Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study

Junho Lee; Sung Hee Lim; Jae Hoon Chung; Wan Song; Hyun Hwan Sung; Byong Chang Jeong; Se Hoon Park

doi:10.4143/crt.2023.1226

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Original Article Genitourinary cancer Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study: Junho Lee¹, Sung Hee Lim¹, Jae Hoon Chung², Wan Song², Hyun Hwan Sung², Byong Chang Jeong², Se Hoon Park^1,; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2024;56(3):871-876.
DOI: https://doi.org/10.4143/crt.2023.1226
Published online: January 16, 2024

¹Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: Se Hoon Park, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea
Tel: 82-2-3410-1779 Fax: 82-2-3410-1754 E-mail: hematoma@skku.edu

• Received: November 15, 2023 • Accepted: January 15, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Abstract

Purpose
The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy.
Materials and Methods
Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m² on days 1 and 8, cisplatin 70 mg/m² on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety.
Results
Among 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% confidence interval, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T category, grade, or the primary site of UTUC were not significantly associated with DFS or MFS.
Conclusion
Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied.
Key words: Upper tract urothelial carcinoma, Adjuvant chemotherapy, Real-world study

Introduction

Upper tract urothelial carcinoma (UTUC), arising from renal pelvis and/or ureter, comprises 5-10% of urothelial carcinomas [1]. Although UTUC clinical features overlap with those of urothelial bladder cancer, differences exist in the standard treatment (e.g., neoadjuvant chemotherapy followed by radical cystectomy for bladder cancer) and prognosis (higher risk of recurrence and death for UTUC) [2]. The high rate of recurrence following radical surgery makes it important to consider adjuvant chemotherapy for patients with UTUC.

The results from the PeriOperative chemotherapy versus sUrveillance in upper Tract urothelial cancer (POUT) trial showed that adjuvant platinum-based chemotherapy significantly improved disease-free survival (DFS) and metastasis-free survival (MFS) in patients with pT2-T4 pN0-N3 M0 or pTany pN1-3 M0 UTUC [3], when compared with surveillance alone. More recently, in CheckMate 274 trial involving patients with high-risk urothelial carcinoma who had undergone radical surgery [4], significantly longer DFS was reported with adjuvant nivolumab than with placebo. Controversy remains, however, because overall survival (OS) was a secondary endpoint in both trials and is yet mature. The lack of benefit with adjuvant nivolumab in patients with UTUC (hazard ratios, 1.22 for renal pelvis and 1.41 for ureter cancer) also requires attention [5]. Finally, in actual clinical practice, the utility of adjuvant chemotherapy in UTUC may be limited due to the decline in renal functions following surgery. Before the publication of the POUT trial [3], our institutional guideline recommended adjuvant chemotherapy involving gemcitabine and cisplatin (GP) for medically-fit patients with pT3/T4 or N+ UTUC [6], not for those with pT2 disease. In an effort to generate real-world data in Korean UTUC patients, we conducted a retrospective review of a prospectively collected cancer chemotherapy registry. Herein, we report the outcomes of pT3/T4 or N+ UTUC patients who received adjuvant cisplatin-based chemotherapy following radical surgery. Although this study is limited by the retrospective nature of the analysis, the present evaluation was also done with the intent to develop improved therapeutic strategies for UTUC patients in a real-world setting and support further prospective studies to better define the patients at high-risk of recurrence.

Materials and Methods

Between January 2019 and December 2020, 185 UTUC patients who received radical nephroureterectomy for curative intent were identified from a cancer registry at Samsung Medical Center (Seoul, Korea). The inclusion criteria for the present retrospective study were as follows: aged over 20; pathologically-proven urothelial carcinoma arising from renal pelvis and/or ureter; complete (R0) resection of primary tumor according to surgical and pathology reports; adequate medical records available; and those who received cisplatin-based adjuvant chemotherapy. Exclusion criteria included patients with history of previous or concurrent bladder cancer, residual and/or metastatic disease, and non-urothelial histologies. Written informed consent was given by all patients prior to receiving adjuvant chemotherapy according to institutional guidelines, and the study was approved by Samsung Medical Center (Seoul, Korea) institutional review board.

Adjuvant chemotherapy consisted of a 1,000 mg/m² dosage of gemcitabine (G) in a 30-minute infusion on days 1 and 8, and cisplatin (P) 70 mg/m² on day 1. Each cycle of adjuvant GP chemotherapy was given every 3 weeks if the patient’s blood counts had reached hemoglobin levels above 8 g/dL, platelet counts above 100,000/m², and absolute neutrophil count above 1,000/m², and non-hematologic toxic effects had subsided. Dosage of subsequent cycles was adjusted according to the toxic effects that developed as a result of the preceding cycle. Chemotherapy was repeated for a maximum of 4 cycles, or until disease recurrence or an unacceptable level of toxicity occurred. All patients received standard supportive regimen including adequate hydration and anti-emetics. No prophylactic administration of hematopoietic growth factors or blood products was given. Follow-up history, physical examinations and toxicity assessments were performed before every 3-week cycle of chemotherapy.

Patients were followed up at 3-month intervals for one year, at 6-month intervals for the next 4 years. Follow-up consisted of physical examination, blood counts and chemistries, chest radiography, abdominopelvic computed tomography, urine cytology, and flexible cystoscopy. During the follow-up period, any suspected recurrence was confirmed by biopsy, if possible. Typical lesions within bladder were accepted as recurrence and treated with transurethral resection. The site and date of the first recurrence, intravesical and/or metastatic, were recorded. The site of recurrence was coded as intravesical if the tumor was detected by cystoscopy (including bladder or contralateral urinary tract), and metastatic if the metastases were found outside the urinary tract. The primary endpoint of the study was DFS. Secondary endpoints included MFS and safety. Toxic effects were graded as 1 to 4 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. The DFS and MFS were calculated from the date of starting adjuvant chemotherapy to the observation of a recurrence and metastases, respectively. Kaplan-Meier product-limit method was used to estimate survival curves. To assess the importance of potential predictive factors for DFS, we performed uni- and multivariate analyses using log-rank test and Cox proportional hazards model. All data were analyzed using R packages (https://www.r-project.org).

Results

Among a total of 185 patients who received radical nephroureterectomy during 2019 and 2020, we identified 89 UTUC patients who were treated with adjuvant GP chemotherapy. According to a review of their medical records, the reasons of no adjuvant chemotherapy included pT2 or lower tumor (n=40), refusal by patients or cisplatin-ineligibility (n=23), evidence of metastases (n=9), non-urothelial (i.e., pure squamous cell or adenocarcinoma; n=9), and unknown (n=15). Eighty percent of patients were male, and the median age was 69 years (Table 1). Five patients (5.6%) had a mixed (i.e., urothelial and other variant) histology tumor. Lymph node dissection was performed in 49 patients, and half (24/49) of them had N+ disease confirmed with surgical specimen.

Baseline creatinine clearance was calculated to be a median of 67 mL/min (range, 48 to 108 mL/min). The median interval from surgery to the beginning of adjuvant chemotherapy was 29 days (range, 21 to 50 days). Of the 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy (Table 1). Four patients discontinued treatment after one or 2 cycles: 3 patients declined further cycles of chemotherapy because of toxic effects or their poor performance status, and one patient had disease progression while receiving treatment. In total, 286 GP cycles were given (median, 3; range, 1 to 4). Dose reduction was required in 24 (8.4%) cycles, and 32 (11.2%) of the cycles were delayed because of toxic effects. All patients were evaluable for toxic effects (Table 2). The most frequently encountered toxic effects included gastrointestinal toxicities and pruritus, which were easily managed with supportive measures. Hematologic toxicities were infrequent, only one episode of febrile neutropenia occurred. In one patient, a period of dialysis was required for acute kidney injury. No complication related to surgery was observed.

With a median follow-up duration of 37 months (range, 34 to 40 months), disease recurrence was recorded in 51 patients (57.3%). The most common site of first recurrence was urinary bladder (n=20), followed by lymph nodes (n=18), lung (n=9), liver (n=5), and bone (n=3). Of note, 39 (43.8%) patients had distant metastases during the follow-up period. The median DFS was 30 months (95% confidence interval [CI], 22 to 39 months), and the median MFS was not reached (Fig. 1). The 3-year DFS and MFS were 44% and 56%, respectively. The median DFS in patients with renal pelvis cancer and ureter cancer were 38 months (95% CI, 30 to 38 months) and 22 months (95% CI, 12 to 32 months), respectively (hazard ratio [HR], 1.58; 95% CI, 0.90 to 2.76). Likewise, the MFS in patients with renal pelvis cancer and ureter cancer were calculated similar (HR, 1.53; 95% CI, 0.81 to 2.91). The multivariate analyses revealed that the main factor associated with recurrence was the lymph node involvement (N0 or not evaluated versus N+; HR, 0.40; 95% CI, 0.18 to 0.91; 2-sided p=0.044). Additionally, the lymph node involvement was an independent predictive factor for MFS (HR, 0.32; 95% CI, 0.13 to 0.80; p=0.018). Shorter DFS or MFS was observed in patients with node-positive disease regardless of age, T category, tumor grade, or the primary site of UTUC (Table 3). For an exploratory purpose, the OS for all patients was checked and the median OS was not reached. The one- and three-year OS rates were 94% and 79%, respectively. Among 50 patients who are metastasis-free as of the data cutoff (September 2023), none died of disease.

Discussion

In the present study, adjuvant GP chemotherapy following radical nephroureterectomy was well tolerated and may improve the DFS and MFS of patients with T3/T4 or N+UTUC. In particular, the predictive significance of the lymph node involvement implies that the eradication of micrometastasis by a more effective systemic therapy is warranted. Due to its relative rarity of UTUC, clinical decision making for patients with UTUC depends on evidences based on bladder urothelial carcinoma [7]. Some studies have shown that UTUC tends to be more advanced than bladder cancer [8,9], mainly due to higher percentages of invasive disease at diagnosis, leading to more aggressive tumor behavior and a higher chance of distant metastases. While the treatment options for muscle-invasive bladder cancer have expanded in recent years to include neoadjuvant chemotherapy [10], adjuvant nivolumab for those at high-risk of recurrence [4], there is little data to support or refute the assertion that we can apply similar principles in the management of UTUC to bladder cancer [11,12]. Although it is recognized that both UTUC and bladder cancer harbor similar morphology and cytogenetic changes [13], as well as their prognostic factors [14], we do not know whether UTUC patients have better outcomes after adjuvant chemotherapy or have a more aggressive disease than those with bladder cancer. However, the long-term survival after curative surgery depends on the stage of the disease, not on the tumor location. Our data were derived from all consecutive patients in a single tertiary cancer hospital, in order to better reflect the patients seen in routine clinical practice.

When interpreting the results, it is of note that the present study represents only a small sample of patients and is retrospective in nature. Because of the lack of definition of locally advanced UTUC, determining the adjuvant chemotherapy following radical nephroureterectomy was mostly based on physician’s decision. So, differences in the indication and cycles of adjuvant chemotherapy were not controlled. After publication of the POUT trial [3], although the DFS benefit was not significant in pT2 disease (HR, 0.64; 95% CI, 0.25 to 1.60), our institutional guidelines have been changed to include patients with pT2 UTUC to receive adjuvant GP chemotherapy. As the present retrospective study excluded patients with pT2 N- disease, chances are that the outcomes obtained from the POUT trial may be better than those from ours. In addition, lymph node dissection was not routinely performed, unless macroscopic visible nodes were present. The prognostic role of lymph node dissection at radical cystectomy is well established and there is also evidence supporting the therapeutic benefit of a thorough dissection [15,16]. However, when planning nephroureterectomy for UTUC, anatomic sites of lymph node dissection have not yet been clearly defined and there is no trial has shown its direct impact on survival [17-19]. These factors might lead to an undefined bias regarding clinical outcomes. And in this retrospective study, the insignificant differences of DFS and MFS between renal pelvis cancer and ureter cancer may have reflected discrepancies in the tumor stage distribution, rather than the true difference in tumor biology.

Distant metastasis in patients with locally advanced UTUC was the most probable cause of mortality. Intravesical recurrence may usually be treated by surgical intervention; however, if distant metastasis occurs, curative treatment is not possible. Despite the consideration, the 3-year MFS of 56% may suggest that adjuvant chemotherapy for 3 to 4 cycles is not sufficient to prevent recurrence or metastasis, for patients with pT3/4 or N+ UTUC. Although it is unclear how many chemotherapy cycles are ideal, it is supposed to take into consideration the nephrotoxicity of cisplatin, advanced age of the patients, and the co-morbidities following radical surgery. In addition to adjuvant chemotherapy, the immune checkpoint inhibitor (ICI) nivolumab was approved in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery based on the phase 3 CheckMate 274 trial [4,5]. When compared with placebo, adjuvant nivolumab produced a 2-fold increase in the median DFS duration in the intention-to-treat population [5]. Whereas adjuvant nivolumab is approved for all-comers in the United States irrespective of primary tumor sites, it is only approved for patients with a high-risk muscle-invasive bladder urothelial carcinoma in Korea. It was suggested that the DFS benefit associated with adjuvant nivolumab versus placebo was not observed in patients with UTUC. Therefore, cisplatin-based chemotherapy still is the standard of care for adjuvant treatment of UTUC in patients who received radical nephroureterectomy and are medically-fit for cisplatin. In metastatic setting, where platinum-based chemotherapy has also been considered a standard first-line therapy for decades, a maintenance strategy with another ICI avelumab following disease control with chemotherapy extended survival [20], and is considered the standard of care. Therefore, adjuvant chemotherapy followed by maintenance with ICIs is a promising strategy, to reduce the risk of recurrence and/or developing metastases.

In conclusion, the frequent occurrence of recurrence and metastases following radical nephroureterectomy for UTUC provided the rationale for adjuvant chemotherapy. The present retrospective study, as well as the randomized POUT trial, would provide a platform upon which to base future studies involving ICIs and other systemic therapies for locally advanced UTUC.

NOTES

Ethical Statement

Written informed consent was given by all patients prior to receiving adjuvant chemotherapy according to institutional guidelines, and the study was approved by Samsung Medical Center (IRB no. 2023-10-068-001) institutional review board.

Author Contributions

Conceived and designed the analysis: Park SH.

Collected the data: Lim SH, Chung JH, Song W, Sung HH, Jeong BC.

Contributed data or analysis tools: Park SH.

Performed the analysis: Lee J, Park SH.

Wrote the paper: Lee J, Park SH.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

Fig. 1.

Kaplan-Meier curves for disease-free survival and metastasis-free survival.

Table 1.

Patient characteristics

	Total (n=89)	Renal pelvis (n=44)	Ureter (n=45)
Age (yr), median (range)	69 (41-86)	69 (44-86)	69 (41-83)
Sex
Male	71 (79.8)	35 (79.5)	36 (80.0)
Female	18 (20.2)	9 (20.5)	9 (20.0)
Smoking history
Never	23 (25.8)	12 (27.3)	11 (24.4)
Current or former	66 (74.2)	32 (72.7)	34 (75.6)
T category
T1	1 (1.1)	0	1 (2.2)
T2	13 (14.6)	3 (6.8)	10 (22.2)
T3	72 (80.9)	39 (88.6)	33 (73.3)
T4	3 (3.4)	2 (4.5)	1 (2.2)
N category (n=49)
N0	25 (28.1)	11 (25.0)	14 (31.1)
N1	11 (12.4)	5 (11.4)	6 (13.3)
N2	13 (14.6)	6 (13.6)	7 (15.6)
NE	40 (44.9)	22 (50.0)	18 (40.0)
WHO grade
2	21 (23.6)	11 (25.0)	10 (22.2)
3	68 (76.4)	33 (75.0)	35 (77.8)
Variant/Mixed histology	5 (5.6)	3 (6.8)	2 (4.4)
Chemotherapy cycles
1 or 2	4 (4.5)	3 (6.8)	1 (2.2)
3	60 (67.4)	29 (65.9)	31 (68.9)
4	25 (28.1)	12 (27.3)	13 (28.9)

Values are presented as number (%) unless otherwise indicated. NE, not evaluated; WHO, World Health Organization.

Table 2.

Maximum grade toxic effects in 89 patients

	Grade 1 or 2	Grade 3 or 4
Neutropenia	10 (11.2)	6 (6.7)
Anemia	26 (29.2)	2 (2.2)
Thrombocytopenia	13 (14.6)	0
Nausea	29 (32.6)	0
Vomiting	26 (29.2)	2 (2.2)
Stomatitis	25 (28.1)	0
Constipation	33 (37.1)	0
Fatigue	20 (22.5)	0
Peripheral neuropathy	25 (28.1)	0
Pruritus	38 (42.7)	0
Azotemia	13 (14.6)	2 (2.2)

Values are presented as number (%).

Table 3.

Multivariate analyses for disease-free survival and metastasis-free survival

Clinical parameter	Disease-free survival		Metastasis-free survival
Clinical parameter	HR	95% CI	HR	95% CI
Age, < median vs. > median	0.99	0.47-2.10	0.73	0.33-1.65
Site, renal pelvis vs. ureter	0.67	0.30-1.50	0.96	0.40-2.70
T category, 1/2 vs. 3/4	0.75	0.29-1.96	0.57	0.20-1.58
N category, NE or N0 vs. N+	0.40	0.18-0.91	0.32	0.13-0.80
Grade, 2 vs. 3	0.79	0.28-2.25	0.48	0.11-2.16

CI, confidence interval; HR, hazard ratio; NE, not evaluated.

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14. Lughezzani G, Burger M, Margulis V, Matin SF, Novara G, Roupret M, et al. Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature. Eur Urol. 2012;62:100–14. Article PubMed
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Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study

Cancer Res Treat. 2024;56(3):871-876. Published online January 16, 2024

DOI: https://doi.org/10.4143/crt.2023.1226

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Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study

Fig. 1. Kaplan-Meier curves for disease-free survival and metastasis-free survival.

Fig. 1.

Adjuvant Chemotherapy for Upper Tract Urothelial Carcinoma: A Real-World, Retrospective Study

	Total (n=89)	Renal pelvis (n=44)	Ureter (n=45)
Age (yr), median (range)	69 (41-86)	69 (44-86)	69 (41-83)
Sex
Male	71 (79.8)	35 (79.5)	36 (80.0)
Female	18 (20.2)	9 (20.5)	9 (20.0)
Smoking history
Never	23 (25.8)	12 (27.3)	11 (24.4)
Current or former	66 (74.2)	32 (72.7)	34 (75.6)
T category
T1	1 (1.1)	0	1 (2.2)
T2	13 (14.6)	3 (6.8)	10 (22.2)
T3	72 (80.9)	39 (88.6)	33 (73.3)
T4	3 (3.4)	2 (4.5)	1 (2.2)
N category (n=49)
N0	25 (28.1)	11 (25.0)	14 (31.1)
N1	11 (12.4)	5 (11.4)	6 (13.3)
N2	13 (14.6)	6 (13.6)	7 (15.6)
NE	40 (44.9)	22 (50.0)	18 (40.0)
WHO grade
2	21 (23.6)	11 (25.0)	10 (22.2)
3	68 (76.4)	33 (75.0)	35 (77.8)
Variant/Mixed histology	5 (5.6)	3 (6.8)	2 (4.4)
Chemotherapy cycles
1 or 2	4 (4.5)	3 (6.8)	1 (2.2)
3	60 (67.4)	29 (65.9)	31 (68.9)
4	25 (28.1)	12 (27.3)	13 (28.9)

	Grade 1 or 2	Grade 3 or 4
Neutropenia	10 (11.2)	6 (6.7)
Anemia	26 (29.2)	2 (2.2)
Thrombocytopenia	13 (14.6)	0
Nausea	29 (32.6)	0
Vomiting	26 (29.2)	2 (2.2)
Stomatitis	25 (28.1)	0
Constipation	33 (37.1)	0
Fatigue	20 (22.5)	0
Peripheral neuropathy	25 (28.1)	0
Pruritus	38 (42.7)	0
Azotemia	13 (14.6)	2 (2.2)

Clinical parameter	Disease-free survival		Metastasis-free survival
Clinical parameter	HR	95% CI	HR	95% CI
Age, < median vs. > median	0.99	0.47-2.10	0.73	0.33-1.65
Site, renal pelvis vs. ureter	0.67	0.30-1.50	0.96	0.40-2.70
T category, 1/2 vs. 3/4	0.75	0.29-1.96	0.57	0.20-1.58
N category, NE or N0 vs. N+	0.40	0.18-0.91	0.32	0.13-0.80
Grade, 2 vs. 3	0.79	0.28-2.25	0.48	0.11-2.16

Table 1. Patient characteristics

Values are presented as number (%) unless otherwise indicated. NE, not evaluated; WHO, World Health Organization.

Table 2. Maximum grade toxic effects in 89 patients

Values are presented as number (%).

Table 3. Multivariate analyses for disease-free survival and metastasis-free survival

CI, confidence interval; HR, hazard ratio; NE, not evaluated.