What Is Needed for Improved Patient Care in Upper Urinary Tract Urothelial Carcinoma?

By: Shin Egawalowast and Takahiro Kimura

Published online: 01 July 2012

Abstract Full Text Full Text PDF (486 KB)

Refers to article:

Prognostic Factors in Upper Urinary Tract Urothelial Carcinomas: A Comprehensive Review of the Current Literature

Giovanni Lughezzani, Maximilian Burger, Vitaly Margulis, Surena F. Matin, Giacomo Novara, Morgan Roupret, Shahrokh F. Shariat, Christopher G. Wood and Richard Zigeuner

Accepted 14 February 2012

July 2012 (Vol. 62, Issue 1, pages 100 - 114)

Upper urinary tract urothelial carcinoma (UTUC) is a rare disease that accounts for approximately 5% of all urothelial tumors [1]. Treatment has been challenging for a number of reasons. First, the small patient population means that special methods and unusually close cooperation are required to obtain high-quality data for the assessment of treatment methods. Second, there is no consensus on the value of lymphadenectomy (LND) in the treatment of UTUC, and few data are available on the proper use and form of adjuvant therapy. Third, tools have only recently become available for the direct and clear visualization of tumors in the upper urinary tract. In conjunction with this review of the literature, we offer our perspective on the study and treatment of UTUC.

This condition has an estimated incidence of 2.08 cases per 100 000 person-years in the United States [1]. According to the Surveillance Epidemiology and End Results (SEER) database of cases diagnosed in 2004–2008 from 17 SEER geographic areas, the age-adjusted incidence rate of cancer of the kidney and renal pelvis was 14.6 per 100 000 men and women per year, and the age-adjusted death rate was 4.0 per 100 000 men and women per year. In 2007, the US Centers for Disease Control and Prevention reported 187 deaths from ureteral carcinoma, and the 2011 European Association of Urology guidelines note only 1–2 new cases per 100 000 inhabitants in Western countries.

Well-designed randomized controlled trials are the gold standard for generating high-level evidence. However, in rare diseases the small patient population can create serious challenges for conducting clinical studies and for analyzing and interpreting their results [2]. If the disease has a low prevalence, a trial enrolling several hundred patients may be impractical or even impossible. In the review by Lughezzani et al, the authors emphasized the importance of integrated cooperation among experts from multiple disciplines to effectively translate accumulated knowledge into better care for patients with UTUC [3].

The ultimate goal of clinical studies is to improve patient care, treatment, and prognosis based on accumulated findings. If ordinary clinical trials are not feasible, then what alternatives can provide a solid foundation for the treatment of this rare malignancy? The combined evaluation of single-case studies may sometimes be the only way to collect evidence. One example of this approach is a nationwide retrospective survey of the outcome of laparoscopic nephroureterectomy for UTUC, commissioned by the Japanese Society of Endourology and ESWL, and covering 1003 cases from 51 centers [4]. Such studies, even though retrospective, can add a wealth of information and provide greater insight into the clinical behavior of this malignancy.

Prospective studies will also clearly be needed, with details described in the study protocol. Particularly for conditions like UTUC, in which the patient population is small, well-planned use of the best available techniques and treatments to obtain and analyze information is essential. To minimize data loss and improve data quality, treatment conditions and data collection should be standardized, stratified, and strictly controlled. This process minimizes variations in treatment practice but requires in-depth discussion and ongoing consensus among all the participating institutions. Success will require an unusually robust consensus system.

After these institutions agree to a single protocol with specific treatment options, each individual center or hospital must then agree to follow that protocol. If the consensus system is rigorously observed, every single participating patient will be able to contribute as much information as possible. A systematic review of all data, based on the treatment options implemented at each institution, will add weight to the evidence. The impact of various choices of treatment and management, reflecting clinical practice at that specific point in time, can thus be compared in a more scientific way. This method will allow truly meaningful statistical analysis as an alternative to classic randomized clinical studies, even when only one or two patients are registered from each institution and those patients are widely separated in time.

Registry systems should also be established under the strong initiative of academic bodies or associations in each individual country or study group. Official support is essential to sustain this type of “horizontal” clinical investigation.

The role of LND in the treatment of urologic malignancy has been hotly debated, with no consensus as of this writing. Some practitioners hold that patients with very early lymph node metastases and no distant disease can potentially be cured by LND. This belief has been held by most surgical oncologists since the original statement by Moynihan in 1908 [5]. Recent stage shift may have resulted in an increasing proportion of patients with earlier lymph node metastases without distant spread in comparison with historical data and may have changed the landscape substantially. However, cancer metastasis is not a simple process, and the biology is complex (eg, only a small proportion of patients with bone marrow–infiltrating tumor cells actually develop clinical bone metastasis, and not all lymph nodes with such cells progress to clinical nodal metastases [6]). To date, no randomized prospective studies in solid tumors of any organ have shown an overall survival advantage related to the extent, or even the performance, of regional nodal dissections, whether lymph nodes harbor metastases or not [7]. Such an issue needs to be addressed frequently to account for confounders, including the impact of earlier detection of tumors in the 21st century.

Kondo et al. have recently advocated the use of template-type LND to improve patient survival in muscle-invasive clinical node-negative UTUC [8]. Accurate assessment of the status of sentinel lymph nodes, which are by definition the first possible sites of metastasis via lymphatic drainage, may also be important. In this regard, the prediction of nodal status in melanoma and breast cancer appears promising. However, retroperitoneal lymphatic drainage from UTUC is substantially more complicated and will necessitate more studies that involve the accurate mapping of retroperitoneal lymphatic drainage and sampling, as well as the identification of these sentinel nodes.

One of the uses of LND is to provide precise staging and calculate the risk of cancer progression when considering adjuvant therapy. If survival is not dictated by the extent or performance of LND but by the biology of the primary tumor per se, we will need to develop and test more effective adjuvant therapy schemes for patients with high-risk disease. Very little is yet known, however, about appropriate use and forms of adjuvant therapy in UTUC. All these efforts may lead to the development of an innovative treatment like autologous adoptive immunotherapy. Further characterization and profiling of trapped cells in lymph nodes or the blood (disseminated tumor cells or circulating tumor cells) are also clearly needed for a better understanding of tumor biology and future innovation. We also anticipate breakthroughs from advanced imaging technologies for detection, localization, and visualization of affected nodes, including positron emission tomography–computed tomography and lymphotropic nanoparticle-enhanced magnetic resonance imaging.

The debate over LND extends to the risk–benefit ratio for this procedure. LND is both time-intensive and costly, and it is associated with an increased risk of complications, including lymphocele, lymphedema, deep venous thrombosis, and pulmonary embolism. A mere “mechanistic approach” to lymph nodes for seeking cure may be too simplistic to solve this conundrum in urologic oncology.

Sessile tumor architecture has been established as an independent predictor of clinical outcome for UTUC patients who undergo radical nephroureterectomy, and today the importance of cystoscopic observation of a tumor is universally recognized in the diagnosis and assessment of bladder carcinoma. Direct, clear visualization of UTUC tumors was not possible until the recent development of small, highly flexible, and highly maneuverable ureteroendoscopes. These digital scopes offer high resolution and enhanced imaging ability, and they provide much easier access to, and direct visualization of, nearly all areas of the upper urinary tract. Although current imaging studies have failed to accurately stage UTUC, we expect this situation to change with the more liberal use of new-generation flexible ureteroendoscopes and modern supplemental diagnostic techniques such as narrow-band imaging and photodynamic techniques. We also believe that upcoming technological advances in this area will further facilitate the early diagnosis and accurate staging of this deadly disease.

Endoscopic tumor assessment and other sophisticated markers will play an increasingly important role in UTUC risk assessment. Because of the need for some form of anesthesia, the current indication may be limited to patients with macroscopic hematuria and/or positive washing cytology from the upper urinary tract but without visible tumor. However, we expect to see this technology more widely adopted in daily clinical practice in the very near future.

Conflicts of interest

The authors have nothing to disclose.


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Department of Urology, Jikei University School of Medicine, Tokyo, Japan

lowast Corresponding author. Department of Urology, Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan. Tel. +81 3 3433 1111 ext. 3561; Fax: +81 3 3433 1260.