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Long-term outcome of radiation therapy for locoregional recurrence of upper tract urothelial carcinoma after nephroureterectomy

BMC Urology volume 25, Article number: 80 (2025) Cite this article

Abstract

Background

The objective was to evaluate the survival outcomes associated with radiation therapy (RT) in cases of postoperative locoregional recurrence of upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU).

Methods

A total of 30 patients undergoing RT for local or regional recurrence of UTUC after RNU from 2002 to 2017 were enrolled. The median follow-up time for patients who survived was 5.9 years. The application of RT comprised two intents: (1) salvage RT for patients who did not respond to chemotherapy or who did not receive chemotherapy, and (2) consolidation RT for patients who showed complete or partial response to chemotherapy. Overall survival (OS) since recurrence, locoregional progression-free survival (LRPFS) after RT, and distant metastasis-free survival (DMFS) after RT were evaluated. Univariate Cox regression analysis was applied.

Results

The median OS since recurrence was 40.0 months, and the 5-year OS, LRPFS, and DMFS rates were 46.6%, 45.0%, and 36.7%, respectively. For 14 patients who underwent salvage RT, the 5-year OS, LRPFS, and DMFS rates were 28.6%, 21.4%, and 21.4%, respectively; for 16 patients undergoing consolidation RT, those rates were 63.5%, 65.8%, and 50.0%, respectively. In univariate analysis, consolidation RT and primary site in the ureter were significant prognostic factors for better OS and LRPFS; an age ≤ 60.0 years was also a significant factor for OS. There was no significant factor for DMFS.

Conclusions

The patients undergoing RT for postoperative locoregional recurrence of UTUC had promising survival outcomes. Future prospective randomized trials to verify the findings are needed.

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Background

It is relatively rare for urothelial carcinoma (UC) to develop in the ureter or renal pelvis; this condition is called upper tract urothelial carcinoma (UTUC). According to the available data, UC is the sixth most common tumor in developed countries [1], but UTUC accounts for only 5–10% of urothelial tumors. While UTUC is not a common malignant tumor in the Western world, it has a relatively high prevalence rate in Asia and the Balkans. The use of aristolochic acid-containing Chinese herbs, arsenic-polluted water, and Balkan endemic nephropathy contribute to this higher prevalence [2]. Radical nephroureterectomy (RNU) with ipsilateral bladder cuff excision and/or retroperitoneal lymphadenectomy is the gold standard treatment for UTUC.

Bladder tumors and UTUC are neoplasms that originate from the urothelium, and they share similar histological features. However, UTUC and bladder tumors show dissimilar behavior as a result of different anatomical involvement and distinct genomic alterations [3]. Several retrospective studies [4,5,6] have reported a locoregional failure rate ranging from 6.2 to 65% in patients with UTUC. Around 80% of patients who suffer from disease recurrence following RNU pass away within two years after recurrence [7]. The current treatment for UTUC is based on bladder UC research. However, the oncological outcome is discrepant between UTUC and bladder UC. UTUC usually has a much poorer prognosis compared with bladder UC [8].

The natural course of UTUC has been extensively studied [9, 10]. Re-operation for locoregional recurrence following RNU is usually not performed. Like the multimodal treatment of bladder UC, salvage chemotherapy and radiation therapy (RT) for recurrent UTUC may be considered, although there is scarce therapeutic outcome data [11, 12]. Moreover, the efficacy of adding RT to chemotherapy is questionable. Hence, this study aimed to evaluate the therapeutic outcome of RT for postoperative locoregional recurrence of UTUC.

Methods

Patient characteristics

This retrospective study was approved by the Chang Gung Medical Foundation Institutional Review Board (201800093B0). From May 2002 to February 2017, a total of 30 patients undergoing RT for local or regional recurrence of UTUC were enrolled. All patients had previously undergone RNU and bladder cuff excision. Hand-assisted retroperitoneal nephroureterectomy was the standard treatment in our hospital. Open nephroureterectomy was only used for patients with locally advanced (T3/T4) or high-grade UTUC. After surgery, the patients were regularly followed up in the clinic with computed tomography (CT) or magnetic resonance (MR) imaging of the abdominopelvic area. Soft tissue recurrence around the primary tumor bed was defined as local recurrence. Nodal recurrence at the retroperitoneal or pelvic lymph node area was defined as regional recurrence. If recurrence occurred in the liver, lung, bone, brain, or another organ, it was defined as distant metastasis. Although bladder recurrence occurs more often, it was considered an independent condition − neither locoregional recurrence nor distant metastasis. The inclusion criteria were (1) age ≥ 18 years; (2) underwent RNU with histologically confirmed upper tract malignancy; and (3) received RT in our hospital for local or regional recurrence of UTUC. The exclusion criteria were (1) a discontinued RT course before cumulated 30 Gy, (2) a short course of palliative RT for symptom relief only, and (3) distant metastasis.

Treatment

The patients received chemotherapy with cisplatin-based regimens, including MVAC (methotrexate, vinblastine, doxorubicin, plus cisplatin) or GC (gemcitabine plus cisplatin). The MVAC regimen included methotrexate 30 mg/m2 on days 1, 15, and 22; vinblastine 3 mg/m2 on days 2, 15, and 22; doxorubicin 30 mg/m2 on day 2; and cisplatin 70 mg/m2 on day 2. The cycle was repeated every 28 days. The GC regimen included a dose of 1000 mg/m2 gemcitabine administered over 30–60 min on days 1, 8, and 15, and 70 mg/m2 cisplatin administered on day 2; the regimen was given every 3 weeks. Adequate hydration was maintained before and after cisplatin administration.

RT was performed using intensity-modulated radiation therapy (IMRT) for 22 patients, three-dimensional conformal radiation therapy (3DCRT) for five patients, volumetric modulated arc therapy (VMAT) for two patients, and conventional 2D radiation therapy for one patient. The delineation of the gross tumor volume (GTV) for the gross recurrent tumor was based mainly on CT. The regional lymphatic drainage area (retroperitoneal lymph nodes for renal pelvis cancer and including pelvic lymph nodes for ureter cancer) could be delineated as the clinical tumor volume (CTV). The margin for CTV to develop the planning target volume (PTV) was 3 mm. The mean prescription dose of RT was 53.2 Gy (range 30–63 Gy). The dose adjustment was based on the radiation oncologist’s decision according to the tumor size, the tumor location away from or close to the organ at risk, and the patient’s performance status.

In this study, we defined the purpose of RT as consolidation versus salvage according to different previous salvage chemotherapy results. Consolidation RT occurred when a patient who had undergone chemotherapy after recurrence, and showed a good response then underwent RT for consolidation. Salvage RT was RT provided for patients who had not shown a response to chemotherapy after recurrence or for patients who had received RT due to the inability or unwillingness to receive chemotherapy. The evaluation of the chemotherapy response was according to RECIST 1.1 criteria.

Follow-up

The patients were regularly followed up after RT until death or became lost to follow-up. All patients returned to the clinic every 3 months during the first 2 years, every 4–6 months during years 3–5, and then every 6–12 months after 5 years. Regular chest X-rays and CT or MR imaging of the abdominopelvic area were arranged, and CT of the chest was done when needed.

Statistical analysis

The oncological outcomes of the overall survival (OS) after recurrence and the OS after RT were evaluated. The locoregional progression-free survival (LRPFS) after RT and the distant metastasis-free survival (DMFS) after RT were also evaluated. The Kaplan–Meier methods with the log-rank test were utilized to determine the 5-year oncological outcomes. Univariate Cox regression models were used to identify the independent variables associated with the oncological outcomes. All data were analyzed using SPSS Statistics Version 22. A p-value of less than 0.05 was considered statistically significant.

Results

In this study, a total of 30 patients were enrolled. The basic demographic data of the patients are presented in Table 1. The median age of the patients was 61.8 years (range 44.5–86.6 years). Of the 30 patients, 25 (83.3%) had locally advanced UTUC (stage III–IV) initially. The primary sites of the tumors included the renal pelvis (n = 13), ureter (n = 13), and both (n = 4). According to the RT purpose, all patients could be divided into the consolidation group (n = 16) and the salvage group (n = 14). The median RT dose was 54 Gy.

Table 1 Patient characteristics
Full size table

The median follow-up time for patients who survived was 5.9 years. The median OS since recurrence was 40.0 months. The 5-year OS rate since recurrence was 46.6% (Fig. 1). Likewise, the 5-year OS rate after RT was 42.5% (Fig. 2). Comparing the different purposes of RT, the 5-year OS rate in the consolidation group was 63.5%. However, the 5-year OS rate in the salvage RT group was 28.6%. The OS was found to be significantly better in the consolidation group (log-rank test, P = 0.014) (Fig. 3).

Fig. 1
figure 1

Overall survival since recurrence

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Fig. 2
figure 2

Overall survival (OS), locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS) after radiation therapy

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Fig. 3
figure 3

Overall survival since recurrence stratified by salvage versus consolidation radiation therapy

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As for local and regional control, the median LRPFS was 15.4 months, and the 5-year LRPFS rate after RT was 45.0% (Fig. 2). In the salvage group, the 5-year LRPFS rate was 21.4%, the same as the 2-year outcome. In the consolidation group, the 5-year LRPFS rate was 65.8%. The LRPFS rate in the consolidation group was significantly superior (log-rank test, P = 0.003) (Fig. 4).

Fig. 4
figure 4

Locoregional progression-free survival stratified by salvage versus consolidation radiation therapy

Full size image

As for distant metastasis after RT, the lung, liver, mediastinal, and supraclavicular lymph nodes were the most common sites. The median DMFS was 13.5 months, and the 5-year DMFS rate after RT was 36.7% (Fig. 2). In the salvage group, the 5-year DMFS rate was 21.4%. In the consolidation group, the 5-year DMFS rate was 50%. The DMFS was not significantly different, but the trend favored the consolidation group (log-rank test, P = 0.07).

The patients with locoregional progression (5 patients) and distant metastasis (19 patients) after RT underwent palliative treatments. For these patients, chemotherapy with MVAC, GC, or gemcitabine plus paclitaxel was given. The patients who suffered a failure from platinum-based chemotherapy were given an immune checkpoint inhibitor, such as pembrolizumab.

In the univariate analysis, consolidation RT and the primary site in the ureter were associated with better OS and LRPFS (Tables 2 and 3). An age ≤ 60 years was also a significant prognosticator for the OS since recurrence (Table 2). No factors were significant for DMFS in the univariate analysis (Table 3).

Table 2 Univariate Cox regression analyses for OS since recurrence and OS after RT
Full size table
Table 3 Univariate Cox regression analyses for LRPFS after RT and DMFS after RT
Full size table

Discussion

For recurrent or locally advanced UTUC, surgical intervention alone may not achieve optimal outcomes. However, research on this topic is still limited, and standardized therapeutic guidelines are lacking. A retrospective study was conducted in southern Taiwan [13]. The patients had stage III and stage IV disease, along with lymph node involvement, or were deemed medically unfit for surgery. After receiving concurrent chemotherapy and RT, the 3-year OS rate was 57.58%, with a corresponding 3-year recurrence-free survival rate of 21.05%. Although not all settings were like our study, combining chemotherapy and RT is a promising option for UTUC patients.

There is still controversy about whether salvage RT benefits patients with recurrent UTUC after RNU. Our findings demonstrated that patients who received local RT to recurrent sites had promising outcomes, especially in the consolidation intent after the response to chemotherapy. If patients could survive the first two years, then the incidence of locoregional failure would subsequently decrease. In one retrospective study from Korea [12] for patients with locoregional recurrence or distant metastasis of UTUC, receiving salvage or palliative RT resulted in a 1-year OS of 53.5% and a 6-month PFS of 41.9%. Their survival outcome was worse than ours and might be due to the study design and the distant metastatic patients. Our previous study [14] reported that female patients had a significantly better OS following RNU for UTUC in Taiwan, an endemic area of UTUC. Similarly, this study found that females had the trend of better DMFS after RT. Future studies are needed to determine the underlying molecular characteristics of endemic UTUC in associated with radiosensitivity.

Postoperative RT for risky UTUC patients after RNU is another issue for debate. In the European Association of Urology guidelines, the role of postoperative RT after RNU remains controversial due to unclear evidence [15]. A retrospective study suggested that postoperative RT is beneficial for patients who have a high likelihood of tumor recurrence, remaining tumor tissue, T4-stage tumors, or high-grade tumors [16]. In addition, Chen et al. [17] disclosed that postoperative RT significantly improved OS in patients with pathological T3–4 UTUC. On the contrary, one retrospective study declared that adjuvant RT after RNU did not improve survival outcomes in patients with pT3N0M0 UTUC [18]. There could be several reasons for the discrepancies in the findings among the studies. First, minimizing the heterogeneity among studies is difficult due to the improvements in RT techniques (3DCRT, IMRT, and VMAT), which contribute to fewer major adverse effects while still maintaining efficacy. Second, evidence regarding the most appropriate radiation dose is lacking.

As for the role of chemotherapy, drawing from the bladder UC and small UTUC studies, platinum-based chemotherapy is effective as a first-line treatment for metastatic UTUC. One Japanese retrospective study found that patients with high-risk UTUC in the salvage chemotherapy group had a higher probability of cancer-specific survival following recurrence or metastasis compared with those in the non-salvage chemotherapy group [11]. Compared with our study, consolidation RT after the response to chemotherapy led to better OS and LRPFS. The Japanese study population included patients with distant metastasis who did not receive RT. Thus, their survival outcome was expected to be relatively worse.

For locally advanced UTUC, a phase 3, open-label, multicenter randomized controlled trial (the POUT trial) revealed that gemcitabine–platinum combination adjuvant chemotherapy started within 90 days after nephroureterectomy significantly improved disease-free survival (DFS) [19]. This result has been updated with a median follow-up of 48.1 months, confirming the chemotherapy benefit in DFS [20]. Czito et al. [21] suggested that concurrent cisplatin and RT improves the survival outcomes for patients with T3/4 and/or node-positive upper tract after RNU. However, optimal cisplatin administration is a challenge for some patients due to the surgical impact on renal function [22]. Cisplatin is administered if the estimated glomerular filtration rate was ≥ 50 mL/min [23]. For patients with limited renal function, split-dose cisplatin is more tolerable and accessible [24]. Otherwise, carboplatin is an alternative regimen for patients who are ineligible for cisplatin-based chemotherapy [25].

From the experience of bladder urothelial carcinoma [26], combining RT and immunotherapy might be an alternative option for recurrent patients who cannot tolerate chemotherapy due to fragility or impaired renal function. Local RT might have the ability to synergize with immunotherapy to improve the treatment outcome. The efficacy and safety of a multimodal strategy with RT, chemotherapy, and immunotherapy in patients with recurrent UTUC requires additional studies to find the most suitable combination.

We also found that the origin from the ureter has better OS and LRPFS following RT for locoregional recurrence of UTUC. The reports of the impact of tumor location on the survival outcomes of UTUC revealed discrepancies in the literature. A study from the Memorial Sloan-Kettering Cancer Center reported no differences in recurrence and cancer-specific survival rates between ureter cancer and renal pelvis cancer [27]. Our previous cancer registry database study of UTUC after RNU also found no difference in OS between ureter and renal pelvis origins [14]. However, some reports revealed that ureter cancer had worse outcomes [28, 29]. Future prospective studies are needed to evaluate the influence of the initial primary origin on the salvage treatment outcomes of recurrent UTUC.

There were several limitations to this study. First, there was a lack of data on salvage chemotherapy alone for comparison, so the benefit of adding RT for consolidation was not evaluated. Second, this study was retrospective and non-randomized. A prospective randomized trial would offer the most effective approach to elucidate the role of concurrent chemoradiotherapy in treating UTUC. Due to the challenges of conducting studies on advanced UC worldwide, much of the information available still originates from retrospective analyses. Nevertheless, due to the rarity of this malignancy, conducting such a study might prove challenging without collaborative efforts among multiple institutions. In addition, we did not perform multivariate analysis in this relatively small sample size study according to the rule of 10 events per variable [30, 31]. Despite these limitations, the current study has generated several significant findings for managing the locoregional recurrence after RNU in patients with UTUC.

Conclusions

Patients with locoregional recurrence of UTUC after RNU did not have dismal survival outcomes. Patients undergoing RT had promising survival outcomes, especially those who underwent consolidation RT. Future prospective randomized trials are needed to verify the findings.

Data availability

The data collected in this research are available from the corresponding author on a reasonable request.

Abbreviations

UC:

Urothelial carcinoma

UTUC:

Upper tract urothelial carcinoma

RNU:

Radical nephroureterectomy

RT:

Radiation therapy

CT:

Computed tomography

MR:

Magnetic resonance

IMRT:

Intensity-modulated radiation therapy

VMAT:

Volumetric modulated arc therapy

GTV:

Gross tumor volume

CTV:

Clinical tumor volume

PTV:

Planning target volume

OS:

Overall survival

LRPFS:

Locoregional progression-free survival

DMFS:

Distant metastasis-free survival

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Authors and Affiliations

  1. Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Ho-Hsiang Chang & Hao-Lun Luo

  2. Department of Urology, Kaohsiung Show Chwan Memorial Hospital, Kaohsiung, Taiwan

    Ho-Hsiang Chang

  3. Division of Hematology-Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Yu-Li Su

  4. Department of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Fu-Min Fang, Chong-Jong Wang & Chun-Chieh Huang

  5. Department of Radiation Oncology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

    Chong-Jong Wang & Chun-Chieh Huang

  6. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chun-Chieh Huang

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Contributions

HLL, YLS and CCH were involved in the conception and design. FMF, CJW and CCH were involved in the acquisition of the clinical data. HHC and CCH were involved in the statistical analysis and drafted the manuscript. HLL, YLS, CCH revised it critically for intellectual content. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Chun-Chieh Huang.

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Ethics approval and consent to participate

This study was approved by the Chang Gung Medical Foundation Institutional Review Board (201800093B0). Informed consent was waived by the Chang Gung Medical Foundation Institutional Review Board because of the nature of retrospective medical record review and no more than minimal risk to the human subject. Clinical trial number: not applicable.

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The authors declare no competing interests.

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Chang, HH., Luo, HL., Su, YL. et al. Long-term outcome of radiation therapy for locoregional recurrence of upper tract urothelial carcinoma after nephroureterectomy. BMC Urol 25, 80 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12894-025-01766-y

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BMC Urology

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