# The Role of Chemotherapy in Upper Tract Urothelial Carcinoma

Authors: Peter H. O'Donnell; Walter M. Stadler
Journal: Advances in Urology
 (2009)

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## Abstract

Locally advanced upper tract urothelial carcinoma has a poor prognosis.  While surgery represents the only potentially curable therapeutic intervention, recurrences are common and typically systemic in nature.  It is thus reasonable to consider perioperative chemotherapy in an effort to decrease the risk of recurrence.  There are very little direct data providing clinical guidance in this scenario.  For urothelial cancer of the bladder, there are randomized phase III data demonstrating a survival advantage with neoadjuvant cisplatin-based combination chemotherapy.  Although arguments favoring adjuvant chemotherapy could be made for upper tract urothelial cancer, the loss of renal function that occurs with nephrectomy can complicate administration of appropriate perioperative treatment.  Therefore, by analogy to urothelial carcinoma of the lower tract, it is argued that cisplatin-based neoadjuvant chemotherapy should be the standard of care for patients with locally advanced upper tract urothelial cancer.


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## Body

## 1. Introduction

Locally
advanced upper  tract urothelial carcinoma has a poor prognosis. Surgical series suggest that, notwithstanding
nodal status, the disease-specific five-year survival rates for stages T2 and
T3 disease are 73% and 40%, respectively, while the median survival for T4
patients is approximately 6 months [1]. Importantly, the vast majority of patients with
invasive upper tract urothelial carcinoma have stage T3 or greater disease at
the time of surgery [2, 3], and, if investigated, at
least 20–25% will have
lymph node involvement at the time of surgery [4–6]. The poor prognosis is furthermore reflected
by mortality estimates in which the mortality to incidence ratio for upper tract
disease is approximately 0.34 [7], whereas for lower tract
urothelial cancer it is 0.20 [8]. This may be due in part to the notorious
difficulty of diagnosing earlier-stage urothelial cancer of the upper tract.The
most common presenting symptom of upper tract urothelial carcinoma, like its
bladder counterpart, is hematuria [1]. Unfortunately, urine cytology is not
particularly sensitive for diagnosing urothelial carcinoma of any location [9, 10]. Anterior grade and retrograde pyelogram, or ureteroscopy
with visualization of the renal pelvices, are technically challenging and not
routinely performed in the evaluation of hematuria. Computed tomography (CT) imaging is also not
very sensitive for early stage disease [11, 12].While surgery
represents the only potentially curable therapeutic intervention for upper
tract urothelial cancer, systemic recurrences are common [1, 3, 13]. It is thus reasonable to consider
perioperative chemotherapy in an effort to decrease the risk of recurrence. Unfortunately, with only approximately 2000 cases
annually in the United States [7, 14], and with the historical
difficulties in accruing urothelial carcinoma patients to clinical trials, there
are very little direct data providing clinical guidance in this scenario. Using
analogy to urothelial carcinoma of the lower tract, we believe that
cisplatin-based neoadjuvant chemotherapy should be the standard of care for
patients with locally advanced upper tract urothelial cancer.


## 2. Is Urothelial Cancer of the Upper Tract Different?

Bladder
and upper tract urothelial carcinomas have traditionally been considered
separate diseases in the urologic and surgical literature mainly because the
surgical approach to these diseases is so different. Yet, recent evidence has suggested that the
anatomic location of disease has no bearing on tumor behavior, in that recurrence
and mortality rates from upper and lower tract carcinomas are similar when
adjusted for tumor stage and grade [15]. Additionally, from a biologic prospective,
there is very little difference between urothelial carcinomas that arise from these
different sites. First of all, the most
important epidemiologic risk factor for urothelial cancer remains exposure to
tobacco products [16, 17], and this is true regardless
of the site of origin. Secondly, the
urothelial tissue itself is histologically indistinguishable by site [18]. Certainly, there are differences in the
underlying stroma and supportive tissue, but the importance of these
differences in the treatment of systemic disease, including the microscopic
systemic disease that is being targeted in perioperative therapy, is
debatable. Thirdly, the molecular
oncogenic events appear to be the same between upper and lower tract urothelial
cancers. For example, for both origins,
chromosome 9 deletions are the most common genetic abnormality [19, 20], and chromosome 9 and p53
alterations appear to be present at similar frequencies in upper and lower
tract lesions [20, 21]. Fourth, it has been the practice of the
medical oncology community to include urothelial carcinoma patients in trials
of metastatic disease, regardless of the site of origin. A number of large studies have thus included
at least a fraction of patients whose initial tumor began in the upper tract
[22–28]. In none of those studies was the site of
origin an important prognostic factor in the context of systemic
chemotherapy. Finally, the high incidence
of secondary (40–50%), or, less
commonly, synchronous (8%) lower tract disease in patients with upper tract
disease [1, 29] also supports the notion that
these cancers actually represent one disease process in such patients. It is thus reasonable to consider systemic
and perioperative chemotherapy for locally advanced upper tract urothelial
cancer by analogy to urothelial cancer of the bladder.For
urothelial cancer of the bladder, there are randomized phase III data
demonstrating a survival advantage with neoadjuvant cisplatin-based combination
chemotherapy. The two largest trials
were conducted by an international collaboration [30] and
by Grossman et al. [31]. A meta-analysis including all neoadjuvant
chemotherapy trials confirms the conclusion [32]. Others have argued that the absolute benefit
of neoadjuvant chemotherapy is modest [33], and that the more accurate
clinical staging afforded by surgery [34] allows better patient
selection on the basis of prognostic factors [35]. Under the assumption of equivalent benefit
irrespective of underlying prognosis, the absolute benefit of perioperative chemotherapy
for poor prognosis patients is certainly going to be greater than that for good
prognosis patients. Nevertheless, the
randomized studies of adjuvant chemotherapy in urothelial cancer of the bladder
have been undersized and underpowered for detecting a clinically significant
benefit [36–40].Although
similar arguments favoring adjuvant chemotherapy could be made for upper tract
urothelial cancer, the loss of renal function that occurs with nephrectomy can
further complicate administration of appropriate perioperative treatment. In this regard, the above noted meta-analysis
[32] demonstrated  survival
benefits with neoadjuvant therapy only when
cisplatin-based combination chemotherapy was utilized, and two randomized
studies in the metastatic setting have strongly suggested that carboplatin,
which is typically substituted for cisplatin in patients with renal
dysfunction, is an inferior agent [41, 42]. Furthermore, the decrement in renal function
associated with nephrectomy is not inconsequential, as evidenced by studies in
renal cancer patients undergoing nephrectomy [43, 44]. This may be even more important in urothelial
cancer patients who are often smokers and have other smoking-related
comorbidities. Finally, anecdotal
experience and early evidence [45, 46] suggest that even among patients
in whom neoadjuvant chemotherapy is indicated, only a minority actually receive
chemotherapy. This raises concerns about
a lack of adherence to chemotherapy recommendations [47] in the urologic community, or
perhaps an unwillingness by patients to be treated. Even if some urologists forgo neoadjuvant
chemotherapy referral in favor of future adjuvant administration, adherence
percentages in the postoperative setting are likely to be even lower, because
of both patient and surgeon factors [48, 49]. Furthermore, despite hypothetical concerns
about the potential for increased surgical morbidity after neoadjuvant
chemotherapy, the data in bladder cancer patients have strongly demonstrated
that this does not occur [49, 50], so we anticipate that the
same would be true for neoadjuvant chemotherapy in upper tract disease.


## 3. Conclusions

Upper
tract urothelial carcinoma, when not metastatic, typically presents with
locally advanced disease. Such disease
has a poor prognosis because of the high risk of systemic recurrence. Although the surgical approach to upper tract
and lower tract urothelial cancers is markedly different, the biology of these
diseases is for the most part indistinguishable. Certainly, the response to therapy appears to
be the same. Given the rarity of upper
tract urothelial cancer and the difficulty of accruing to clinical trials, recommendations
for perioperative chemotherapy must currently be based on similarities to its
lower tract counterpart. In this regard,
neoadjuvant chemotherapy is the standard of care based on improvements in
survival in well-conducted phase III trials. Such data does not exist with
adjuvant therapy in bladder cancer, and adjuvant therapy for upper tract
disease is further complicated by the difficulty of administering
cisplatin-based regimens to patients who may suffer a decrement in renal
function following nephrectomy.
Therefore, until and unless specific trials are conducted, the most
reasonable standard for locally advanced upper tract urothelial cancer is
neoadjuvant, cisplatin-based combination chemotherapy prior to nephrectomy and
surgical resection.



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