Journal of Medical Sciences

ORIGINAL ARTICLE
Year
: 2022  |  Volume : 42  |  Issue : 4  |  Page : 175--179

Risk and predictors of patients receiving neoadjuvant chemotherapy followed by radical cystectomy or transurethral resection alone for muscle-invasive bladder cancer: A single-institute experience


Pei-Jhang Chiang1, Kai-Hsiung Ko2, En Meng1, Tai-Lung Cha3, Guang-Haun Sun1, Dah-Shyong Yu1, Chien-Chang Kao3,  
1 Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Division of Urology, Department of Surgery, Tri-Service General Hospital; Graduate School of Medical Sciences, National Defense Medical Center, Taipei, Taiwan

Correspondence Address:
Dr. Chien-Chang Kao
Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No- 325, Cheng-Kung Rd, Sec 2, Neihu 114, Taipei
Taiwan

Abstract

Background: Upper urinary tract urothelial carcinoma and muscle-invasive bladder cancer (MIBC) incidence rates are high in Taiwan. Our patients with MIBC are commonly managed with a radical cystectomy (RC); however, recurrence rates remain high. Aim: We aimed to establish a protocol regarding neoadjuvant chemotherapy (NAC) followed by RC or transurethral resection (TUR) alone from 2008 to 2013. We outline the efficacy and prognosis of NAC followed by RC. Methods: This was a retrospective study. The clinical data of 38 patients who underwent NAC from 2008 to 2013 at a single institution were retrospectively reviewed. Patients were divided into Group 1 (NAC with RC) and Group 2 (NAC with TUR alone). Age, sex, tumor size, prechemotherapy characteristics, and oncological outcomes were analyzed. Results: Group 1 had worse chemotherapy responses than Group 2 (48% vs. 71%, P = 0.0002). There were no significant differences in the 3-year progression-free survival and overall survival (OS) between the groups. High-risk patients were defined as having a tumor size >5 cm, concurrent hydronephrosis, and adverse pathological features. High-risk Group 1 patients had a better 3-year OS than high-risk Group 2 patients (13/17, 76%; and 3/5, 63%; respectively). Conclusion: In high-risk patients or patients with poor chemotherapy responses, NAC followed by RC with pelvic lymph node dissection resulted in a significantly increased 3-year OS. NAC with TUR alone was suitable only for low-risk patients with good chemotherapy responses.



How to cite this article:
Chiang PJ, Ko KH, Meng E, Cha TL, Sun GH, Yu DS, Kao CC. Risk and predictors of patients receiving neoadjuvant chemotherapy followed by radical cystectomy or transurethral resection alone for muscle-invasive bladder cancer: A single-institute experience.J Med Sci 2022;42:175-179


How to cite this URL:
Chiang PJ, Ko KH, Meng E, Cha TL, Sun GH, Yu DS, Kao CC. Risk and predictors of patients receiving neoadjuvant chemotherapy followed by radical cystectomy or transurethral resection alone for muscle-invasive bladder cancer: A single-institute experience. J Med Sci [serial online] 2022 [cited 2022 Sep 26 ];42:175-179
Available from: https://www.jmedscindmc.com/text.asp?2022/42/4/175/353041


Full Text



 Introduction



Bladder cancer is the second most common urinary tract cancer and accounts for approximately 2000 new cancer patients and 400 deaths in Taiwan each year.[1] Approximately 25% of patients with bladder cancer present with muscle-invasive bladder cancer (MIBC).[2] Radical cystectomy (RC) with pelvic lymph node dissection (PLND) is the current gold standard for MIBC. However, even after RC, the 5-year mortality rate stays around 50%–70%.[2] Therefore, we report our experience with the MIBC treatment strategy of neoadjuvant chemotherapy (NAC) followed by RC and identify high-risk patients who could not be treated with transurethral resection (TUR) alone.

 Materials and Methods



Upon approval from the Institutional Review Board, all patients undergoing maximal TUR and three-dimensional magnetic resonance imaging (3D-MRI) for confirmed MIBC from 2008 to 2013 were identified. Patients who received chemotherapy before surgery were enrolled, and those who died of surgical complications or were lost to follow-up were excluded. Patients were enrolled in the high-risk group if they had any of the following adverse features: a tumor size >5 cm, concomitant hydronephrosis, stage cT3b-T4a, or a variant histology.

Comprehensive clinical, pre-RC laboratory, and final pathological data were collected and extensively reviewed to ensure completeness and accuracy. Cisplatin-based NAC was first the choice for patients with normal renal function, and gemcitabine plus carboplatin (GCarbo) was administered for patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. After three doses of NAC, all patients underwent a repeat staging TUR and 3D-MRI before the RC. NAC response was measured on MRI, and patients with a good response were defined as having tumor shrinkage >50% and diminished hydronephrosis.

Outcomes of interest included overall survival (OS), progression-free survival (PFS), and pathological downstaging rate. Kaplan–Meier methods were used to calculate OS. Follow-up was defined as time from RC to death or loss to follow-up (OS and disease-specific survival) or to the documented date of disease recurrence (PFS). Pearson's Chi-square analysis was used to identify variables differing between high- and low-risk patients. Reviews of age, sex, tumor size, prechemotherapy characteristics, and oncological outcomes were analyzed. All analyses were performed using IBM SPSS version 18.0 (IBM Co., Armonk, NY, USA), and P < 0.05 was statistically considered significant.

Radical cystectomy

RCs were performed by a single surgeon and included an extended bilateral PLND with en bloc RC and urinary diversion. Tumor staging was based on the American Joint Committee on Cancer Staging Manual.

Chemotherapy

Patients undergoing NAC were administered three cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) at 28-day intervals, three cycles of gemcitabine plus cisplatin (GC) at 21-day intervals, and three cycles of GCarbo at 21-day intervals.

Ethics statement

All clinical investigations were in accordance with the ethical guidelines of the Declaration of Helsinki, and ethical approval was obtained from the Institutional Review Board of the Tri-Service General Hospital (TSGHIRB NO. 1-103-05-093). Informed written consent was obtained from all patients in this study.

 Results



Of 69 patients enrolled who underwent an RC at the Tri-Service General Hospital between 2008 and 2013, 38 patients with MIBC received NAC. After at least three cycles of NAC, patients were restaged according to cystoscopy and 3D-MRI to assess their chemotherapy response. Twenty-five patients received NAC followed by RC (Group 1), and 13 patients underwent TUR or active surveillance (Group 2) due to their decisions and tumor downstaging. The median follow-up of eligible patients was 38 months. The patient demographic and clinical characteristics are displayed in [Table 1]. Differences in age, tumor size and number, concomitant carcinoma in situ, hydronephrosis, clinical T stage, body mass index, and Eastern Cooperative Oncology Group performance status between the groups were not statistically significant, except sex. On average, the renal function (eGFR) of Group 2 patients was better than that of Group 1 patients (85.85 vs. 61.27 mL/min/1.73 m2, P = 0.01). Those who received cisplatin-based chemotherapy in Group 2 were more likely to reach higher tumor shrinkage percentages than those who did not (71% vs. 48%, respectively, P = 0.002) [Table 2].{Table 1}{Table 2}

[Table 2] shows the 3-year OS of both groups. Five out of 25 patients in Group 1 and 3 out of 13 patients in Group 2 (80% vs. 77%) died during follow-up. Group 1 had better long-term outcomes than Group 2, although the difference was not statistically significant (P = 0.103) [Figure 1]. When patients were divided into specific subgroups, the high-risk group patients treated with NAC followed by RC had significantly better outcomes (76%) than those treated with NAC plus TUR alone (63%) (P = 0.03). There was no significant difference in the 3-year survival between low-risk group patients treated with NAC followed by RC and NAC plus TUR alone (85% vs. 88%, respectively) [Table 3] and [Figure 2].{Figure 1}{Table 3}{Figure 2}

Among 25 patients in Group 1, there were four patients (16%) with clinical complete remission (ycT0) after NAC as assessed by cystoscopy and MRI study [Figure 3], and only one patient had complete pathological downstaging (ypT0). These four patients received three cycles of GC.{Figure 3}

 Discussion



As a standard therapy for MIBC, an RC with PLND results in a 50% 5-year disease-free survival.[3] A meta-analysis of NAC data in a study conducted by the Southwest Oncology Group showed a better 5-year OS in patients treated with surgery and NAC compared to patients treated with surgery alone (57% vs. 43%, P = 0.06); the neoadjuvant regimen used included three cycles of MVAC.[4] Platinum-based NAC combinations, such as MVAC and GC, are preferable regimens capable of reducing the risk of death at 5 years by 6%.[4],[5],[6] GCarbo is suitable for patients who have an eGFR <60 mL/min, who are fit for cystectomy, and who have a good response rate.[7],[8]

Although the benefit of NAC has been established, treatment strategies with NAC are not widely used in routine clinical practice,[9] and this may be due to severe chemotherapy toxicity and delayed timing. The interval between initial MIBC diagnosis and RC should not exceed 12 weeks, and three cycles of NAC are generally recommended.[10]

Before NAC, we would initially perform a TUR and study 3D-MRI results and histological adverse features (lymphovascular invasion, micropapillary, and sarcomatoid differentiation) to divide patients into subgroups based on tumor risk. A high-risk group was defined as having a tumor size >5 cm, concomitant hydronephrosis, stage cT3b-T4a, or a variant histology. Complete pathological responses (ypT0) and tumor downstaging rates were higher in patients treated with NAC followed by RC than in patients treated with RC alone. Complete pathologic responses occurred in 31.3% and 7.7%, and tumor downstaging occurred in 56.3% and 25.9% of patients treated with combined therapy and RC alone, respectively.[11]

While NAC followed by RC became a level 1 evidence-recommended treatment for MIBC, <25% of patients have been receiving this treatment modality.[12],[13] Possible explanations for this include increasing preoperative morbidity, delayed RC, and limited OS benefits from NAC. NAC does not predict increased operation time, postoperative complications, reoperations, or wound dehiscence.[14] A cystectomy beyond 10 weeks after NAC may compromise patient survival.[15] Recently, randomized trials and meta-analyses demonstrated that patients who underwent cisplatin-based NAC followed by RC had better survival than patients who underwent cystectomy alone for MIBC treatment.[4],[12] However, the 5-year OS increased only 5% in the former patients as the study did not divide patients into subgroups according to tumor risk.[4]

This retrospective analysis of patients achieving complete or partial responses following NAC was nonrandomized but compared well-matched populations who were all treated at a single institution. We found that patients with MIBC, especially high-risk patients, receiving TUR alone following NAC had a similar PFS but significantly worse OS than those treated with RC. We considered that the potential target of NAC is micrometastasis, and patients who underwent NAC could achieve high chemotherapy response rates as they have a better performance status before surgery than those who did not.

In our study, cisplatin-based chemotherapy was the first-choice treatment for patients with normal renal function, and there was a significant difference in tumor downstagings between the aforementioned patients who underwent cisplatin-based chemotherapy and those who did not. In the surgery group, four patients (16%) who received GC had complete tumor downstaging (ycT0) as assessed by a postchemotherapy image study. However, there were still residual tumors in specimens after the cystectomy in three patients.

In our hospital, we arranged for at least three cycles of NAC followed by RC for MIBC treatment. However, many high-risk patients had a poor prognosis. Thus, we focused on early-detected chemotherapy responses after two cycles of chemotherapy as assessed by cystoscopy, MRI, or computed tomography. If chemotherapy responses were poor or the tumor progressed, an immediate RC would be performed.

In our study, low-risk patients with good renal function who received NAC followed by TUR had a 3-year OS of up to 88%. However, the standard treatment for high-risk patients is NAC followed by RC. Our results indicate that carefully selected patients with a high risk of MIBC may have a 3-year OS of approximately 76% if an RC is performed.

Study limitations include its retrospective nature, a low case number, variability in chemotherapy regimens, and the inevitable missing data from select patients in a single-institutional cohort. It would be desirable to objectively quantify the actual benefit of NAC in the Taiwanese population, and further prospective randomized trials are ongoing.

 Conclusion



As an MIBC treatment strategy, it is important to identify high-risk patients with the following features: a tumor size >5 cm, concomitant hydronephrosis, stage cT3b-T4a, a variant histology, or a poor chemotherapy response. In high-risk patients, NAC followed by RC with PLND resulted in a significantly increased 3-year OS. In addition, NAC decreases occult lymph node metastasis and inhibits circulating micrometastasis. NAC with TUR alone was suitable only for low-risk patients with good chemotherapy responses.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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