A case of neoadjuvant chemotherapy‐resistant muscle‐invasive bladder cancer that markedly responded to pembrolizumab before conversion radical cystectomy

Abstract

Introduction
Recently, perioperative use of immune checkpoint inhibitors has improved the prognosis of muscle‐invasive bladder cancer. It is unclear whether radical cystectomy or systemic pembrolizumab is the optimal next treatment in patients with muscle‐invasive bladder cancer and progressive disease in the pelvic lymph node following neoadjuvant chemotherapy (NAC).

Case presentation
A 62‐year‐old woman with cT3N0M0 bladder cancer and high programmed death‐ligand 1 expression developed solitary obturator lymph node metastasis following 5 cycles of neoadjuvant chemotherapy. Six subsequent cycles of pembrolizumab shrank the lymph node significantly, and conversion radical cystectomy was planned. Pathologically, only carcinoma in situ around the scar of transurethral resection of bladder tumor remained in the primary tumor, and the accumulation of foamy macrophages and fibrosis without viable tumor cells was observed in the dissected lymph node. Eighteen months passed without a recurrence following radical cystectomy.

Conclusion
Pembrolizumab administration before radical cystectomy achieved a good response in a patient with obturator lymph node metastasis following neoadjuvant chemotherapy.

Full text

Case Report
A case of neoadjuvant chemotherapy-resistant muscle-invasive
bladder cancer that markedly responded to pembrolizumab before
conversion radical cystectomy
Ichiro Yonese,
1
Noboru Numao,
1
Kentaro Inamura,
2
Yusuke Yoneoka,
1
Ryo Fujiwara,
1
Yosuke Yasuda,
1
Tomohiko Oguchi,
1
Shinya Yamamoto,
1
Takeshi Yuasa
1
and Junji Yonese
1
Departments of
1
Urology, Cancer Institutes Hospital and
2
Pathology, Cancer Institutes Hospital, Japanese Foundation for Cancer
Research, Tokyo, Japan
Abbreviations & Acronyms
cis = carcinoma in situ
CRP = C-reactive protein
CT = computed tomography
GC = gemcitabine and cisplatin
Hb = hemoglobin
ICI = immune checkpoint inhibitor
LDH = lactate dehydrogenase
LN = lymph node
LNM = lymph node metastasis
MIBC = muscle-invasive bladder
cancer
MRI = magnetic resonance imaging
NAC = neoadjuvant chemotherapy
NLR = neutrophil lymphocyte ratio
pCR = pathological complete response
PD-L1 = programmed death-ligand 1
PLND = pelvic lymph node dissection
PLT = platelet
RARC = robot-assisted radical
cystectomy
RC = radical cystectomy
SII = systemic immune-inflammation
index
TURBT = transurethral resection of
bladder tumor
WBC = white blood cell
c-GTP = c-glutamyltranspeptidase
Correspondence: Noboru Numao M.D.,
Department of Urology, Cancer Institute
Hospital, Japanese Foundation for Cancer
Research, 3-8-31 Ariake, Koto-ku, Tokyo
135-0063, Japan. Email: noboru.numao@
jfcr.or.jp
How to cite this article: Yonese I, Numao
N, Inamura K et al. A case of neoadjuvant
chemotherapy-resistant muscle-invasive
bladder cancer that markedly responded to
pembrolizumab before conversion radical
cystectomy. IJU Case Rep. 2023; https://
doi.org/10.1002/iju5.12669.
This is an open access article under the
terms of the Creative Commons Attribution
License, which permits use, distribution
and reproduction in any medium, provided
the original work is properly cited.
Received 30 August 2023; accepted 1
November 2023.
Introduction: Recently, perioperative use of immune checkpoint inhibitors has
improved the prognosis of muscle-invasive bladder cancer. It is unclear whether radical
cystectomy or systemic pembrolizumab is the optimal next treatment in patients with
muscle-invasive bladder cancer and progressive disease in the pelvic lymph node
following neoadjuvant chemotherapy (NAC).
Case presentation: A 62-year-old woman with cT3N0M0 bladder cancer and high
programmed death-ligand 1 expression developed solitary obturator lymph node
metastasis following 5 cycles of neoadjuvant chemotherapy. Six subsequent cycles of
pembrolizumab shrank the lymph node significantly, and conversion radical cystectomy
was planned. Pathologically, only carcinoma in situ around the scar of transurethral
resection of bladder tumor remained in the primary tumor, and the accumulation of
foamy macrophages and fibrosis without viable tumor cells was observed in the
dissected lymph node. Eighteen months passed without a recurrence following radical
cystectomy.
Conclusion: Pembrolizumab administration before radical cystectomy achieved a good
response in a patient with obturator lymph node metastasis following neoadjuvant
chemotherapy.
Key words: bladder cancer, conversion surgery, neoadjuvant chemotherapy,
neoadjuvant immunotherapy.
Keynote message
It is unclear whether RC or systemic pembrolizumab is the better next treatment in patients
with MIBC that has progressed in the pelvic LN following NAC. In such cases, pembrolizu-
mab with a view to converting RC could be an option.
Introduction
NAC before RC and PLND demonstrated prolonged survival in localized MIBC
1–3
and is
recommended as standard treatment.
4
However, in a minority of cases, MIBC showed pelvic
LNM following NAC.
5
It is unclear whether RC or systemic immunotherapy is more effective
for these cases.
Before the advent of ICIs, the prognosis was poor for patients with residual MIBC or
LNM after NAC.
6,7
Recently, perioperative use of ICIs improved the prognosis of MIBC.
8,9
Adjuvant nivolumab was shown to improve the prognosis of residual MIBC or LNM after
NAC in the phase III CheckMate 274 trial.
8
The effectiveness of neoadjuvant immunotherapy
was also reported in the phase II PURE-01 trial.
9
However, we could find no reports describ-
ing systematic immunotherapy with a view to conversion RC in MIBC patients with pelvic
LNM after NAC. Here, we report a patient with cT3N0M0 bladder cancer developing obtura-
tor LNM following NAC who markedly responded to pembrolizumab before conversion RC
with PLND.
©2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association. 1
IJU Case Reports (2023) doi: 10.1002/iju5.12669

Case presentation
A 62-year-old woman visited her doctor because of gross
hematuria in 2021. Urine cytology revealed the presence of
atypical cells. Cystoscopy and MRI revealed a nodal tumor
of VI-RADS score 2 in the left lateral wall (Fig. 1). TURBT
revealed pT2 and G3 urothelial carcinoma with cis (Fig. 2a).
Contrast-enhanced CT showed no metastasis or upper urinary
tract tumor. Four cycles of neoadjuvant GC (gemcitabine;
100 mg/m
2
Days 1, 8, 15, and cisplatin; 70 mg/m
2
Day 2)
every 4 weeks were planned and started at 80% dose; the
fourth cycle was reduced to 70% due to myelosuppression.
The patient was referred to us for RARC. We resumed the
fifth cycle of GC at a 70% dose because of the waiting
period before RARC. However, after the fifth cycle, a preop-
erative CT revealed a solitary left obturator LNM (30 mm)
with fluorodeoxyglucose uptake in positron emission
tomography-CT (ycT3N1). We considered this case to be
associated with a high recurrence rate after RC, and the dis-
ease was unable to be resected with curative intent. We
began treatment with pembrolizumab 200 mg every 3 weeks
with a view to conversion RC in case the LNM shrunk.
Three weeks after the first administration of pembrolizumab,
the LNM (16 mm) had shrank markedly. After 6 cycles, the
LNM had shrunk to an insignificant size, and we planned
conversion RC. NLR and SII (NLR 9PLT count [910
3
/
lL])
10
were decreasing concurrently with shrinkage of the
LNM (Fig. 3). No immune-related adverse effects were
observed.
RARC with PLND and extracorporeal urinary diversion
were performed in 2022. Total operative time and console time
were 447 and 272 min, respectively. The estimated blood loss
during surgery was 200 mL. Pathologically, only the cis
around the scar of TURBT remained in the primary tumor. The
dissected obturator LN showed an accumulation of foamy mac-
rophages and fibrosis without viable tumor cells (Fig. 2c), sug-
gesting a good therapeutic effect. Immunohistochemical
evaluation using anti- PD-L1 monoclonal antibody (clone 28–8)
and the TURBT specimen showed PD-L1 expression in the
majority (60%) of tumor cells (Fig. 2b). No systemic therapy
was added following RC. Eighteen months passed without a
recurrence.
Discussion
To the best of our knowledge, there are no reports of preop-
erative pembrolizumab administration for progressive MIBC
following NAC. One report compared pCR to pembrolizumab
for chemotherapy-resistant upper tract urothelial carcinoma.
11
In the present case, the LNM following neoadjuvant GC dis-
appeared with pembrolizumab, which made it possible to per-
form conversion RC.
It is unclear whether RC or systemic pembrolizumab is
better as the next treatment in MIBC patients with pelvic
LNM following NAC. In the former cases, the maximal sur-
vival time of 32 ypN+patients after RC was 3.17 years.
7
Another study reported that 5-year overall survival of patients
with residual cancer (ypT2-4 or ypN+) after NAC was 21%,
whereas that of cases with pCR was 82%.
12
Occult LNM
after RC also showed a poor prognosis.
13,14
In the PURE-01
study of neoadjuvant pembrolizumab, all MIBC patients
enrolled in the study underwent RC, and 42% of patients
achieved pCR.
9
Considering the poor prognosis of ypN+
cases after NAC and RC, systemic immunotherapy with a
view to converting RC may increase the possibility of cure.
In our patient, after pembrolizumab administration, adjuvant
nivolumab was covered by Japanese insurance. Subgroup
analysis of the CheckMate 274 trial demonstrated the advan-
tage of adjuvant nivolumab in pN+cases.
8
The treatment
sequence combining RC and systemic immunotherapy for
chemotherapy-resistant cases is an issue yet to be resolved. In
the present case, pembrolizumab before RC was effective.
Systemic immunotherapy before RC could lead to further
advancement and a missed opportunity for RC. To estimate
Fig. 1 MRI images of cT3N0M0 bladder cancer
before TURBT: (a) sagittal view of the T2-WI
image; (b) axial view of the T2-WI image; (c) axial
view of the DWI image; (d) axial view of the
contrast-enhanced image.
2©2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.
I YONESE ET AL.

the efficacy of ICIs, PD-L1 expression demonstrated predic-
tive value in several clinical trials and meta-analyses.
8,9,15,16
Neoadjuvant pembrolizumab achieved pCR in 54.3% of cases
with high PD-L1 expression, compared with 13.3% of cases
with low PD-L1 expression.
9
In the present case, the primary
tumor showed high PD-L1 expression. Assessment of PD-L1
expression could be useful in determining the treatment of
progressive MIBC after NAC.
Fig. 2 Microscopic examination of the TURBT specimen of the primary tumor showed pT2 and G3 urothelial carcinoma in hematoxylin and eosin staining (a) with
PD-L1 expression in the majority of tumor cells (b). The dissected obturator LN showed an accumulation of foamy macrophages and fibrosis without viable tumor
cells (c).
Fig. 3 Time-course of metastatic obturator LN (a) with prognostic factors associated with metastatic urothelial carcinoma (b, c). NLR and SII represent neutrophil/
lymphocyte and PLT 9neutrophil/lymphocyte, respectively. NLR and SII improved concurrently with the shrinkage of the metastatic LN (b).
©2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association. 3
Pembrolizumab before radical cystectomy

A recent risk stratification of metastatic urothelial cancer
indicated that NLR, Hb, LDH, and CRP were predictive fac-
tors of response to pembrolizumab.
17,18
SII and c-GTP were
shown to be prognostic factors for urothelial carcinoma.
10,19
In the present case, NLR and SII were improving concur-
rently with the shrinkage of the LNM (Fig. 3). These factors
could be useful in assessing the effect of neoadjuvant therapy
before conversion surgery.
Conclusions
Pembrolizumab administration in advance of conversion RC
achieved a good response in a patient with obturator LNM
after NAC.
Author contributions
Ichiro Yonese: Conceptualization; investigation; visualization;
writing –original draft. Noboru Numao: Conceptualization;
investigation; supervision; visualization; writing –review and
editing. Kentaro Inamura: Investigation; visualization; writing –
review and editing. Yusuke Yoneoka: Writing –review and
editing. Ryo Fujiwara: Writing –review and editing. Yosuke
Yasuda: Writing –review and editing. Tomohiko Oguchi:
Writing –review and editing. Shinya Yamamoto: Writing –
review and editing. Takeshi Yuasa: Writing –review and
editing. Junji Yonese: Writing –review and editing.
Conflict of interest
Author T.Y. was supported by grants from MSD.
Approval of the research protocol by
an Institutional Reviewer Board
Not applicable.
Informed consent
Informed consent was obtained from the patient for publica-
tion of this case report.
Registry and the Registration No. of
the study/trial
Not applicable.
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4©2023 The Authors. IJU Case Reports published by John Wiley & Sons Australia, Ltd on behalf of Japanese Urological Association.
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