognosis.[10]
Survivin was recently measured in the urine of patients with TCC of the bladder and was found to be highly sensitive and specific for the presence of this malignancy.[11]
Transitional tumors spread conventionally in a cephalad to caudad direction. For instance, studies have shown a high rate of recurrence in the distal ureteral stump in patients treated with nephrectomy and incomplete ureterectomy. Conversely, TCC rarely recurs proximal to the level of resection of a ureteral lesion.
Approximately 30-75% of patients with upper tract urothelial tumors develop bladder tumors at some point during their cancer course. The risk of upper tract TCC in patients with a bladder malignancy is 2-4%, but as high as 21-25% in patients with carcinoma in situ. Thus, higher grade seems to increase the risk of upper tract disease. An analysis of 1069 bladder cancer patients with 10-year follow-up showed an upper urinary tract recurrence in 2.5% of patients at a median time interval of 3.3 years.[12]
Lymphatic extension is another pattern observed in TCC. The most common locations for spread, depending on the site of the primary tumor, include paraaortic, paracaval, ipsilateral common iliac, and the pelvic lymph nodes.
Hematogenous seeding also occurs, with the liver, lung, and bone being common sites for metastases.
Rates of distribution for transitional cell carcinoma are 58% for the renal pelvis, 35% for the ureter (73% of which are located in the distal ureter), 7% for both the renal pelvis and ureter, and 2-5% for bilateral involvement.
Gross or microscopic hematuria (75%) is the most common clinical presentation of urothelial tumors of the renal pelvis and ureters.
Flank pain (20%) results from gradual obstruction/distention of the collecting system or acute colic due to obstruction by a blood clot.
Lumbar mass is noted in 10-20%.
Dysuria (6%) is reported; some patients report irritative lower urinary tract symptomatology such as burning upon urination.
Weight loss, anorexia, flank mass, or bone pain are symptoms of advanced disease that manifest in a minority of patients.
Nephroureterectomy with excision of the bladder cuff is the criterion standard treatment for all forms of upper tract transitional cell carcinoma (TCC). Contemporaneously, it is indicated in patients with large-volume renal pelvis TCC, regionally extensive disease, and high-grade or high-stage lesions.
Laparoscopic nephroureterectomy is being used in many cases and offers the potential benefits of lower blood loss and shorter hospitalization. Cancer control outcomes appear to be equivalent.
Segmental ureterectomy coupled with ureteral reimplantation can be used for lower-grade superficial urothelial tumors located in the distal ureter.
Renal-sparing surgery (including segmental ureterectomy or endoscopic or percutaneous resection) is typically used in patients with small, lower-grade, superficial lesions. Additionally, patients who would be at risk for dialysis after nephroureterectomy and those who are medically unfit for radical surgery can be offered minimally invasive and renal-sparing techniques.
The renal pelvis is the portion of the urinary collecting system formed by the confluence of two or three major calices. The ureter is a 20- to 30-cm tubular structure lying on the psoas muscle. It follows an S-shaped curve, passing medially to the sacroiliac joint and then coursing laterally near the ischial spine before passing medially to penetrate the base of the bladder. It passes through a submucosal tunnel to empty into the bladder.
The renal pelvis and ureter are lined by a transitional epithelium. The next layer is the lamina propria. External to the lamina propria is smooth muscle arranged in a spiral and longitudinal manner. The outermost adventitia is composed of fibrous connective tissue.
Relative contraindications that must be addressed prior to surgical treatment include the following:
Surgical treatment is generally not warranted in patients with advanced metastatic disease. Instead, medical management (ie, chemotherapy) should be instituted.
Laboratory studies that should be ordered include the following:
Excretory urography, commonly referred to as intravenous pyelography (IVP), has traditionally been used to evaluate the upper urothelial tract, but has been primarily replaced with multidetector computed tomography (CT).[82, 83] Approximately 50-75% of patients with urothelial tumors of the renal pelvis and ureters have a radiolucent filling defect that is characteristically irregular and in continuity with the wall of the collecting system. (See the image below.) Approximately 10-30% of such tumors cause obstruction or nonvisualization of the collecting system.
View Image | Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of transitional cell carcinoma (TCC). Blunting of the involved .... |
Noncontrast CT scanning can be performed, followed by a contrast study, with particular interest in the excretory phase — a so-called CT urogram. Plain radiography, which demonstrates drainage and anatomy, can also be performed after CT scanning. Transitional cell carcinomas (TCCs) are usually visible as an irregular filling defect. They tend to be hypovascular in comparison with the rest of the kidney and demonstrate minimal increased attenuation (enhancement) following intravenous contrast injection. See the images below.
View Image | CT scan demonstrating right renal pelvis transitional cell carcinoma (TCC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew.... |
View Image | CT scan demonstrating left distal ureteral transitional cell carcinoma (TCC). The left ureter is dilated and a medial filling defect is noted. Courtes.... |
CT scanning sensitivities and specificities based on lesion size are as follows:
CT scanning has limited value in staging TCC because stage Ta or superficial lesions cannot be differentiated from T2 or invasive lesions (see Staging). However, CT scanning is helpful in demonstrating peripelvic or periureteral tumor extension, thereby assisting with staging of aggressive disease. Hydronephrosis and obstruction are associated with a higher degree of invasiveness.
As with CT scanning, magnetic resonance imaging (MRI) is also of limited use in staging early TCC; however, it may have greater utility in more advanced disease or in patients with limited renal function. European Association of Urology guidelines note that although CT urography is generally preferred to MRI urography for diagnosing and staging, MR urography is indicated in patients who cannot undergo CT urography, usually when radiation or iodinated contrast media are contraindicated. However, the use of MR urography with gadolinium-based contrast media should be limited in patients with severe renal impairment (creatinine clearance < 30 mL/min), due to the risk of nephrogenic systemic fibrosis.[1]
There is interest in fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT for staging in TCC, but, at present, this technique does not appear to have significant advantages over MRI.[84]
Cytopathology of voided urine samples yields low sensitivity, especially for low-grade tumors, which results in normal cytology results in up to 80% of cases. The sensitivity of cytopathology increases for higher-grade tumors, which tend to shed more tumor cells. Cytology yields an accuracy of 83% in patients with high-grade disease. Cytology is less sensitive for upper tract transitional cell carcinoma (TCC) than for bladder cancer.
Cytology samples should be taken from as near the suspected lesion as possible (ie, within the calyceal system). Positive cytology has been related to more advanced (invasive) disease.[13] Selective washings of both the upper tracts and the bladder can aid in tumor localization. Cytology plays a role in urothelial tumor surveillance in conjunction with cystoscopy/ureteroscopy.
Fluorescence in situ hybridization (FISH) can be performed using probes for altered genes on chromosomes 3, 7, 17, and 9p21. FISH (UroVysion) is a useful test for detecting urinary tract cancer, as it yields a greater sensitivity for lower-grade tumors than cytology and other tests (as high as 76.6-100% vs 21-24% for cytology).[14, 15] Ureteral cancer has been detected with FISH during evaluation for hematuria.[16] FISH has equal specificity when compared with cytology (as high as 100%).
Ureteroscopy can be used for direct visualization of a tumor. Important to note is that it can be used to obtain tissue for a diagnosis and grade in 90% of cases.[17] Staging information regarding depth of invasion, however, is more difficult to obtain.
Each of the following should be obtained in a suspected case of upper tract TCC:
For cystoscopy, a small fiberoptic scope is inserted through the urethra in order to visualize the bladder. This ambulatory/clinical procedure is usually well tolerated by both women and men. A 16F flexible cystoscope is typically used in men, whereas women can undergo either rigid or flexible cystoscopic examination. This procedure is mandatory to rule out coexistent bladder lesions, which occur with a frequency of 8-13%.[1] Cystoscopy is also essential for postoperative surveillance to monitor for bladder tumor development; recurrence in the bladder occurs 15-51% of patients.[18]
In retrograde urography (see image below), contrast is injected into the ureteral orifice with the aid of a cystoscope. This can be performed with fluoroscopic guidance or with standard radiography plates. Retrograde urography allows better visualization of the collecting system than excretory urography by increasing the distention of the urinary collecting system. Retrograde pyelography is preferable in patients with azotemia and/or contrast allergy. Overall, retrograde urography is more than 75% accurate in establishing a diagnosis of urothelial cancer.
View Image | Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral transitional cell carcinoma (TCC). Ureteral dilation distally and prox.... |
Since the advent of rigid and flexible ureteroscopes, ureteropyeloscopy is used increasingly for the diagnosis of upper tract urothelial tumors. Biopsy forceps or cytology brushings can be used to collect tissue. This procedure yields an accuracy of 86% in diagnosing renal pelvis tumors and 90% in diagnosing ureteral tumors. Large size, broad base, and nonpapillary pattern favor tumor invasiveness. Studies have demonstrated that 85% of TCC lesions in the renal pelvis are papillary. The complication rate associated with ureteropyeloscopy is approximately 7%; these include perforation, complete disruption, and ureteral stricture.
Percutaneous nephroscopy is not indicated for the diagnosis of urothelial tumors of the renal pelvis and ureters because of the theoretical risk of tumor cell implantation in the retroperitoneum and nephrostomy tube tract. It is used for treatment in selected situations.
Nevertheless, Huang et al concluded that percutaneous biopsy is safe and effective for diagnosis of upper tract urothelial lesions that are not amenable to endoscopic biopsy. In their study of 26 upper tract lesions in 24 patients, percutaneous biopsy provided tissue diagnosis in 85% of cases; the three recurrences in the nephrectomy bed developed at sites remote from the biopsy site and thus were not attributed to tract seeding.[19]
The distribution of tumor stages and grades differs from study to study. Stage and grade yield the greatest prognostic value.
The National Comprehensive Cancer Network (NCCN) guidelines grade urothelial histologies according to the World Health Organization (WHO)/International Society of Urological Pathology (ISUP) classification as follows[86] :
Squamous cell carcinoma and adenocarcinoma use the following grading classifications[86] :
Staging is based on the depth of tumor invasion and classified using the tumor, node, metastases (TNM) system.[85]
Primary tumor categories are as follows:
Regional lymph node categories are as follows:
Distant metastasis categories are as follows:
The location of the tumor can affect the findings. Renal pelvis tumors are more commonly invasive than bladder tumors, possibly because of delayed diagnosis and a less well-developed muscle layer.
Table 1. American Joint Committee on Cancer Prognostic Groups
View Table | See Table |
The two forms of medical therapy for upper tract transitional cell carcinoma (TCC) are topical treatments and systemic.
Topical chemotherapeutic agents are delivered by instillation and consist of bacillus Calmette-Guérin (BCG), which is the preferred agent, or mitomycin C. These agents can be administered either percutaneously or from a retrograde approach through a ureteral catheter. For high-grade disease, topical instillation therapy is most appropriate in patients for whom radical surgery is absolutely or relatively contraindicated—those with bilateral disease and/or limited renal function.
The safety of these agents as adjuvant therapy has been well studied in bladder cancer; however, their efficacy in decreasing recurrence rates, delaying tumor progression, and improving survival rates in upper urinary tract cancer has not been firmly established.[21] Furthermore, the administration of these agents often requires hospitalization and skilled nursing to prevent hyperperfusion and systemic absorption.
BCG is an attenuated form of Mycobacterium tuberculosis, and its use carries a small but significant risk of BCG sepsis. To prevent adverse systemic effects, BCG should not be used in patients with hematuria.
Because of an ongoing shortage of BCG in the United States, the National Comprehensive Cancer Network[86] and several urologic societies have recommended strategies on prioritizing use of intravesical BCG and alternative treatment approaches for some patients.
Systemic chemotherapy is often reserved for patients with metastatic disease.
Primary therapy
Primary treatment is with BCG, which can be used for carcinoma in situ and can be curative, but it is reserved for those who are not surgical candidates. Recurrence rates are high (50%).[22]
Adjuvant therapy
Adjuvant topical treatments include retrograde or percutaneous instillation of mitomycin C. There is no demonstrable benefit of BCG in these settings.[23] The efficacy of these agents in treating upper tract urothelial carcinoma is not well established because of the small retrospective studies with heterogeneous patients and tumor characteristics.
Keeley and Bagley reported on the use of mitomycin administered via a retrograde catheter in 19 patients.[24] They noted a 54% recurrence rate at a mean follow-up of 30 months. No patient had disease progression. With a single postoperative intravesical dose of mitomycin C administered after nephroureterectomy for TCC, the risk of a bladder tumor was reduced by 40% in the first year following surgery.[25]
The efficacy and safety of doxorubicin as adjuvant therapy has been explored in a limited number of patients. Of 10 patients evaluated, 50% had disease-free upper tracts at 4-53 months. In this series, doxorubicin was given via continuous infusion to improve dwell time and efficacy. No treatment-related toxicities were observed.[26]
Prospective randomized studies are needed to determine the efficacy and optimal use of these agents as adjuvant therapy for superficial upper tract TCC, especially in the setting of endoscopic surgery.
Chemotherapy
MVAC (methotrexate, vinblastine, doxorubicin [Adriamycin], cisplatin) was once considered standard treatment. However, this combination yields only a modest survival advantage, and optimal dosing is often limited owing to severe toxicity.
The combination of gemcitabine with cisplatin yields response rates, time to progression, and survival rates similar to those of MVAC, but with less toxicity. Gemcitabine with cisplatin is now considered first-line therapy.
Adjuvant and neoadjuvant chemotherapy
The use and potential benefit of both adjuvant and neoadjuvant chemotherapy is largely extrapolated from bladder cancer data and retrospective chart reviews, but recent studies have suggested a potential for benefit (see Table 2, below). A recurrence-free rate as high as 50% has been demonstrated; however, a survival benefit has not yet been definitively proved. Studies addressing the issue have few patients and are nonrandomized.[27] One important consideration is the use of neoadjuvant rather than adjuvant chemotherapy in this unique population, as removal of the kidney frequently has a direct impact on the patient's capacity to undergo chemotherapy, due to decreased renal function.
Table 2. Adjuvant and Neoadjuvant Trials for Upper Tract Transitional Cell Carcinoma.
View Table | See Table |
In the Upper Tract Urothelial Carcinoma Collaboration, the use of adjuvant chemotherapy did not result in longer cancer-specific survival; however, in that study, the patients who received chemotherapy had higher grade and stage disease (P < 0.001). The study included 1390 total patients; 542 were identified as high-risk (pT3N0, pT4N0, and/or N+) and 121 (22%) received adjuvant therapy.[28]
A compelling study in which patients with biopsy-proven high-grade disease who received neoadjuvant chemotherapy were compared against historical controls noted a complete response in 14% of patients and and a significant rate of downstaging.[29] This is noteworthy, as neoadjuvant therapy potentially provided a cure in patients who otherwise are at very high risk.
Neoadjuvant chemotherapy has been shown to confer survival advantage in two retrospective studies. Urakami et al concluded that clinical response of the tumor to neoadjuvant chemotherapy predicts the survival outcome in urothelial carcinoma with clinical lymph node metastasis treated with consolidative surgery.[30] In a retrospective cohort study by Porten et al, patients treated with neoadjuvant chemotherapy had 5-year disease-specific survival of 90% vs 58% without it.[31]
The findings from those non-randomizd studies will be the highest level of evidence supporting a survival benefit for neoadjuvant chemotherapy until the data from the two prospective studies currently in progress (NCT02412670 and NCT01261728) become available. Adjuvant chemotherapy use is limited by renal insufficiency or performance status after nephroureterectomy, as discussed below.
Radiation therapy
Radiation can play a palliative role in controlling pain and hemorrhage associated with advanced upper tract urothelial carcinoma.
Czito et al reported on the use of adjuvant radiotherapy after resection of T3 or T4 and/or node-positive upper tract TCC. In this retrospective analysis of 31 patients treated from 1970-1997, radiation with concurrent cisplatin chemotherapy improved 5-year survival rates.[32]
Prospective studies are needed to better define the role of radiation therapy in the multimodal management of upper tract TCC.
Chemotherapy
As noted above, gemcitabine with cisplatin has replaced MVAC, which was the historical standard treatment. However, no strong evidence supports the use of systemic chemotherapy in metastatic disease. This is attributed to the relative rarity of metastatic upper tract TCC and the absence of prospective trials.[27] Furthermore, approximately 50% of patients with metastatic urothelial carcinoma are not candidates for cisplatin-based therapy.[33]
Exclusion criteria for cisplatin-based chemotherapy are as follows:
In patients with limited renal function, chemotherapy options are limited but can consist of the following:
De Santis et al randomized patients to gemcitabine and carboplatin versus methotrexate, carboplatin, and vinblastine and found statistically similar outcomes.[34]
A retrospective study by Huang et demonstrated the benefit of aljuvant chemotherapy in the setting of pT3 disease. The study included 171 patients with pT3N0M0 disease treated with nephroureterectomy between 2004 and 2014. Median followup was 35.8 months. Patients who received adjuvant therapy (n=60) had statistically signifcantly better 5-year cancer-specific survival, compared with those treated with surgery alone (n=111); (80.5% vs 57.6%, P = 0.010), as well as better recurrence-free survival (74.4% vs 52.9%, P = 0.026).[36]
Although there was no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072), there was a trend toward better overall survival in the patients who received postoperative chemotherapy. On multivariable analysis age (P = 0.018), tumor location (P = 0.003) and adjuvant chemotherapy (P = 0.001) were predictors of cancer-specific survival.[36]
A retrospective study by Lucca et al in 263 patients who underwent radical nephroureterectomy for lymph node–positive upper tract urothelial carcinoma, 107 (41%) of whom received three to six cycles of adjuvant chemotherapy, the use of adjuvant chemoterapy had no significant impact on cancer-related mortality, on univariable (P = 0.49) and multivariable (P = 0.11) analysis. However a stratified analysis showed a 34% reduction of cancer-related mortality with adjuvant chemotherapy in the subgroup with pT3-4 with lymph node positivity (P = 0.019).[37]
Non–cisplatin-based chemotherapy has been tried as a less toxic alternative. However, a comprehensive search of the literature did not find benefit from it.[38]
According to European Association of Urology (EAU) guidelines, conservative management is appropriate for low-risk upper tract urothelial carcinomas.[1] EAU indications of low risk are all of the following:
The EAU recommends offering kidney-sparing surgery as the primary treatment option for these low-risk tumors.[1] Possible approaches are as follows:
Nephroureterectomy with excision of the bladder cuff is considered the standard therapy in patients with high-volume renal pelvis transitional cell carcinoma (TCC), regionally extensive disease, and high-grade or high-stage lesions.
Segmental ureterectomy coupled with ureteral reimplantation is indicated in patients with ureteral tumors located in the distal ureter, generally of lower grade and stage. Unfortunately, because of the multifocal nature of TCC, the ipsilateral recurrence rate is 25% or greater after segmental ureterectomy.
Renal-sparing surgery, including segmental ureterectomy and endoscopic therapy, maintains a vital role in the management of upper tract urothelial tumors. Typically, patients with small, low-grade superficial lesions are the best candidates for this approach. Some investigators use this approach more frequently in patients with a solitary kidney, bilateral disease, compromised renal function, synchronous tumors, or greater baseline operative risk.
Nephroureterectomy is the standard for large, high-grade tumors of the renal pelvis and proximal ureter that are organ-confined or locally advanced. Nephroureterectomy is also recommended for multifocal, recurrent, low-grade tumors, which are found to be less amenable to ureteroscopic management.
Classically, this procedure involves removal of the kidney, ureter, and bladder cuff via a thoracoabdominal or flank approach, with a separate lower-quadrant Gibson incision. Laparoscopic approaches to the radical nephroureterectomy are now commonplace and offer some postoperative benefits. Open, pure laparoscopy; hand-assisted laparoscopy; and, recently, robotic-assisted laparoscopic nephroureterectomy are the currently employed techniques.
National Surgical Quality Improvement Program (ACS NSQIP) data on nephroureterectomy showed that 69% of cases between 2006 and 2012 were completed with a minimally invasive approach and that perioperative complications were similar for open and minimally invasive techniques. Length of hospital stay, however, was shorter for minimally invasive nephroureterectomy.[40]
In both open and laparoscopic surgeries, care is taken to excise the entire distal ureter and bladder cuff to prevent local recurrence. Excision of the cuff has a survival benefit.[41]
There are multiple effective approaches,[42] as follows:
Xylinas et al retrospectively compared transvesical, extravesical, and endoscopic methods of bladder cuff excision, and found that recurrence-free survival, cancer-specific survival, and overall survival were similar with all three approaches. However, the endoscopic approach was associated with a higher risk of subsequent bladder recurrence. The study population included 2681 patients from 24 international centers.[43]
Lymphadenectomy, which generally requires little additional operative time, is performed for staging purposes, and potentially offers a therapeutic benefit.
The indications and oncologic surgical principles for laparoscopic nephroureterectomy are similar to those of the open approach.
Pure laparoscopic transperitoneal and retroperitoneal approaches, as well as hand-assisted laparoscopic approaches, have been described. The optimal technique depends largely on surgeon experience.
Management of the bladder cuff remains variable. Some investigators prefer hand-assisted laparoscopic en bloc excision of the distal ureter with closure of the cystotomy defect.
Operative time is comparable to that of the standard open procedure.
Laparoscopic nephroureterectomy offers the benefits of minimally invasive surgery, including less blood loss, shorter hospitalization, and improved cosmetic result.[44]
Recent studies have shown comparable oncologic outcomes with open and laparoscopic nephroureterectomy.[44, 45]
Simone et al conducted a randomized control trial that demonstrated significantly lower blood loss (104 vs 430 mL, P< 0.001) and shorter hospital stay (2.30 vs 3.65 d, P< 0.001) for laparoscopic nephroureterectomy compared with open surgery. Their group also demonstrated a nonsignificant difference in 5-year cancer-specific survival (89.9% vs 79.8%) and 5-year metastasis-free survival rates (77.4% vs 72.5%) favoring open surgery.[44]
A 2012 meta-analysis of observational studies comparing open versus laparoscopic nephroureterectomy showed significantly lower urinary recurrence and distant metastasis favoring the laparoscopic approach. Local recurrence was found to be comparable.[46]
Many surgeons consider large and locally advanced (T3/T4) tumors to be contraindications to laparoscopic surgery.
High-grade and/or large distal ureteral tumors are most commonly managed with distal ureterectomy with ureterovesical reimplant. Jeldres et al showed equivalent 5-year cancer-specific survival rates when compared with nephroureterectomy, regardless of stage.[47]
Ureteroscopy offers a renal-preserving alternative to traditional nephroureterectomy and is used in patients with compromised renal function, bilateral upper tract disease, or other medical contraindications to nephroureterectomy. Ureteroscopic ablation is now the preferred choice for low-grade upper tract TCC. However, management of upper tract tumors with this approach is associated with the need for multiple additional procedures versus more definitive surgical management.
Ureteroscopy allows biopsy and treatment of tumors along the entire upper urinary tract. Cold-cup biopsy forceps or a flat-wire basket is used for tissue diagnosis and to determine tumor grade to plan for future intervention.
The use of Nd:YAG and Ho:YAG lasers, as well as small 2F-3F electrosurgical devices, enable ureteroscopic resection, coagulation, and ablation of upper tract tumors under direct vision.
A systematic review of ureteroscopic and percutaneous management by Cutress et al determined that approximately 20% of patients eventually required nephroureterectomy. Upper tract recurrence was high, at 52% for endoscopy and 37% percutaneous management. Overall survival in the pooled analysis was 72% for ureteroscopic management and 79% for percutaneous approach. The disease-specific survival rate was 91% for ureteroscopy and 89% for percutaneous resection.[21]
Cutress et al also reported their 20-year experience with endoscopic management.[48] Seventy-three patients had longer follow-up than most studies, at a mean of 63 months. Nineteen percent of patients proceeded to nephroureterectomy. The upper tract recurrence rate was 68%. The overall survival rate was 69.7% and the disease-specific survival rate was 88.9% at 5 years.
In another study of 90 patients with upper tract TCC managed endoscopically who had a history of bladder cancer, the recurrence-free survival rate at 5 years was only 29%. The authors of this study recommended a low threshold for more aggressive surgical intervention based upon stage and grade migration.[49]
Grasso et al published their 15-year experience of ureteroscopic and extirpative therapy and concluded that uteroscopic management was an acceptable option for managing low-grade disease.[50]
The following are technical considerations for ureteroscopic treatment of upper tract tumors[51] :
Percutaneous therapy allows the use of larger scopes with improved maneuverability and visibility to ablate larger tumors in the renal pelvis and upper ureter. Percutaneous access may be used to administer topical therapeutic agents such as BCG or mitomycin. This approach is an acceptable alternative to nephroureterectomy in patients with low–grade disease. However, as with all organ-preserving strategies, vigilant follow-up surveillance is required.
Percutaneous techniques allow a renal-sparing approach and are well suited for large-volume disease of the renal pelvis and proximal ureter.
Percutaneous access to the diseased renal unit is established, followed by tract dilation. This allows the passage of nephroscopes, laser fibers, biopsy forceps, and electrosurgical resection devices to completely resect and ablate tumors under direct vision.
Percutaneous access also allows for a deeper resection and more accurate staging than ureteroscopy for tumors of the renal pelvis and kidney.
Tumor seeding of the nephrostomy tract, although rare, has been reported and is associated with high-grade lesions.
No randomized studies have been performed, and no studies have had good long-term follow-up. Selection bias confounds nonstandardized studies. Tumors treated with endoscopic management are generally smaller, of low grade, and of low stage.
The 5-year disease-specific survival rate in patients with low-grade disease is statistically similar for conservative treatment and immediate nephroureterectomy, at 86.2-100% vs 87.4-89%, respectively.[51, 52]
Silberstein et al, in a 2012 study, showed that although oncologic outcomes were similar, a significantly larger decrease in glomerular filtration rate was noted in patients undergoing nephroureterectomy compared with endoscopic treatment.[53]
Several studies have demonstrated a significant survival advantage in patients undergoing extensive regional lymphadenectomy at the time of open nephroureterectomy. In a retrospective analysis of 169 patients who underwent nephroureterectomy for non-metastatic upper tract urothelial carcinoma, Kondo et al reported a definite survival advantage in lymph node–positive patients with higher T stages, namely pT3 and above, who underwent a complete lymphadenectomy. Multivariate analysis showed that complete lymphadenectomy was a significant prognostic factor for cancer-specific survival (P = 0.009) as well as T stage (pT3 or less, P = 0.0004) and tumor grade (G3, P = 0.0001).[54]
A multi-institutional retrospective study by Matin et al identfied characteristic patterns of lymph node metastasis in upper tract urothelial carcinoma, depending on the side and anatomical location (eg, renal pelvis; proximal, mid-, or distal ureter) of the primary tumor. On the basis of those data, these authors constructed standardized templates for lymph node dissection.[55] See the image below.
View Image | Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumor.... |
For tumors in the right pelvis and upper ureter, Matin et al concluded that a dissection template encompassing the right hilar, paracaval, and retrocaval regions will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region to the template will improve coverage to 95.8%.[55]
For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes will increase the coverage to 90.2% of involved nodes.[55]
The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation.[55]
For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side. However, adding paracaval groups for tumors on the left side and para-aortic groups for those on the right side will improve coverage to almost 100%.The final decision regarding the utility and extent of lymphadenectomy is at the discretion of the surgeon and can be modified by the intraoperative findings.[55]
Lymphadenectomy has both diagnostic and therapeutic purposes. In the TALL (T staging, architecture [papillary vs sessile], lymphovascular invasion, lymphadenectomy) multivariable prognostic variable created by Youssef et al, absence of lymphadenectomy is a poor prognostic factor.[56]
Follow-up is largely determined by tumor grade and stage and the procedure performed. In cases in which a radical nephroureterectomy is performed, local recurrence is uncommon. Bladder recurrence rates vary per report, from 15-50%. The bladder should be surveyed routinely.
In patients managed conservatively or with endoscopic techniques, closer follow-up intervals are warranted. Surveillance ureteroscopy under local anesthesia in the clinic is feasible and well tolerated in selected patients. The high rate of recurrence mandates strict postoperative surveillance for any renal-sparing treatment strategy used for upper-tract urothelial tumors.
The American Urological Association has no guideline on follow-up and surveillance. A generally accepted surveillance protocol consists of cystoscopy and selective urine cytology at 3-month intervals postoperatively for the first year and every 6 months during the second year. CT urography, excretory urography, or retrograde ureteropyelography can be performed at 3- to 6-month intervals to evaluate the upper tract. Ureteroscopy is the most sensitive tool for detecting recurrence and is performed routinely at 3-month intervals initially, with the frequency increasing to 6 months after the first year. At 2-5 years, cystoscopy and ureteroscopy are continued at 6-month intervals.
As mentioned above, ureteroscopy is the preferred surveillance tool for detecting recurrences after endoscopic ablation of upper tract transitional cell carcinoma (TCC).
Ureteroscopy with biopsy and cytology yields a sensitivity of 93.4% and specificity of 65.2%. In the same series, surveillance with retrograde pyelography had a sensitivity and specificity of 71.7% and 84.7%, respectively.[57]
Voided urine cytology and microscopic hematuria yield a low sensitivity but reasonable specificity in detecting upper tract recurrences.
Upon any recurrence, the endoscopic cycle is restarted.
The contralateral collecting system is studied radiographically once yearly with CT urography, retrograde pyelography, or intravenous pyelography and cytology. Surveillance cystoscopy and imaging of the contralateral upper tract is also required to detect recurrences in patients treated with nephroureterectomy.
Several novel markers in addition to urine cytology and fluorescence in situ hybridization (FISH) may be helpful in detecting recurrent urothelial carcinoma. A prospective study by Siemens et al determined that the accuracy of diagnostic markers was as follows[58] :
For patient education resources, see the Cancer and Tumors Center and Kidneys and Urinary System Center, as well as Bladder Cancer, Blood in the Urine, Intravenous Pyelogram, and Cystoscopy.
Complications related to nontreatment include disease progression, obstruction, bleeding, infection, metastasis, and death. See the images below.
View Image | CT scan demonstrating bulky right renal pelvis transitional cell carcinoma (TCC) replacing the majority of the renal parenchyma. A pericaval lymph nod.... |
View Image | CT scan demonstrating metastatic transitional cell carcinoma (TCC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the s.... |
With open nephroureterectomy, the potential risks of surgery include bleeding, infection, injury to surrounding bowel or viscera, and abdominal wall laxity due to neurapraxia. Open procedures are associated with an increased risk of postoperative pulmonary complications relative to the laparoscopic approach. The 30-day perioperative mortality is 1.8%. Risk of positive surgical margin is 8.5%.[59]
With laparoscopic nephroureterectomy, bleeding, infection, injury to surrounding bowel or viscera, and port site hernia are potential complications that should be fully discussed with patients during the informed consent process.
With endoscopic surgery, the overall complication rate is 14% for ureteroscopic intervention (11% stricture rate) and 27% for percutaneous management.[21] Ureteral perforation, delayed ureteral stricture, extraluminal tumor spillage, and tumor propagation are some of the complications associated with ureteroscopic surgery. In addition, the reliability in staging tumors is lacking with this approach. Percutaneous surgery carries a risk of immediate and delayed bleeding, a theoretical risk of tumor seeding, and a risk of pleural cavity violation, potentially resulting in hydrothorax that necessitates chest tube drainage.
With medical therapy, instillation of topical chemotherapeutic agents is associated with collecting system scarring, obstruction, systemic absorption, sepsis, and toxic agranulocytosis due to heightened perfusion pressures. Medical therapy carries a complication profile similar to that of nontreatment.
Survival after total nephroureterectomy (5-year survival by stage) is as follows:
For all patients with upper tract urothelial cancer, the unadjusted 5-year survival rate is approximately 57%. On multivariate analysis, only stage and age were significant prognostic factors for survival.[59]
Gandaglia et al examined the Surveillance, Epidemiology, and End Results (SEER) database of 9899 upper tract urothelial cancer patients undergoing radical nephroureterectomy and determined that cancer-specific mortality was 18.1%, other-cause mortality was 9.1%, and bladder cancer mortality was 31.2%. Both cancer-specific mortality and other-cause mortality increased with age. Although cancer-specific mortality and bladder cancer mortality increased with advancing stage, all-cause mortality remained stable.[60]
A multivariate competing risk regression model showed that besides age and stage, risk factors for higher cancer-specific mortality included the following[60] :
Bladder cancer mortality correlated with ureteral location, stage, and grade.[60]
Reported recurrence rates vary. Rink et al (2012) report an overall recurrence rate of 24% in their study population of 2494 patients treated with radical nephroureterectomy. Approximately 80% of those patients who had recurrence died within 24 months after the recurrence. A shorter time of recurrence to death was related to pT3 and pT4 stages, ureteral tumor location, omission of a lymph node dissection, and shorter time to recurrence.[61]
Biopsy grade is generally accepted as accurate and correlates to pathologic findings.[10] Conversely, owing to the difficulties in obtaining muscle in biopsy specimens and the limitations of imaging, the up-staging rate is 45%.[62]
Advanced age has previously been shown to be related to poor clinical outcomes, including cancer-specific and overall survival.[63] However, a study by Chromecki et al found that a high percentage of elderly patients who underwent radical nephroureterectomy were cured, suggesting that chronological age alone is an unreliable criterion for outcome in older patients.[64]
American Society of Anesthesiologists scores significantly correlate with cancer-specific survival after radical nephroureterectomy.[65]
Active smoking, a smoking history of at least 20 years, and smoking at least 1 cigarette per day is significantly associated with advanced disease, greater recurrence, and worse cancer-specific mortality. Patients who quit smoking more than 10 years ago have better oncologic outcomes.[66]
Tumor location, (ie, renal pelvis versus ureter) is inconsistently reported to affect prognosis, with some articles suggesting a worse prognosis for ureteric location and others showing no difference.[10]
Hydronephrosis predicts advanced pathologic stage, metastasis, and cancer-specific survival.[13, 67, 68]
For patients with a higher body mass index who were treated with radical nephroureterectomy, a study by Ehdaie et al found that overall survival rates were diminished.[69]
A history of bladder cancer and a delay to definitive therapy are associated with worse outcomes. Tumor characteristics that predict worse outcomes include the following[10, 70] :
In future, endoscopic ablative procedures will be used more commonly for low-grade, low-stage disease and in patients in whom renal-sparing therapy is indicated.
New agents for topical instillation therapy of upper tract urothelial tumors are being developed.
New markers are being investigated for diagnosis, prognostication, and surveillance. Mini-array comparative hybridization-based tests, like those under new investigation for bladder cancer, may be helpful in the future.[71]
Makise et al identified Melanoma Associated Antigen A (MAGE-A) as a promising prognostic indicator, as well as a potential future immunotherapeutic target for UTUC. Expression of MAGE A was associated with higher histologic grade; concomitant carcinoma in situ; higher Ki -67 proliferation index; and infiltration of CD3-, CD8-, and CD45RO-positive lymphocytes .High MAGE-A expression was significantly associated with shorter metastasis-free survival after nephroureterectomy.[72]
UTUC tumors also demonstrate mismatch repair deficiency, which can be utilized for targeted immunotherapy. Castro et al demonstrated, through molecular profiling, the presence of the hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy in a patient with sporadic, high-grade urothelial carcinoma of the renal pelvis. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6. Immunohistochemical staining for programmed cell death ligand-1 (PD-L1) revealed 2+ staining in 80% of cells. The patient had a complete remission with immunotherapy utilizing MEDI4736 and MEDI0680, demonstrating the potential of this therapy in selected patients.[73]
Urothelial carcinoma is also susceptible to checkpoint inhibition. In a landmark paper, Alexandrov et al characterized the prevalence of somatic mutations across human cancer types. Leading the way with the highest mutational burden were melanoma and non–small cell lung cancer (both adenocarcinoma and squamous cell carcinoma), the tumor types for which checkpoint inhibition have proven the most efficacious to date, followed closely by urothelial carcinoma.[74]
The first studies evaluating checkpoint inhibitors in urothelial carcinoma of the bladder involved ipilimumab, a monoclonal antibody against cytotoxic T lymphocyte–associated antigen. In a "window of opportunity" study, 12 patients with high-grade T1/2 urothelial carcinoma who received two doses of ipilimumab prior to radical cystectomy demonstrated measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. Increased freqency of those cells may be a biomarker that correlates with increased likelihood of clinical benefit.[75]
In a subsequent study (NCT01524991), the addition of ipilimumab to chemotherapy with gemcitabine and cisplatin led to increased levels of circulating CD4+ and CD8+ cells and induced a potentially more immunostimulatory environment.[76]
Updated safety and efficacy results were presented at the Genitourinary Cancers Symposium in January 2016.[77] In 36 evaluable patients, the overall response rate was 64%, with 5 patients (14%) achieving a pathologic complete response. A high rate of adverse events were noted, namely 72% grade 3/4 adverse events and autoimmune adverse events. The study did not meet its primary endpoint of improved 1-year overall survival (OS).
Use of the PD-1 inhibitor pembrolizumab (MK-3475) in a large, multi-arm phase I trial that included 33 patients with recurrent or metastatic PD-L1–positive urothelial carcinoma.resulted in an overall response rate of 28%. The median OS was reported as 12.7 months. Three patients achieved complete remission.[78]
Data have also emerged for atezolizumab. In the MPDL3280A trial, which accepted urothelial carcinoma patients irrespective of PDL-1 staining status, the overall response rate was 34%, with 87 total patients evaluable, but notably, the response rate was 50% in the 46 patients with immune clel 2/3 status, with nine complete responses. Azetolizumab has been granted a “breakthrough therapy designation “ based on those results.[79]
Another PD-1 inhibitor, nivolumab, is currently being studied in a phase II single-arm study in patients with platinum-refractory metastatic urothelial carcinoma. In the near future, checkpoint inhibitors could be combined for better results. The above studies on metastatic urothelial carcinoma could be extrapolated to UTUC in the future.
In the near future, personalized genetic profiling of primary or metastatic tumor cells may become readily available for routine clinical decision-making, potentially allowing for identification of patients who are likely to respond to systemic therapy .[80]
Staging is often inadequate with currently available imaging. Future approaches should include the capability to delineate invasive from superficial disease.
Guidelines on the diagnosis and treatment of urothelial tumors of the renal pelvis and ureters have been published by the following organizations:
The NCCN guidelines recommend including the following tests in the workup of suspected renal pelvic and ureteral tumors[86] :
Additional imaging studies, such as renal or bone scanning, may be indicated by the test results or presence of specific symptoms. Evaluation for Lynch syndrome should be considered for those at high risk.
The EAU guidelines in general concur with NCCN and include the following key recommendations[1] :
The NCCN guidelines provide treatment recommendations based on grade and tumor location. For low-grade renal pelvic tumors, the guidelines recommend the following treatment[86] :
For high-grade renal pelvic tumors and upper ureter tumors, NCCN treatment recommendations include the following[86] :
For low-grade mid-ureter tumors, NCCN recommended treatment options include the following[86] :
For high-grade mid-ureter tumors, NCCN recommended treatment options include the following[86] :
For distal ureter tumors, NCCN recommended treatment options include the following[86] :
For metastatic disease in both renal pelvis and ureter tumors, systemic therapy is recommended.[86]
The EAU guidelines include the following key treatment recommendations[1]
Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral transitional cell carcinoma (TCC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.
Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral transitional cell carcinoma (TCC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.
Stage Tumor Node Metastasis 0a Ta N0 M0 0is Tis N0 M0 I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 IV T4 NX, N0 M0 Any T N1 M0 Any T N2 M0 Any T Any N M1
Reference Study design Outcome Number of patients enrolled Leow JJ, Martin-Doyle W, Fay AP, et al. 2014
Systematic review and meta analysis Pooled hazard ratio (HR) for overall survival (OS) was 0.43 (95% confidence interval [CI], 0.21–0.89; P = 0.023) for adjuvant therapy group compared with controls without adjuvant therapy Prospective study (n = 36) investigating adjuvant carboplatin–paclitaxel and nine retrospective studies, with a total of 482 patients receiving cisplatin-based or non-cisplatin–based AC after nephroureterectomy Porten S, Siefker-Radtke AO, Xiao L, et al. 2014
Retrospective review between neoadjuvant chemotherapy group and initial surgery group Neoadjuvant chemotherapy had improved OS and disease-specific survival (DSS) with a 5-year DSS rate of 90.1% and a 5-year OS rate of 80.2% versus DSS and OS rates of 57.6% for those who underwent initial surgery (P = 0.0204 and P = 0.0015, respectively Neoadjuvant chemotherapy +surgery (n =31) and surgery only (n= 81)
Huang YC, Chen MF, Shi CS, et al. 2015
Retrospective review of patient records with pT3N0M0 upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy and adjuvant therapy versus control group Statistically significant differences were found between the adjuvant and control groups in 5-year cancer-specific survival rates (80.5% vs 57.6%, P = 0.010) and recurrence-free survival rates (74.4% vs 52.9%, P = 0.026), but no statistically significant difference in overall survival (71.9% vs 49.0%, P = 0.072) Postoperative adjuvant chemotherapy (n= 60) vs surgery only (n=111) Urakami S, Yuasa T, Yamamoto S, et al.2015 Retrospective analysis of clinicopathological response to induction chemotherapy and identification of prognostic factors for OS Clinically objective response to the induction chemotherapy occurred in 75% of patients. Histopathological analysis indicated pT0 status in 20% and pN0 in 33%. Clinical tumor response correlated significantly with achievement of pathological complete response 60 urothelial cancer patients; primary cancer site was the urinary bladder (n= 31; 52%) and upper urinary tract (n=29; 48%) Lucca I, Kassouf W, Kapoor A, et al. 2015
Retrospective analysis of data of patients with lymph node (LN)–positive UTUC, who underwent full surgical resection followed by adjuvant chemotherapy (AC) In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). 263 patients with LN-positive UTUC underwent full surgical resection. Study group (n=107, 41%) received three to six cycles of AC, while controls (n=156; 59.3%) were treated with RNU alone Kim DK, Kim JW, Jung HD, et al.2019 Systematic review and meta analysis of adjuvant therapy after radical nephroureterectomy (RNU) in patients with locally advanced UTUC
Compared with patients who underwent RNU only, those who received adjuvant chemotherapy after RNU had HRs for disease-free survival of 0.59 (P = 0.001), cancer-specific survival of 0.73 (P = 0.02), and OS of 0.84 (P = 0.02) 11 studies, comprising 1496 patients who underwent RNU alone and 798 patients who received ACH after RNU NCT02412670
Prospective phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery for patients with high-grade UTUC
Expected to complete by Feb 2020 NA NCT01261728 Prospective phase II study of gemcitabine and cisplatin as neoadjuvant chemotherapy in patients with high-grade UTUC Expected to complete by Dec 2020 NA