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. [32] 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. (Open Table in a new window)
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 |
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. [33]
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. [34] 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. [35] 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. [36]
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. [37]
Prospective studies are needed to better define the role of radiation therapy in the multimodal management of upper tract TCC.
-
Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). 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.
-
CT scan demonstrating bulky right renal pelvis upper tract urothelial carcinoma (UTUC) replacing the majority of the renal parenchyma. A pericaval lymph node metastasis is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
-
CT scan demonstrating metastatic upper tract urothelial carcinoma (UTUC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the spine. The superior portion of the right kidney is observed. 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%.
Tables
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 |
