© Springer International Publishing Switzerland 2015
Isidoro Di Carlo (ed.)Noncolorectal, Nonneuroendocrine Liver Metastases10.1007/978-3-319-09293-5_1414. Liver Metastases from Ureteral and Bladder Cancer
(1)
Department of Urology, Tokyo Medical and Dental University Graduate School, 1-5-45, Yushima, Bunkyo, Tokyo 113-8519, Japan
14.1 Incidence
14.1.1 Epidemiology and Risk Factors of Urothelial Cancers
Urothelial cancers are the fourth most common tumors after prostate (or breast), lung, and colorectal cancer [1]. They are classified as lower urinary tract (bladder and urethra) or upper urinary tract (renal pelvis and ureter). Bladder cancers account for over 90 % of urothelial cancers [2]. Renal pelvic cancers are about twice as common as ureteral cancers. In 17 % of cases with upper urinary tract cancers, concurrent bladder cancers are present [3].
Smoking is the most common risk factor for them. Occupational exposure to aromatic amines and polycyclic aromatic hydrocarbons are other important risk factors. The impact of diet and environmental pollution is less evident [4]. There are familial cases of upper urinary tract cancers associated with hereditary nonpolyposis colorectal carcinoma [5].
14.1.2 Metastatic Pattern and Liver Metastases of Urothelial Cancers
While urothelial cancers spread to any organ, the most common metastatic locations are lymph nodes, lung, liver, and bone. Shinagare et al. evaluated the metastatic pattern of muscle-invasive bladder cancer [6]. Of 150 patients with metastatic urothelial cancer, the most common metastatic sites were lymph nodes (69 %), bone (47 %), lung (37 %), liver (26 %), and peritoneum (16 %). Ninety percent of the patients with liver metastases had multiple lesions, but only 10 % had a solitary liver metastatic lesion. Five percent of patients with liver metastasis had portal venous thrombosis [6]. Wallmeroth et al. investigated the metastatic behavior of bladder cancers with autopsies of 367 patients with muscle-invasive bladder cancer [7]. Metastases were found in 68 % of them and the most common metastatic sites were regional lymph nodes (90 %), liver (47 %), lung (45 %), and bone (32 %).
Shinagare et al. investigated the metastatic pattern of upper urinary tract cancers [8]. Of 52 patients with metastatic upper urinary tract cancer, lymph nodes (75 %), lung (65 %), liver (54 %), bone (39 %), and peritoneum (19 %) were the most common metastatic sites. Tumor location within the upper urinary tract has no effect on metastatic pattern. Ninety-two percent of the patients with liver metastases had multiple lesions, whereas only 7 % had a solitary liver metastasis.
Although liver metastases from urothelial cancers are common, those are considered a systemic disease associated with a dismal prognosis.
14.2 Natural History
14.2.1 Histology of Urothelial Cancers
More than 95 % of urothelial cancers are derived from the urothelium [1]. Morphological variants such as micropapillary, clear cell, neuroendocrine, and lymphoepithelial variants are associated with high-grade cancers [1]. Squamous cell carcinoma is associated with chronic inflammatory and infectious disease mainly associated with urolithiasis [9]. Other histological subtypes are adenocarcinomas, small cell carcinomas, and sarcomas [10].
14.2.2 Advanced/Metastatic Urothelial Cancers
At the initial diagnosis of bladder cancer, 30 % of cases are diagnosed as muscle-invasive disease and approximately 30 % of patients diagnosed with muscle-invasive disease have undetected metastases [11]. In contrast to bladder cancers, 60 % of upper urinary tract cancers are invasive at diagnosis [12].
Median survival in patients with locally advanced or metastatic urothelial cancer treated with chemotherapy was approximately 14 months and a 5-year survival rate was 14 %. Patients with visceral metastases had a median overall survival of 10 months and a 5-year survival rate of 6.8 % [13]. Especially, Abe et al. reported the median survival of those patients with visceral metastases beyond the lung was only 7 months [14].
14.2.3 Prognosis and Risk Factor of Metastatic Urothelial Cancers
Some investigators reported that the presence of visceral metastasis was of independent significance. Bajorin et al. reported Karnofsky performance status of <80 % and presence of visceral metastases were independent prognostic factors of poor survival after treatment with the standard chemotherapy [15]. Abe et al. demonstrated that absence of liver, bone, and local recurrence and resection of metastasis were independent significant predictors of prolonged survival [14].
14.3 Diagnosis
14.3.1 The Radiological Evaluation of Liver Metastases from Urothelial Cancers
Although liver metastases are common in patients with disseminated urothelial cancer, there is little data to suggest specific imaging features that enable metastases of urothelial cancers to be distinguished from other hypovascular liver metastases [16]. Computed tomography is the diagnostic techniques of choice to detect metastases to liver [17]. On CT imaging, the liver metastases of urothelial cancers were usually of low attenuation [6]. When there is uncertainty regarding the interpretation of CT, MRI or positron emission tomography CT may be employed [16]. T2-weighted MRI image of liver metastases usually demonstrates multiple foci of T2 hyperintensity. Gd-enhanced T1-weighted image demonstrates peripheral enhancement of these metastatic liver lesions [18]. Fludeoxyglucose positron emission tomography/CT is reported to improve staging because of its higher sensitivity for metastatic disease [19].
14.4 Treatment
14.4.1 Treatment Strategy for Metastatic Urothelial Cancers
Metastatic urothelial cancers, even if limited to a single site, are considered disseminated disease, and therefore systemic therapy is the mainstay of treatment.
According to the European Association of Urology (EAU) guideline [1, 17], the current mainstay of treatment for patients with metastatic urothelial cancer is systemic combination chemotherapy. Urothelial cancers are chemosensitive tumors and respond to several active agents, but recurrence after response to chemotherapy is inevitable.
Nearly half of patients diagnosed with metastatic urothelial cancer will eventually develop liver metastases [7]. As other distant metastases, the treatment strategy for liver metastases of urothelial cancer is systemic combination chemotherapy. Role of liver-directed therapies including surgery and interventional radiology has remained controversial in metastatic urothelial cancer.
14.4.2 Chemotherapy
Standard First-Line Chemotherapy
Combination chemotherapy including cisplatin has been the standard chemotherapy regimen for metastatic urothelial cancers since the late 1980s. Methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) regimen has been proven superior to cisplatin monotherapy [20]. In the late 1990s, some phase II trials of gemcitabine in combination with cisplatin (GC) demonstrated a response rate of over 40 % in the treatment of chemotherapy-naive patients with metastatic urothelial cancer [21, 22]. A randomized phase III study showed similar efficacy with response rate (GC, 49.4 %; MVAC, 45.7 %); however, a better safety profile was observed with GC [23]. In the updated analysis of the trial, overall survival was similar in both regimens with a median survival of 14.0 months for GC and 15.2 months for MVAC and the 5-year overall survival rates were 13.0 and 15.3 %, respectively [13]. Currently, the lower toxicity of GC has been a new standard regimen. As the further intensified chemotherapy, PCG regimen (paclitaxel, cisplatin, and gemcitabine) did not result in a significant improvement in overall survival in a randomized phase III trial, comparing PCG to GC, although the overall response rate was higher with PCG [24].
According to the EAU guideline, GC, PCG, MVAC, or high-dose MVAC with granulocyte colony-stimulating factor are recommended for above patients with normal renal function [17]. For patients with impaired renal function or whose performance status is unsatisfactory, using carboplatin is recommended instead of cisplatin.
Second-Line Chemotherapy
Second-line chemotherapy regimen for metastatic urothelial cancers remains controversial. Above all, vinflunine (VFL), a microtubule inhibitor, seems to be a reasonable second-line option for patients with progression after a platinum-containing regimen. In a randomized phase III study of VFL and best supportive care (BSC) versus BSC alone [25], VFL demonstrates a survival advantage in the eligible patient population without any harmful effect on quality of life. Currently, VFL is the only European Medicines Agency-approved agent in the second-line setting [17].
14.4.3 Surgery
Although role of surgery for liver metastases from colon cancer is well established [26], it is controversial in patients with metastatic non-colorectal cancer including urothelial cancers. Although a few cases of surgical intervention for liver metastasis, including a case of resection of solitary liver metastases without prior chemotherapy [27], have been reported, it is not generally considered the standard practice.
Post-chemotherapy Surgery for Residual Tumors
Although several investigators have indicated the importance of surgery for residual tumors after achieving a major clinical response to chemotherapy [28–30, 14], the impact on survival remains controversial. Moreover, selection of patients who receive benefits from post-chemotherapy surgery is not well established.
Of the 30 patients whose residual metastases were completely resected resulting in a complete response (CR) to MVAC chemotherapy plus surgery, 33 % remained alive at 5 years, similar to results attained for patients achieving a CR to chemotherapy alone [28]. Investigators at the MD Anderson Cancer Center observed 31 patients with metastatic urothelial cancer (lung in 24 cases, distant lymph nodes in 4, brain in 2) undergoing metastasectomy, with the intent of rendering these patients free from disease [30]. The median overall survival time from diagnosis of metastases was 31 months and they suggested that post-chemotherapy surgery for residual metastases is feasible and could contribute to long-term disease control, when integrated with effective chemotherapy and the tumor was considered surgically resectable with clear margins. Abe et al. reported 12 patients underwent metastasectomy (7 patients received lobectomy) of 48 patients with metastatic urothelial cancer underwent systemic chemotherapy [14]. The median overall survival in this group was 42 months, whereas that in patients without metastasectomy was 10 months. They described that lung metastases would be one of the good indications whereas; patients with liver metastasis did not seem to be likely candidates for metastasectomy because they usually had other sites of metastases.
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