147Controversies in the Management of Upper Tract Urothelial Cancer
Case 1: A 53-year-old male presented with a right renal mass that was 21.2 cm in maximal diameter, with ipsilateral hydronephrosis, a 1 cm hepatic lesion, and bilateral sub-centimeter pulmonary nodules. He had a ureteroscopic biopsy that showed papillary urothelial carcinoma.
Question 1: Is surgery an option for this patient?
For metastatic renal cell carcinoma (RCC), cytoreductive nephrectomy has been shown to have a survival benefit. Since some upper tract urothelial cancers (UTUC) have a similar location and pattern of spread as RCC, one could hypothesize that some patients with these tumors may also benefit from cytoreductive surgery.
Unfortunately, there are no randomized trials examining cytoreductive surgery and/or metastatectomy in UTUC. However, there are retrospective studies evaluating the benefit of surgery in metastatic urothelial cancer, in which UTUC cases comprise 20% to 56% in the cohorts (1–4). In these retrospective studies there is suggestion that some patients may benefit from surgery (Table 22.1).
With lack of randomized controlled trials or robust retrospective data, the question of surgery in metastatic UTUC is controversial. However, the question may arise in select cases, especially those who have no comorbidities and a limited metastatic burden. Some experts advocate chemotherapy followed by surgical intervention only if clinical downstaging is seen radiographically. Retrospective data do seem to suggest some benefit to metastatectomy in cases with limited metastasis, but the benefit of cytoreductive surgery without metastatectomy is not known. Intervention in this setting must be in carefully selected patients who understand the limited known benefit.
150Case 2: A 53-year old underwent a radical nephroureterectomy and lymph node dissection (LND) for a urothelial carcinoma of the renal pelvis. He completed 4 cycles of adjuvant Gemcitabine + Cisplatin. One year later he was noted to have a 2 cm left lower lobe lung nodule. Biopsy of this lesion was consistent with urothelial cell carcinoma. On CT imaging of the chest/abdomen/pelvis there were no other sites of disease.
Question 2: Should this patient undergo resection of the lung nodule?
Metastatectomy appears to have some survival benefit in limited retrospective studies, some of which were discussed earlier in this section. Those most likely to benefit from such an approach are those with small volume metastasis (e.g., isolated visceral metastasis or nodal metastasis) and in the context of chemotherapy (5). However, this is a controversial issue that will require further analysis as there are inherent biases in retrospective studies, including small case numbers and lack of generalizability. Metastatectomy may be considered in select cases, but it should not be widely adapted in the community without further data, preferably via randomized or multicenter prospective studies. Randomized studies remain quite hard to accrue in a disease as rare as UTUC, but multicenter cooperative group efforts can potentially provide future answers to questions like this.
Question 3: Should this patient undergo neoadjuvant therapy before resection of the lung metastasis or adjuvant therapy afterwards?
Some experts have argued that neoadjuvant chemotherapy should be given prior to metastatectomy. The rationale behind this approach is that it allows the treating physicians to see who will and will not respond to chemotherapy. Those who respond are the ones who obtain the benefit from metastatectomy in the published retrospective trials (5).
Case 3: A 63-year-old male patient undergoes imaging and endoscopic diagnosis to confirm a high-grade 4 cm renal pelvis tumor. Depth of invasion is difficult to determine due to bulk of tumor in the renal pelvis. Staging imaging shows 151no evidence of lymphatic or distant metastasis, and his estimated glomerular filtration rate (eGFR) is greater than 60.
Question 4: What is the preferred sequence of definitive treatment?
Although no level 1 evidence provides the answer to this question, the current recommendation, being tested in prospective studies, is for the patient to receive neoadjuvant cisplatin-based chemotherapy followed by radical nephroureterectomy with regional LND. Limited retrospective data support this approach (6). The most important reasons for this are the known rates of clinical understaging of upper tract primary lesions and the expected reduction in renal function with nephroureterectomy that could potentially preclude cisplatin-based chemotherapy in an adjuvant setting.
Case 4: A patient undergoes nephroureterectomy and lymphadenectomy for a pT1 high grade (HG) UTUC.
Question 5: Is lymphadenectomy necessary in this situation and if so to what extent?
No prospective data exist to address this question, and retrospective data generally come from small cohorts, due to the low incidence of this disease. However, a retrospective multicenter study of 1,130 patients with pT1-T4 disease who underwent radical nephroureterectomy suggested those staged pT2 and higher have better CSS and disease specific survival with lymphadenectomy (7).
Because it is exceedingly difficult to accurately stage UTUC tumors prior to nephroureterectomy, with a very high rate of understaging by endoscopic biopsy, a regional LND is recommended for all patients undergoing radical nephroureterectomy. The recommended template and number of lymph nodes that defines an adequate dissection remain areas of active study.