Authors: María Esther Garza-Montúfar, Gibrán Domingo Carballo-Rosario, Carlos Marcel García-Pérez
Categories: Research Report, Hydronephrosis, Uterine cervical cancer, Urinary diversion, Survival analysis, Ureteral obstruction
Source: Gynecologic Oncology Reports
Authors: María Esther Garza-Montúfar, Gibrán Domingo Carballo-Rosario, Carlos Marcel García-Pérez
•Urinary diversion significantly improves survival in advanced cervical cancer patients with hydronephrosis.•Bilateral renal involvement and ECOG ≥ 1 are associated with worse survival in patients undergoing urinary diversion.•The type of urinary diversion whether unilateral or bilateral do not significantly impact overall survival.
Cervical cancer (CC) is the 4th most common cancer in women and a significant cause of cancer-related deaths globally (Interntatinal Agency for Research on Cancer, 2023). Notably, only 44 % of cases are diagnosed at a localized stage (Siegel et al., 2023).
Hydronephrosis is a frequent complication of CC, affecting 23.9 % of all cervical cancer patients (Maguire et al., 2020) and up to 44 % of those with advanced disease (Rose et al., 2010). This condition significantly impairs survival (Patel et al., 2015) and can be caused by locoregional disease extension or treatment related complications. Untreated hydronephrosis can lead to death due to renal failure or sepsis. There is still a lack of consensus regarding the management of these patients.
The benefit of invasive urinary diversion remains unclear; while some studies suggest that urinary diversion does not improve survival and may even negatively impact quality of life (Nóbrega et al., 2022), it is important to consider that multiple factors influence survival in these patients, not solely urinary diversion; therefore urinary diversion should not be dismissed as a treatment option for obstructive uropathy in CC patients. In clinical practice, therapeutic decisions are influenced by several factors, including the need for systemic therapy, short-term oncological prognosis, surgical and anesthetic risk, clinical stage, renal function, and the preferences of the patient and their family.
The aim of this study was to evaluate the impact of urinary diversion on survival in patients with advanced CC (primary, recurrent or progression) and associated hydronephrosis; additionally, we sought to determine the influence of other patient-related factors on survival. As a secondary objective, we assessed the potential influence of the type of urinary diversion on survival.
Retrospective study of survival in CC patients and associated hydronephrosis, treated in the period from 2011 to 2023 in two hospitals of the Instituto Mexicano del Seguro Social (UMAE 25 and HGZ 33) in northern Mexico. We included all consecutive patients with primary disease as well as those with recurrent or progressive disease.
The medical records were reviewed and the following data was age, FIGO 2018 classification (Bhatla et al., 2019), histological type (squamous cell carcinoma, adenocarcinoma and others), renal function before and after urinary diversion, hydronephrosis laterality, comorbidities, oncologic treatment, whether or not the patient received urinary diversion treatment, type of diversion, and complications related to surgical treatment.
Patients with hydronephrosis diagnosed prior to cancer diagnosis, or secondary to surgical trauma, urolithiasis, or other non CC related pathology were excluded. Hydronephrosis was confirmed via abdominal computed tomography (CT) or ultrasound. FIGO stage was assigned by the oncologist based on radiological and clinical findings. We defined recurrence as the re-appearance of the tumor (local or metastatic) following curative treatment, with no prior evidence of residual disease on imaging or physical examination; and progression as the occurrence of an increase in the size of lesions or the appearance of new lesions in patients.
At our institutions, the standard treatment for patients with CC requiring urinary diversion is endoscopic placement of a double J catheter using rigid cystoscope under fluoroscopic guidance. If unsuccessful, percutaneous or open nephrostomy tubes are placed. Treatment selection within this cohort was influenced by surgeon expertise, available hospital resources, patient comorbidities and patient preference.
Data analysis was performed using Statistical Package for the Social Sciences (SPSS) version 22.0. Categorical data are presented as percentages, while numerical data are expressed as mean ± SD or median (minimum–maximum) according to data distribution. Chi Square test was employed to assess relationships between categorical variables. For comparisons of numeric variables, the U Mann-Whitney and Wilcoxon Rank Test were utilized. Overall survival (OS) was calculated using the Kaplan- Meier method, with the date of hydronephrosis diagnosis as the starting point. The Log-rank test was used to compare the impact of different variables on OS.
Univariate and multivariate Cox regression models were employed to identify prognostic factors for OS. Covariates with a p value <0.05 in the univariate test were selected for multivariate model. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were calculated. A p-value <0.05 was considered statistically significant. This study was approved by the local Health Ethic Committee No 1904, with the registration R-2022-1904-112.
A total of 228 patients with hydronephrosis associated with cervical cancer were included, with a median age of 47 years (range 22–86 years), and the median follow-up was 9 months (range 0.2–93.7 months). The most frequent clinical stage at the time of hydronephrosis diagnosis was IVA in 101 patients (44.3 %), followed by IIIB in 61 patients (26.8 %). Comorbidities were present in 92 patients (40.4 %). The predominant histological type was squamous cell carcinoma in 180 patients (78.9 %) and adenocarcinoma in 28 patients (12.3 %); renal involvement was bilateral in 66.7 % of patients, with a median creatinine level of 1.5 mg/dL. Table 1 shows detailed patient characteristics and treatment modalities received during the course of the disease. Urinary diversion was performed in 192 patients (84.2 %), and 36 patients (15.8 %) were managed conservatively (due to patient preference, comorbidities, or medical decision).Table 1Patient demographic and clinical characteristics (n = 228).n (%)Age (years)*47 (22–86)FIGO Clinical StageIIIB61 (26.8)IIIC112 (5.3)IIIC217 (7.5)IVA101 (44.3)IVB37 (16.2)Comorbidities†92 (40.4)Diabetes mellitus38 (16.7)Hypertension59 (25.9)Autoimmune disease4 (1.8)Second primary6 (2.6)Others13 (5.7)HistologySquamous cell carcinoma180 (78.9)Adenocarcinoma28 (12.3)Not specified20 (8.8)TreatmentExternal beam radiation49 (21.5)CCRT41 (18.0)CCRT + BT34 (14.9)External beam radiation + BT24 (10.5)Hysterectomy + CCRT12 (5.3)Hysterectomy + external beam radiation12 (5.3)Hysterectomy + CCRT + BT6 (2.6)Not specified9 (3.9)Other schemes12 (5.3)No treatment received29 (12.7)Creatinine (mg/dL)*1.5 (0.3–29)Affected kidneysBilateral152 (66.7)Unilateral71 (31.1)Not specified5 (2.2)ECOG‡054 (26.1)184 (40.6)43 (20.8)2321 (10.1)45 (2.4)FIGO = International Federation of Gynecology and Obstetrics, CCRT = Concurrent chemoradiotherapy, BT = brachytherapy, ECOG = Eastern Cooperative Oncology Group.*Median, minimum–maximum.†The sum of frequencies is greater than 100 % because 28 patients had >1 comorbidity.‡Not available in 21patients.
The median Overall Survival (mOS) of the studied patients was 15.5 months (95 % CI 11.8–19.1 months). Table 2 shows the comparison of survival using the Kaplan-Meier test; no difference in mOS was demonstrated in patients based on age or the presence of comorbidities such as diabetes mellitus and hypertension. Patients in stage IIIB had better mOS (27.3 months) than those in advanced disease (15.8 months in stage IIIC and 10.2 months in stage IV, p = 0.002); those with creatinine > 1.5 mg/dL had worse survival (mOS 8.9 vs 21.5 months, p=<0.001). Patients in whom hydronephrosis was diagnosed during disease progression had worse survival compared to those with hydronephrosis in recurrence or primary disease (mOS 8.5 vs 20.1 months and 15.6 months respectively, p = 0.003). Those who received chemoradiotherapy during the course of the oncological disease had better survival (mOS 21.5 months), followed by those who received radiotherapy alone (mOS 14.2 months), and those who did not receive treatment had worse survival (mOS 3.7 months). Bilateral kidney involvement was associated with worse survival (11.2 vs 21.6 months, p = 0.001), and patients undergoing urinary diversion had significantly longer mOS (16 vs 5.6 months, p=<0.001).Table 2Survival analysis stratified by interest variables (n = 228).Overall survival-months (median, IC 95 %)p*Age0.912≤ 50 years15.5 (11.7–19.3)> 50 years15.8 (8.7–22.8)FIGO Clinical Stage0.002IIIB27.3 (8.8–45.7)IIIC15.8 (7.2–23.6)IV10.2 (7.9–12.4)Diabetes mellitus0.801Present11.9 (4.8–19)Absent15.5 (11.5–19.5)HTA0.969Present15.6 (7.8–23.5)Absent14.4 (10.4–18.3)Creatinine<0.001≤ 1.5 mg/dL21.5 (14.1–28.9)> 1.5 mg/dL8.9 (5.9–12)Disease coursePrimary disease15.6 (12.2–19)0.003Recurrence20.1 (16–24.2)Progression8.5 (4.4–12.6)Treatment†No treatment3.7 (1.8–5.6)< 0.001Radiotherapy alone14.2 (10.4–17.9)Chemoradiotherapy21.5 (14.3–28.8)Kidneys affected0.001Bilateral11.2 (6.4–16)Unilateral21.6 (3.8–39.3)Urinary diversion< 0.001None5.6 (0.01–11.1)Ureteral stent/Nephrostomy16 (12.6–19.3)ECOG< 0.001050.1 (22.3–77.8)115.8 (12–19.5)28.4 (2.3–14.4)3 y 43.7 (0–9.1)Radiotherapy = external beam radiation or external beam radiation plus brachytherapy (with or without surgery).FIGO = International Federation of Gynecology and Obstetrics, ECOG = Eastern Cooperative Oncology Group.Chemoradiotherapy = Chemotherapy plus external beam radiation or /and brachytherapy (with or without surgery).*Log Rank test.†The treatment received during the course of the oncological disease.
In univariate Cox regression analysis (introducing variables with p < 0.05 in the Kaplan-Meier test), FIGO clinical stage IV (HR 2.1, 95 % CI 1.3–3.2), creatinine > 1.5 mg/dL (HR 2.2, 95 % CI 1.5–3.3), disease progression (HR 2.5, 95 % CI 1.3–4.9), bilateral kidney obstruction (HR 1.9, 95 % CI 1.3–2.9), not undergoing urinary diversion (HR 2.2, 95 % CI 1.4–3.5) and ECOG ≥ 1 were associated with worse mOS. On multivariate analysis, all variables except creatinine level remained significant prognostic factors for mortality (Table 3). Treatment with radiotherapy (multivariate HR 0.2, 95 % CI 0.1–0.5) or chemoradiotherapy (multivariate HR 0.1, 95 % CI 0.06–0.3) during the course of the disease behaved as protective factors against mortality in both univariate and multivariate analyses.Table 3Univariate and multivariate analysis of prognostic factors for mortality by Cox proportional hazard regression (n = 228).Univariate analysisMultivariate analysisHR (95 % CI)pHR (95 % CI)pFIGO Clinical StageIIIB (reference)IIIC1.4 (0.7–2.6)0.2242 (0.9–4.3)0.075IV2.1 (1.3–3.2)0.0012.1 (1.1–3.9)0.016Creatinine≤1.5 mg/dL (reference)> 1.5 mg/dL2.2 (1.5–3.3)< 0.0011 (0.6–1.7)0.767Disease courseRecurrence (reference)Primary disease1.3 (0.7–2.5)0.2791.2 (0.5–2.7)0.639Progression2.5 (1.3–4.9)0.0064.0 (1.6–9.8)0.002Treatment†No treatment (reference)Radiotherapy alone0.2 (0.1–0.4)< 0.0010.2 (0.1–0.5)0.001Chemoradiotherapy0.1 (0.09–0.3)< 0.0010.1 (0.06–0.3)< 0.001Kidneys affectedUnilateral (reference)Bilateral1.9 (1.3–2.9)0.0012.3 (1.3–4)0.002Urinary diversionYes (reference)None2.2 (1.4–3.5)0.0012.2 (1.1–4.2)0.012ECOG 0 (reference)12.2 (1.3–3.8)0.0022.1 (1.1–3.8)0.1223.6 (2–6.5)< 0.0011.8 (0.9–3.5)0.743,45 (2.6–9.7)< 0.0017.3 (3.1–16.8)< 0.001Radiotherapy = external beam radiation or external beam radiation plus brachytherapy (with or without surgery).FIGO = International Federation of Gynecology and Obstetrics, HR = Hazard radio Chemoradiotherapy = Chemotherapy plus external beam radiation or /and brachytherapy (with or without surgery), ECOG = Eastern Cooperative Oncology Group.*Cox regression.†The treatment described is that received during the course of the oncological disease.
There was no difference in clinical and demographic characteristics between patients with and without urinary diversion (Table 4).Table 4Comparison of demographic and clinic characteristics of patients with and without urinary diversion.No urinary diversion (n = 36) (n%)Urinary diversion (n = 192) (n%)pAge (years)*44 (31–81)48 (22–86)0.683†Comorbidities11 (30.6)81 (42.2)0.19‡FIGO Clinical Stage0.711‡IIIB8 (22.2)53 (27.6)IIIC1, IIIC24 (11.1)25 (13.0)IVA, IVB24 (66.7)114 (59.4)Creatinine (mg/dL)*1.84 (0.6–11.4)1.34 (0.3–29)0.922†No treatment5 (16.1)24 (13.6)0.712‡Bilateral25 (71.4)127 (67.6)0.651‡ECOG0.191‡04 (12.1)50 (28.7)114 (42.4)70 (40.2)29 (27.3)34 (19.5)3,46 (18.2)20 (11.5)FIGO = International Federation of Gynecology and Obstetrics, ECOG = Eastern Cooperative Oncology Group.*Median, minimum–maximum.†U Mann-Whitney.‡Chi square.
Out of the 192 patients with urinary diversion, 111 (57.8 %) underwent placement of unilateral or bilateral Double-J stents, while 81 (42.2 %) underwent unilateral or bilateral nephrostomy. The median levels of creatinine prior to urinary diversion were 1.3 mg/dL (range 0.3–29 mg/dL), and after urinary diversion, it was 1 mg/dL (range 0.2–8.6 mg/dL) (p=<0.001, Wilcoxon Rank). Complications secondary to urinary diversion occurred in 70 patients (36.5 %), more frequently in patients with nephrostomy than in those with Double-J stents (50.6 % vs. 26.1 %, p=<0.001). The most common complication was diversion dysfunction in 36 patients (18.8 %) (Table 5).Table 5Comparison of complications according to diversion type (n = 192).Ureteral stent (n = 111)Nephrostomy (n = 81)pComplications†29 (26.1)41 (50.6)<0.001Dysfunction (n = 36)9 (8.1)27 (33.3)< 0.001Complicated UTI (n = 33)15 (13.5)18 (22.2)0.114Hematuria (n = 11)7 (6.3)4 (4.9)0.687UTI = Urinary tract infectionChi square.†Some patients experienced more than one complication.
In this cohort, bilateral hydronephrosis and poor performance status were significant risk factors for mortality in both univariate and multivariate analyses. Neither the type of urinary diversion performed, nor its laterality (unilateral or bilateral), influenced patient prognosis (Table 6).Table 6Univariate and multivariate analysis of prognostic factors for mortality in patients undergoing urinary diversion by Cox proportional hazard regression (n = 228).Univariate analysisMultivariate analysisHR (95 % CI)pHR (95 % CI)pKidneys affectedUnilateral (reference)Bilateral1.9 (1.2–3.1)0.0022 (1.2–3.5)0.005Type of urinary diversionUreteral stent (reference)Nephrostomy1 (0.7–1.5)0.7290.7 (0.4–1.1)0.155Urinary diversionBilateral (reference)Unilateral1 (0.6–1.4)0.9941.1 (0.7–1.8)0.567ECOG0 (Reference)11.9 (1.1–3.2)0.0191.8 (1–3.1)0.03523.5 (1.9–6.5)< 0.0013.3 (1.7–6.1)< 0.0013,43.8 (1.8–7.9)< 0.0013.6 (1.7–7.6)0.001*Cox regression, ECOG = Eastern Cooperative Oncology Group.
The management of advanced CC patients complicated by hydronephrosis presents a clinical challenge. Balancing the potential benefits of surgery against the risks of an invasive procedure in a potentially frail patient is a complex decision that requires careful consideration of individual patient factors.
Hydronephrosis is an independent prognostic factor in patients with locally advanced CC (Pradhan et al., 2011). Urinary diversion can improve renal function and may enhance survival in patients with significant hydronephrosis, even in patients with severe kidney injury (Lapitan and Buckley, 2011, Liang et al., 2019); nevertheless, the consensus regarding its benefits remain somewhat controversial (Tatenuma et al., 2020), with some studies reporting no significant difference in overall survival (Damian et al., 2022, Goklu et al., 2015, Nóbrega et al., 2022); Rose et al (Rose et al., 2010) were among the first to report improved mOS in patients with stage IIIB cervical cancer and hydronephrosis who underwent urinary diversion (34 vs 17 months, p = 0.0078). Our findings corroborate these results, showing a significant association between urinary diversion and improved survival (16 vs 5.6 months, p < 0.001); which persisted on multivariate analysis.
Renal function, as assessed by creatinine levels, is a critical factor in determining a patient's treatment options; although the optimal creatinine level for guiding decisions about urinary diversion remains unclear (Nóbrega et al., 2022), a cutoff of 3 mg/dL has been proposed as a prognostic factor (Salunkhe et al., 2020). While our study revealed a significant association between elevated creatinine levels (> 1.5 mg/dL) and decreased survival (8.9 vs 21.5 months, p= < 0.001), this association was not independent of other prognostic factors when considered in a multivariate analysis. Notably, urinary diversion remained a robust predictor of survival, suggesting that its benefits extend to patients with compromised renal function. By treating hydronephrosis and improving renal function allows patients to be suitable for platinum-based chemotherapy (National Comprehensive Cancer Network, 2024) a cornerstone of treatment that is associated with improved survival outcomes in patients with locally advanced disease (Nóbrega et al., 2022). In our cohort, patients who received chemotherapy at some point during their disease course had better mOS compared to those who received only radiotherapy or no treatment.
Bilateral hydronephrosis has been associated with poorer survival outcomes in previous studies (Dhani et al., 2023, Pradhan et al., 2011). Our findings corroborate these results, even when restricted to patients who underwent urinary diversion (HR 2, 95 % IC 1.2–3.5, p = 0.005). Regardless of the type of urinary diversion employed, survival does not differ significantly between patients who underwent unilateral or bilateral diversion, even in those with bilateral renal involvement. This finding has important implications for clinical decision-making, particularly when considering invasive procedures such as ureterostomy or nephrostomy.
Our results are consistent with those reported in the literature (Noegroho et al., 2021, Rose et al., 2010, Salunkhe et al., 2020), demonstrating a significant increase in mortality as patients’ functional status declines. Undoubtedly, patients' performance status must be a critical factor in decision-making regarding potentially invasive surgical procedures. This is particularly relevant for patients with poor general health and other adverse prognostic factors such as disease progression and metastatic disease, given the associated surgical risks, life expectancy, quality of life implications of catheter use, and the potential impact on both the patient and their family.
Both ureteral stents and nephrostomies are associated with complications such as pain, urinary tract infections, nausea, renal failure and urinary tract bleeding (Patel et al., 2015). The incidence of these complications is similar between the two techniques (Tan et al., 2019), and there is no significant difference in their impact on overall survival (Dhani et al., 2023). In our study group, patients who underwent nephrostomy placement experienced a higher incidence of complications, with catheter dysfunction being the most common, leading to hospitalizations and re-interventions for catheter repositioning. These findings suggest that, whenever feasible, ureteral stent placement should be preferred. However, it should be noted that catheter replacements may become more difficult as the disease progresses, especially in cases of direct tumor invasion.
Multivariate analysis revealed that the number of kidneys affected (with bilateral involvement associated with poorer outcomes), performance status (with decreased survival in patients with poorer performance), and urinary diversion were significant predictors of survival. While urinary diversion was associated with improved survival, the specific type (ureteral catheter/nephrostomy) or whether it was unilateral or bilateral did not significantly impact survival in the group of patients who underwent successful urinary tract obstruction relief. These findings should be considered when making therapeutic decisions for critically ill patients, with the goal of minimizing risk and surgical time.
To the best of our knowledge, this study presents one of the largest homogenous cohorts of patients with hydronephrosis secondary to cervical cancer, all with advanced stage disease (FIGO > IIIB). Patients included in this study were those referred to the urology department by oncology upon the diagnosis of hydronephrosis, either with the aim of improve or preserve renal function and allow for subsequent systemic therapy, provide palliative care or resolve infection; following urinary diversion, patients continued their follow-up care with oncology, where treatment decisions were made by the treating service. The reported complications were limited to those requiring hospitalization, which may underestimate the overall complication rate. The decision to manage patients conservatively was not solely based on clinical or oncological factors, leading to potential bias in the study findings. Surgical decisions were made by the attending physicians, which is subject to variation over the study period, and was based on both the patient’s clinical condition and the availability of materials for urinary diversion This study was restricted to patients with hydronephrosis, preventing direct comparison with patients without this condition.
The survival of patients with hydronephrosis secondary to CC is influenced by factors such bilateral involvement, performance status, clinical stage, course and treatment of the underlying malignancy and undergoing a urinary diversion. Our findings indicate that urinary diversion is associated with improved survival rates, regardless of the specific diversion type or laterality (unilateral or bilateral). It is imperative that patients receive thorough information about the treatment goals and potential complications before proceeding with any intervention.
All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by María E. Garza-Montúar, Gibrán D. Carballo-Rosario and Carlos M. García-Pérez. The first draft of the manuscript was written by María E. Garza-Montúfar. Gibrán D. Carballo-Rosario and Carlos M. García-Pérez revised and edited the manuscript. All authors read and approved the final manuscript.
Ethical approval was waived by the local Ethics Committee No 1904 of the Instituto Mexicano del Seguro Social, with the registration R-2022-1904-112, in view of the retrospective nature of the study and all the procedures being performed were part of the routine care.
María Esther Garza-Montúfar: Writing – original draft, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Gibrán Domingo Carballo-Rosario: Writing – review & editing, Formal analysis, Data curation, Conceptualization. Carlos Marcel García-Pérez: Writing – review & editing, Formal analysis, Data curation, Conceptualization.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.