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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 29  |  Issue : 1  |  Page : 25-32

Comparative analysis between radical cystectomy and trimodality therapy for clinical Stage II Bladder Cancer: Experience from a tertiary referral center


1 Department of Urology, National University Hospital, College of Medicine, National University, Taipei, Taiwan
2 Division of Urology, Department of Surgery, Cardinal Tien Hospital, Taipei, Taiwan
3 Division of Radiation Oncology, Department of Medical Imaging, National University Hospital, Hsin-Chu Branch, Hsin-Chu City, Taiwan
4 Division of Radiation Oncology, Department of Oncology, National University Hospital; Graduate Institute of Oncology, National University College of Medicine, Taipei, Taiwan

Date of Web Publication23-Feb-2018

Correspondence Address:
Huai-Ching Tai
Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_13_17

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  Abstract 

Objectives: To analyze the clinicopathologic characteristics and oncologic outcomes between radical cystectomy (RC) and trimodality therapy (TMT) for patients with clinical stage II bladder urothelial carcinoma (UC). Methods: Between January 2004 and September 2013, the medical records of 93 consecutive patients with clinical stage II bladder cancer (cT2N0M0) diagnosed at National Taiwan University Hospital were retrospectively reviewed, including 66 with RC and 27 with TMT. Univariate and multivariate Cox regression analyses were performed to determine prognostic factors. Results: The median follow-up time was 34.1 months. There were no significant differences between the TMT and RC group with respect to age, gender, cancer grade and the presence of hydronephrosis. The 5-year overall survival rate (74%) and the 5-year cancer specific survival rate (76%) showed comparable results between RC and TMT group. The overall recurrence rate was 38 % (RC: 41% vs. TMT: 30%, p=0.35). Presence of hydronephrosis demonstrated statistically significant association with tumor recurrence (HR: 2.05, 95% CI 1.04-4.04, p=0.04). Patients with diabetes mellitus (DM) were independently correlated with poorer overall survival (HR: 2.73, 95% CI 1.09-6.82, p= 0.03) and cancer-specific survival (HR: 3.32, 95% CI 1.28-8.65, p= 0.01.) Conclusions: TMT is an optimal therapeutic option in selected patients with clinical stage II bladder UC. In our study, despite the method of treatment, presence of hydronephrosis increased cancer recurrence risk and DM demonstrated a significantly negative effect on overall survival and cancer-specific survival.

Keywords: Bladder cancer, cystectomy, diabetes mellitus, hydronephrosis, trimodality therapy, urothelial carcinoma


How to cite this article:
Hong JH, Lin YH, Lu YC, Chiang Y, Tai HC, Huang KH, Cheng CH, Pu YS. Comparative analysis between radical cystectomy and trimodality therapy for clinical Stage II Bladder Cancer: Experience from a tertiary referral center. Urol Sci 2018;29:25-32

How to cite this URL:
Hong JH, Lin YH, Lu YC, Chiang Y, Tai HC, Huang KH, Cheng CH, Pu YS. Comparative analysis between radical cystectomy and trimodality therapy for clinical Stage II Bladder Cancer: Experience from a tertiary referral center. Urol Sci [serial online] 2018 [cited 2019 Sep 17];29:25-32. Available from: http://www.e-urol-sci.com/text.asp?2018/29/1/25/226027


  Introduction Top


Bladder cancer is a common malignancy responsible, in 2012, for an estimated 429,800 new cases and 165,100 deaths worldwide.[1] In Taiwan, the incidence rate for invasive bladder cancer was 1481 males and 574 females/100,000 in 2013 according to the Taiwan Cancer Registry.

For patients with muscle-invasive bladder cancer (MIBC), the gold standard treatment is radical cystectomy (RC), with a 5-year survival rate of about 50%.[2] Nevertheless, this procedure encompasses a 90-day complication rate of 64%, a 90-day readmission rate of 32%, and a mortality rate of 6%.[3]

For patients who may not be good candidates for surgery or who demand to retain their bladders, bladder-preservation therapy integrating the concurrent delivery of chemotherapy and radiotherapy after radical transurethral resection of the bladder tumor (TURBT), known as trimodality therapy (TMT) has become feasible and is well tolerated. In previous decades, several studies have supported TMT as a cogent conservative treatment, providing an alternative option in selected patients with MIBC due to similar survival outcomes compared to RC.[4],[5]

Patients with locally advanced disease (cT3/4) have distinctly worse survival rates in a setting of both bladder preservation therapy and RC.[6] In addition, it is not feasible to directly compare outcomes of locally advanced bladder urothelial carcinoma (UC) undergoing radical or preserving therapy due to a discrepancy in clinical-pathologic stage.[7]

Our study hereby placed an emphasis on patients with clinical stage II bladder UC, trying to minimize heterogeneity and potential bias. The purpose of our study was to evaluate the oncologic outcomes in this group of patients following TMT or RC, and to further analyze the risk factors associated with poor outcomes.


  Methods Top


Patients and setting

Between January 2004 and September 2013, the medical records of 225 consecutive patients diagnosed with MIBC who were treated with curative intent (either RC or TMT) at National Taiwan University Hospital were retrospectively reviewed. Eligible candidates had clinical stage T2 disease after comprehensive evaluation and staging radiology (either computed tomography [CT] scans or magnetic resonance imaging [MRI]), which was qualified after pathology-proven muscle invasion and clinically supported by retrospectively reviewing the CT/MRI results of each patient.

Patients with significant radiographic lymph node metastasis before treatment (n = 4), having a prior history of upper tract UC (n = 30), receiving neoadjuvant chemotherapy (n = 5), with missing data (n = 3), with T1/carcinoma in situ (Cis) (n = 33), with T3/4 disease (n = 32), or with residual or recurrent tumors in second-look cystoscopy (n = 25) were excluded. Finally, 93 patients with clinical Stage II disease (cT2N0M0) were eligible for the analysis, including 27 with TMT and 66 with RC. TMT incorporates the concurrent delivery of chemotherapy and radiotherapy after radical TURBT and a complete resection of the bladder tumor, verified during subsequent negative second-look cystoscopy, followed by induction chemotherapy. The regimen of chemotherapy and the setting of radiotherapy follows the protocol detailed in our previously published studies.[8],[9]

Patients received posttreatment follow-up at outpatient clinics, with physical examinations, serum biochemistry tests, and urinalysis performed at each visit. Postoperatively, radiographic evaluation, including abdominal/pelvic CT or MRI and chest radiography, was performed at 3- or 6-month intervals, and at least once a year. Bone scans were performed if clinically indicated. For patients in the TMT group, follow-up with periodical cystoscopy and urine cytology was arranged at 3-month intervals in the 1st year, 6-month intervals in the 2nd and 3rd years, and annual intervals in the following years.

Patient demographics and other variables, including age, gender, comorbidities, laboratory findings, imaging study results, and follow-up outcomes were obtained from medical charts. Laboratory diagnostics included complete blood cell counts, serum creatinine, urinalysis, fasting serum glucose, and hemoglobin A1c (HbA1c). Pathological evaluations included tumor stage, grading, the presence of Cis, tumor locations, tumor multifocality, and a description of lymph node metastasis.

This study was approved by the Institutional Review Board and Ethics Committee of National Taiwan University Hospital (NTUH). According to the provisions of the Institutional Review Board of NTUH, informed consent was not required for this unalloyed retrospective chart review study. Patient personal information was anonymized and de-identified before analysis.

Definitions

The start of the follow-up period was defined as the date of induction chemotherapy in the TMT group, and of RC in the RC group. The end of the follow-up period was that of the last accessible record. In the TMT group, clinical recurrence was defined either as bladder recurrence documented by cystoscopy or a lesion identified by radiography. In the RC group, clinical recurrence was defined as a radiographic finding of locoregional/distal recurrence with/without pathological evidence.

Time to recurrence was calculated as the period from initial curative treatment, which represented RC or initial radical TURBT, respectively, to the date of the first documented clinical recurrence. Recurrence-free survival (RFS) was defined as the time elapsed between the initiation of curative treatment and documented recurrence to the last follow-up, with death from any cause before recurrence being censored. Overall survival (OS) was defined as the time elapsed between the initiation of curative treatment and death from all causes, to the last follow-up with patients who were still alive being censored at the date of the last follow-up. Cancer-specific survival (CSS) was defined using the same measurement with death from bladder cancer.

Statistical analysis

The data cutoff date for statistical analysis was March 20, 2015. We compared the proportion of patients with different clinicopathologic features using a two-sided Fisher's exact test. All included variables were dichotomous. The log-rank test, hazard ratio (HR) with a 95% confidence interval (CI) based on Cox regression, and the Kaplan–Meier method was used to compare subgroups of patients with respect to survival. Univariate and multivariate Cox logistic regression analyses were performed to identify prognostic factors of survival. Kaplan–Meier plots were used to display the RFS, OS, and CSS for 93 bladder UC patients classified by treatment strategy. Statistical significance was set at P ≤ 0.05. All statistical analysis was performed using SPSS version 20.0 (IBM Corp., Armonk, NY, USA).


  Results Top


Basic patient demographic characteristics

The baseline characteristics of patients are shown in [Table 1]. The mean age of the present cohort was 67.04 ± 10.78 years without group differences (RC: 67.3 ± 11.1 years vs. TMT: 66.5 ± 10.1 years, P = 0.94). Men tended to be more dominant than women in both treatment groups with a similar distribution (P = 1.00). The proportion of nonsmokers was comparable in both groups (RC: 74% vs. TMT: 70%, P = 0.80). A higher distribution of chronic kidney disease was found in the RC group, but this was not statistically significant (RC: 59% vs. TMT: 37%, P = 0.07). The presence of hydronephrosis was reported in less than half of both groups, with 47% in the RC group and 44% in the TMT group (P = 1.00).
Table 1: Clinicopathological characteristics of 93 cT2N0M0 MIBC patients receiving radical cystectomy or trimodality treatment

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  Pathologic and Oncologic Results Top


Pathologic outcomes are illustrated in [Table 1]. Nearly, all patients showed high-grade disease on pathological analysis. Less Cis was found in patients treated with TMT (RC: 32% vs. TMT: 7%, P = 0.02). For all patients in the RC group, a standard pelvic lymph node dissection was performed. Pathology staging showed that 49 (74%) patients did show nodal involvement, while the other 17 patients had lymph node involvement (pN+). The median number of pelvic lymph nodes retrieved was 10 (interquartile range, [IQR]: 7–15). Nodal involvement was as follows: seven patients with pN1, nine with pN2, and one with pN3.

The overall median follow-up time was 34.1 months. The median OS in our cohort was 27.1 months (13.2–54.0 months) for RC and 52.0 months (38.0–91.0 months) for TMT, correspondingly (P = 0.05). The overall 5-year survival rate was 74% (RC: 69% vs. TMT: 86%, P = 0.13). The 5-year CSS rate (76%) also showed a comparable result (RC: 71% vs. TMT: 86%, P = 0.07). [Figure 1] demonstrates the RFS (a), OS (b) and CSS (c) for each treatment. At the time of analysis, a total of 19 patients had died, including 16 in the RC group and three in the TMT group. Seventeen patients died due to cancer progression or recurrence, consisting of 14 in the RC group and three in the TMT group. Only two out of the 19 patients died from a noncancer cause: one died of heart failure and the other of septic shock.
Figure 1: (a) Kaplan–Meier unadjusted recurrence free survival curves stratified by treatment. (b) Kaplan–Meier unadjusted overall survival curves stratified by treatment. (c) Kaplan–Meier unadjusted cancer-specific survival curves stratified by treatment

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The overall recurrence rate was 38% and RFS at 5 years stood at 57%. The recurrence rate was higher in the RC group than in the TMT group but did not show statistical significance (RC: 41% vs. TMT: 30%, P = 0.35). The median RFS was 24.0 months (8.5–53.5 months). The median RFS with respect to each group was as follows – (RC: 18 months [6.0–50.3 months], TMT: 38.0 months [28.0–89.0 months], P = 0.07.).

Risk factors for recurrence and survival

Using a Cox proportional hazards regression model, multivariate analysis showed a statistically positive association between the presence of hydronephrosis and the risk of recurrence (HR, 2.03, 95% CI 1.03–4.00, P = 0.04), [Table 2]. The presence of diabetes mellitus (DM) in patients independently correlated with poorer OS (HR: 2.74, 95% CI 1.09–6.83, P = 0.03); [Table 3] and CSS (HR: 3.32, 95% CI 1.28–8.69, P = 0.01); [Table 4].
Table 2: Univariate and multivariate cox proportional hazard models for recurrence

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Table 3: Univariate and multivariate cox proportional hazard models for overall mortality

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Table 4: Univariate and multivariate cox proportional hazard models for cancer specific mortality

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  Discussion Top


In the present study, a total of 93 Stage II bladder cancer patients received curative-intent therapies (either RC or TMT). Of these, patients with preceding hydronephrosis before therapeutic management with either treatment showed worse RFS. In addition, diabetic patients in both treatment groups also displayed poor OS and CSS.

Although there are known comparable survival results between RC and bladder preservation therapy, patients who use the latter approach are usually highly selected. Even though unanimously accepted criteria do not exist to date, ideal candidates for bladder preservation therapy include those with a completely resected bladder tumor, no evidence of diffuse multifocal tumors, no tumor-related hydronephrosis, no extensive CIS, and the ability to endure chemotherapy.[4],[7],[10] Several studies have highlighted the presence of hydronephrosis as a poor prognostic factor.[4],[5],[11] In our study, 47% (n = 31) and 44% (n = 12) of patients submitted to RC and TMT groups, respectively, were observed to have hydronephrosis without a significant difference between groups. In line with a previous investigation, our study also demonstrated an increased risk of recurrence in patients with hydronephrosis. Nevertheless, even though bladder preservation therapy is discouraged in this subgroup of patients, it is noteworthy to address the importance of proper patient selection, as well as satisfying both patients' preferences and physicians' clinical judgments.[7] Due to retrospective limitations, we failed to uncover extra insights into the true mechanism of hydronephrosis among our patients. For hydronephrosis patients in the TMT group, the median serum creatinine level was 1.15 (IQR: 1.00–1.30). Mann–Whitney U-test for the renal function between patients, with and without hydronephrosis, did not show a significant difference (P = 0.51). Of 12 patients with initial hydronephrosis, ten patients showed a remission in hydronephrosis after TURBT without a urinary diversion. One patient with bilateral hydronephrosis received a right percutaneous nephrostomy insertion and left side ureteral stent insertion, despite the lack of recurrence of a bladder tumor after initial radical TURBT and induction chemotherapy. However, the patient soon showed lymph node metastasis in the neck after trimodality treatment. The other patient had a right mild hydronephrosis with an atrophic kidney; and therefore, a urinary diversion was not needed. Bartsch et al. have demonstrated that irrespective of the etiology of the hydronephrosis, the prognostic impact of hydronephrosis in patients with bladder cancer has been shown to independently correlate with RFS.[12]

A study of large multi-institutional cohort of 1502 patients by Rieken et al., who evaluated diabetic patients who submitted to RC, demonstrated that DM treated without the use of metformin was positively associated with bladder cancer mortality (cancer-specific mortality, HR 1.53, 95% CI 1.12–2.09, P = 0.007; any-cause mortality, HR: 1.52, 95% CI 1.16–2.00, P = 0.003).[13] A study of a more recent but smaller cohort in Asia also supported this finding: Oh et al. investigated 200 bladder cancer patients who underwent RC and observed that patients with DM displayed worse cancer-specific and OS rates than non-DM patients.[14] Furthermore, Froehner et al. developed an easily applicable single condition-based mortality index from 932 patients undergoing RC and used DM as one composition to calculate a final mortality index.[15] Consistent with these results, we also found that patients with DM had a 2.7-fold risk of all-cause death (OS HR: 2.74, 95% CI 1.09–6.83, P = 0.03) and 3.3-fold risk of cancer-specific death (CSS HR: 3.32, 95% CI 1.28–8.69, P = 0.01).

Most of the previous studies evaluating the negative impact of DM on bladder cancer patients were performed under one treatment setting. However, we undertook different treatment strategies, including RC and bladder preservation therapy together. In the present study, we not only collected data on variables relating to survival, such as tumor grade and the presence of Cis but also adjusted treatment factors in a multivariate analysis and found that DM is a significant factor for OS and CSS. However, several controversial results exist between European studies and those of other regions. Goossens conducted a retrospective cohort study using data from the UK Clinical Practice Research Datalink and showed that neither the risk of BC nor the mortality from BC was increased in patients with type 1 or type 2 DM, which was in line with a subgroup analysis from a previous meta-analysis.[16],[17],[18]

In addition to regional differences, heterogeneity in the association of BC could also be observed during different stages of DM. According to a Taiwanese National Health Insurance database, the risk of bladder cancer was significantly increased for a diabetes duration of more than 1 year and decreased with increasing DM duration.[19] The possible confounding of a detection bias was questioned because increased medical attention could not fully explain the different risks of bladder cancer among different stages of diabetes. With an increased duration in diabetes comes an increased consideration for confounding factors such as insulin use, other anti-diabetic medications, or other chronic complications. In the present study, a total of 21 patients were diagnosed with diabetes, with only 11 patients having a fasting plasma glucose level >126 mg/dL. We could only obtain reports of HbA1c on five patients, four of which were more than 6.5%. No further information on antidiabetic drugs or insulin exposure was obtained.

The roles of DM or the indirect effect of certain antidiabetic drugs on survival of bladder cancer are still under investigation. Some studies have put forward the hypothesis that glycosaminoglycan degradation is involved in the pathogenesis of bladder cancer as a result of carcinogen exposure, and tumor cell adherence and implantation. The evidence for this hypothesis was further strengthened by recent reports of an increased risk of bladder cancer in patients treated with oral pioglitazone.[20],[21] A prospective 12-year follow-up cohort of more than 80,000 patients with type 2 DM in Taiwan showed that insulin users had a significantly higher risk of bladder cancer mortality than nonusers (HR: 1.88–2.50, P < 0.05).[22] In contrast, reports in urologic oncology suggested the preventive role of metformin on cancer recurrence, CSS, and any cause survival.[13],[23],[24] The antiproliferative effect metformin exerts, as observed in previous various cancer models, may offset the cancer-promoting effect of diabetes.[25],[26]

The decision-making on which a treatment strategy is based depends not only on a patient's preferences but also on the judgment of the physician. The resectability of TURBT is not totally reflected in tumor grade or numbers. The perception that patients who receiving bladder preservation therapy were usually not suitable for aggressive surgery has been disproven because, in the present study, we did not observe a significant clinical frailty in the TMT group. Both groups displayed similar age and comorbidities. From Kaplan–Meier plots displaying RFS, OS, and CSS by two different treatment groups, we observed an insignificant but marginal survival advantage in the TMT group. Although in multivariate analysis, the impact of treatment strategies on recurrence and survival vanished. It is postulated that through our selection process and the TMT protocol used, properly selected patients may achieve satisfying outcomes. However, when counseling patients about TMT treatment, they should be informed of the risk of developing acute chemotherapy-related toxicity (mainly hematologic) or long-term radiation-related toxicity. According to the National Cancer Institute Common Toxicity Criteria, version 4.0., the most acute reactions after induction chemotherapy or CCRT were manageable [Supplementary Table 1]. In the TMT group, the most commonly observed hematologic toxicity was anemia during induction chemotherapy and thrombocytopenia during CCRT, respectively. Toxicity data relating to treatment were not from patients' reported reactions, which may underestimate chemotherapy or radiation-related toxicities.



Limitations

Our study has several limitations. First, a selection bias inevitably existed due to the retrospective nature of the study since those who were not surgically suitable for RC may have been assigned to the TMT group. We had limited patient numbers for each clinical variable. Further, prospective large-scale studies are needed to validate our findings. Even though the presence of hydronephrosis was assumed to be a poor prognostic factor, we included nearly half of all patients with hydronephrosis in the TMT group based on physicians' judgments and patients' preferences. Second, we did not have any information on the duration of diabetes because the ascertainment of diabetes was based on medical records. We also did not have any information on antidiabetic drugs or insulin exposure. Third, Gray et al. reported a 19.3% upstage with clinically node-negative, but pathologically node-positive, from the national cancer data base.[27] Compared to the large cohort study, the present data yielded a relatively higher discrepancy in the clinical-pathologic stage, which would be associated with an increased risk of death. In addition, the observation of a survival advantage in the TMT group may result from a different follow-up period for each group. Eight out of sixty-six patients in the RC group could only be traced for less than half year, and three patients died within 6 months after undergoing a RC. In contrast, patients in the TMT group had an average follow-up period of more than 1 year. It is possible that patients in the TMT group had a higher compliance and were more willing to receive regular cystoscopic follow-up at the expense of retaining their bladder. In addition, in the present study, the recurrence rate was higher in the RC group but multiple factors may be associated with tumor recurrence. The depth of invasion, nodal status, extent of lymphadenectomy, and surgical margin should be considered for high risk patients.[28] In the RC group, 54% (n = 36) of patients were found to be pathologically locally advanced (pT3/4). Although this was statistically insignificant, the higher recurrence rate in the RC group should be interpreted with caution.


  Conclusions Top


In our retrospective analysis, our protocol for TMT offers an optimal alternative treatment option in properly selected patients. Despite the method of treatment, the presence of hydronephrosis increased the risk of cancer recurrence. Physicians should integrate individual patients' preference and their evidence-based professionalism. Having DM demonstrated a significantly negative effect on OS and CSS. The treating physician should recognize this common comorbidity when dealing with bladder cancer patients with diabetes. Whether DM is a possible modifiable prognostic factor for oncologic outcomes should be assessed in future studies.

Acknowledgment

Assistance in statistical analysis was provided by the National Translational Medicine and Clinical Trial Resource Center (founded by the National Research Program for Biopharmaceuticals at the National Science Council of Taiwan; NSC101-2325-B-002-078).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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