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382 Miyake et al. | Journal of Clinical and Translational Research 2023; 9(6): 381-391
urinary tract UC (UTUC) [1]. According to reports of muscle- through posters and/or websites using the opt-out method [20].
invasive UTUC in the 2000s, 5-year cancer-specific survival (CSS) We reviewed the medical charts of 214 consecutive patients with
rates of pT2, pT3, and pT4 were 75 – 84%, 54 – 56%, and 0 – bladder cancer who underwent RC between 2000 and 2021 at the
12%, respectively [2-4]. A randomized control trial (RCT) [5] and Nara Medical University Hospital and 1,775 patients with UTUC
recent meta-analyses of 11 retrospective studies [6] revealed that who underwent RNU between 1995 and 2018 at four hospitals
for high-risk UTUC, RNU with both neoadjuvant chemotherapy across Western Japan (Figure 1). Inclusion criteria were as follows:
(NAC) and adjuvant chemotherapy (AC) provides better survival (1) Patients receiving NAC for invasive UC before radical surgery
than RNU alone. In the latest European Association of Urology and (2) pathologically diagnosed ypT2≤ and/or ypN+ UC in the
Guidelines on UTUC, the evidence level of AC was positive level radical surgery specimens. Exclusion criteria were as follows:
1b, and platinum-based AC was recommended for patients having Patients with critical data missing. Of 1989 patients, 95 (4.8%)
muscle-invasive UTUC and/or pN + disease without NAC [7]. who received NAC followed by radical surgery, RC, or RNU and
In muscle-invasive bladder cancer (MIBC), cisplatin-based NAC diagnosed with ypT2≤ tumors and/or ypN+ were eligible for the
followed by radical cystectomy (RC) is the current standard care analysis (Figure 1A).
based on level 1 evidences [7-9]. A systematic review and meta-
analysis including 15 RCTs with >3000 patients demonstrated 2.2. Image interpretation for MIUC
that cisplatin-based NAC decreased the risk of mortality by All radiographic data of computed tomography (CT), CT
approximately 20% compared to RC without NAC [10]. urography, and/or magnetic imaging resonance (MRI) taken
The pathologic response to NAC, frequently defined as before the initiation of NAC were uploaded in a cloud medical
≤ yielding pathological (yp) T1 and ypN0 was associated with imaging platform (Ambra Health, New York, NY, USA).
favorable survival outcome after RC or RNU for patients with The images were reevaluated and interpreted by a radiologist
MIUC [11-13]. In contrast, residual MIUC disease, that is, (Marugami N.) with special expertise in urogenital imaging, who
ypT2≤ and/or ypN+ after NAC, was a strong poor prognostic factor was blinded to any other clinicopathological variables. Tumor
for disease recurrence and death. Recently, the CheckMate 274 trial stage (according to the Eighth Edition American Joint Committee
demonstrated that adjuvant nivolumab provided significant benefit on Cancer tumor-node-metastasis staging system) was determined
on disease-free survival in NAC-treated patients with residual based on multiplanar reconstruction, including axial, sagittal, and
MIUC disease and/or ypN+ [14]. Although adjuvant nivolumab coronal CT images. To determine the clinical T stage (≤cT2, cT3,
is recommended for the disease subset in several guidelines [7-9], or cT4) of UTUC, the investigator performed comprehensive
many patients having UC are elderly and vulnerable, and immune assessment using tumor appearance (filling defect/mass or wall
checkpoint inhibitors (ICIs) can cause divergent immune-related thickening/stricture), margin (smooth or spiculated/irregular),
adverse events, which are sometimes serious and lethal, requiring texture (homogeneous, heterogeneous), hydronephrosis, and
high-dose steroids [14-18]. Moreover, updated data of the calcification [21,22].
CheckMate 274 trial demonstrated that Grade 3 – 4 treatment-
related adverse events occurred in 18.2% and 7.2% of patients in 2.3. Radical surgery and pathologic response to NAC
the nivolumab and placebo arms, respectively [19]. Because the
patient subset indicated for adjuvant nivolumab in the guidelines RC was performed with open surgery, standard laparoscopic
is heterogeneous, it would be vital to select patients who are likely surgery, and robotic surgery with lymph node dissection (LND)
to benefit from this treatment. and urinary diversion. The LND procedures, including removal of
The association between response to NAC and survival the obturator, external iliac, common iliac, and parasacral lymph
outcomes after RC or RNU remains unclear. We hypothesized that node chains, were performed basically according to the extended
patients with pre-NAC cT3 and post-NAC ypT2 (down-staged) template [23]. RNU was performed through open or laparoscopic
could have better prognosis compared to those with pre-NAC retroperitoneal access using a standard procedure consisting of
cT2 and post-NAC ypT2 (no-changed). This study investigated whole kidney dissection, including the perirenal fat with the ureter
the potential association by stratifying NAC-treated patients and adjacent segment of the bladder cuff [24]. The methods used
with MIUC into three groups: Down-staged ypT2≤, no-changed for the LND were inconsistent among surgeons and hospitals,
ypT2≤, and up-staged ypT2≤ groups. which changed over time. In general, a template-based dissection
that was dependent on the tumor location was performed in our
2. Methods collaborative academic hospitals for patients with UTUC [25].
We focused on pathologic response to NAC by comparing pre-
2.1. Study cohorts of NAC-treated MIUC patients and data NAC cT and post-NAC ypT categories. Patents with ypT less than
collection
cT and ypN0 were categorized into the down-staged ypT2≤ group,
This retrospective multicenter study was approved by the irrespective of their cN status. Patents with ypT more than cT and
ethics committee of each participating institute (reference ID: those with cTany cN- and ypTany ypN+ were categorized into an
1298, 1958, 2891, H30-048, and 2018-036) of the Nishinihon up-staged ypT2≤ group. Patients who met neither the down-staged
Uro-Oncology Collaborative Group framework. Informed ypT2≤ group nor the up-staged ypT2≤ group were categorized
consent was obtained from the participants or bereaved families into a no-changed ypT2≤ group.
DOI: http://dx.doi.org/10.18053/jctres.09.202306.23-00106