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Introduction Bladder cancer is one of the most common malignancies worldwide, causing an estimated 17,000 deaths in the United States each year
.
Platinum-based chemotherapy is the first-line treatment option for invasive bladder cancer, and pembrolizumab can be used as second-line treatment in the KEYNOTE-045 study
.
The study also showed that pembrolizumab worked better with increased PD-L1 expression
.
But this is still controversial
.
This case reports a patient with locally advanced T4 bladder cancer who achieved a complete response (CR) with pembrolizumab after progression on chemotherapy and radiotherapy
.
With discontinuation due to adverse events, there were no signs of recurrence more than 2 years after treatment discontinuation
.
Basic information of the case A 69-year-old Japanese man complained of gross hematuria
.
At age 57, there was a history of non-muscle-invasive bladder cancer
.
At that time, MRI showed a bladder diverticulum but no tumor in the bladder, and the pathological result of the specimen obtained by transurethral resection of bladder tumor (TURBT) was carcinoma in situ only in the bladder diverticulum (Figure 1A and B)
.
The patient received no additional therapy after TURBT
.
MRI showed locally invasive T4 bladder cancer invading the branch of the internal iliac artery originating from the diverticulum (Fig.
1C)
.
TURBT and pathological examination revealed high-grade invasive urothelial carcinoma (UC) (Figure 1D)
.
The patient refused total cystectomy and opted for bladder-sparing therapy
.
The patient first received chemotherapy with cisplatin + gemcitabine + radiotherapy (60 Gy/30 fr), but the pathological results after TURBT again suggested residual high-grade invasive urothelial carcinoma
.
The patient subsequently received second-line chemotherapy with methotrexate + vinblastine + epirubicin + carboplatin, but the disease continued to progress (Fig.
1E,F), and the patient developed pain and swelling in the left leg
.
Coincidentally, pembrolizumab was just approved in Japan at the time, so pembrolizumab was started
.
After 6 courses of treatment, computed tomography (CT) showed that the tumor had shrunk by 50%, achieving a partial response (Fig.
2A)
.
After 9 courses of treatment, frequent bladder irrigation was required due to recurrent urinary retention due to tissue necrosis (Fig.
2B)
.
Because of the palliative treatment of urinary retention, the investigators performed only a ureterocutaneous fistula and no total cystectomy
.
After surgery, the necrotic tissue disappeared
.
After 6 courses of treatment, the tumor shrank completely, confirming complete remission
.
After a total of 20 courses of treatment, treatment was discontinued due to ACTH deficiency and rash due to pembrolizumab treatment-related adverse reactions
.
The patient remained in CR more than 24 months after discontinuation of pembrolizumab (Figure 2C-E)
.
We used the Ventana sp263 assay to detect PD-L1 expression in TURBT samples at three time points
.
The initial TURBT samples showed negative PD-L1, the PD-L1 in TURBT samples before chemoradiation was 5%, and PD-L1 expression became more than 10% after chemoradiation (Fig.
3A-C)
.
Figure 1 Imaging and pathological findings before and after chemoradiation
.
(A) MRI imaging results from 12 years ago
.
Arrows indicate bladder diverticulum; no obvious tumor in the bladder; (B) pathology results of TURBT samples 12 years ago; (C) MRI imaging results
.
Arrows indicate that the cancer is located in the bladder diverticulum and has invaded the pelvis and left iliac artery; (D) TURBT sample pathology results before chemoradiotherapy; (E) CT scan results of chemoradiotherapy, arrows indicate disease progression; (F) TURBT sample disease after chemoradiotherapy Physiological results
.
Figure 2 Imaging and cystoscopy findings during pembrolizumab treatment
.
(A) CT scan results, arrows indicate partial response; (B) cystoscopy; (C) CT scan results 2 years after treatment discontinuation, arrows indicate atrophic bladder and fluid accumulation in diverticula; (D) treatment discontinuation 2 MRI results 2 years later, arrows indicate the atrophic bladder and fluid accumulation in the diverticulum; (E) Cystoscopy results 2 years after cessation of treatment
.
Figure 3 (A) The first TURBT sample showed no PD-L1 expression; (B) TURBT sample before chemotherapy showed low PD-L1 expression by 1%-5%; (C) TURBT sample showed up-regulated PD-L1 expression after chemotherapy (10% -20%)
.
Discussion Pembrolizumab was approved by the FDA in 2017 for the second-line treatment of locally advanced or metastatic bladder cancer after cisplatin resistance
.
The KEYNOTE-045 subgroup analysis showed that the median OS of patients with PD-L1 >10% and <1% was 8.
0 months vs 5.
2 months, respectively
.
In addition, the CR rates in PD-L1>1% and PD-L1<1% subgroups were 9.
1% (10/110) and 7.
3% (11/151), respectively
.
The results suggest that PD-L1 expression may be a predictor of immune checkpoint efficacy
.
In this case, dynamic changes in PD-L1 expression were found during treatment
.
Figure 3 shows that PD-L1 is not expressed in the initial TURBT samples, the PD-L1 expression is low (1%-5%) in the pre-chemotherapy samples, and PD-L1 expression is up-regulated (10%-20%) after chemoradiotherapy
.
In July 2020, avelumab was approved by the FDA for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma in remission or stable disease after chemotherapy
.
Therefore, clinicians need a biomarker to determine the need for continued chemotherapy or maintenance therapy with immune checkpoint inhibitors
.
If possible, assessment of PD-L1 expression in tumor tissue after chemotherapy may predict the response of immune checkpoint inhibitors
.
Conclusions In this case report, a patient with stage T4 locally invasive bladder cancer achieved CR with pembrolizumab after progression on chemoradiotherapy
.
After discontinuation of pembrolizumab, the patient had not relapsed for more than 2 years
.
The researchers found that PD-L1 expression changes dynamically with chemotherapy use, and PD-L1 expression may be a predictor of treatment response before the use of immune check inhibitors
.
References: Horibe Y, Nakata W, Tsujimura G, et al.
A case of long-term complete remission of locally advanced T4 bladder cancer treated with pembrolizumab, Urology Case Reports (2021), doi: https://doi.
org/ 10.
1016/j.
eucr.
2021.
101959.
.
Platinum-based chemotherapy is the first-line treatment option for invasive bladder cancer, and pembrolizumab can be used as second-line treatment in the KEYNOTE-045 study
.
The study also showed that pembrolizumab worked better with increased PD-L1 expression
.
But this is still controversial
.
This case reports a patient with locally advanced T4 bladder cancer who achieved a complete response (CR) with pembrolizumab after progression on chemotherapy and radiotherapy
.
With discontinuation due to adverse events, there were no signs of recurrence more than 2 years after treatment discontinuation
.
Basic information of the case A 69-year-old Japanese man complained of gross hematuria
.
At age 57, there was a history of non-muscle-invasive bladder cancer
.
At that time, MRI showed a bladder diverticulum but no tumor in the bladder, and the pathological result of the specimen obtained by transurethral resection of bladder tumor (TURBT) was carcinoma in situ only in the bladder diverticulum (Figure 1A and B)
.
The patient received no additional therapy after TURBT
.
MRI showed locally invasive T4 bladder cancer invading the branch of the internal iliac artery originating from the diverticulum (Fig.
1C)
.
TURBT and pathological examination revealed high-grade invasive urothelial carcinoma (UC) (Figure 1D)
.
The patient refused total cystectomy and opted for bladder-sparing therapy
.
The patient first received chemotherapy with cisplatin + gemcitabine + radiotherapy (60 Gy/30 fr), but the pathological results after TURBT again suggested residual high-grade invasive urothelial carcinoma
.
The patient subsequently received second-line chemotherapy with methotrexate + vinblastine + epirubicin + carboplatin, but the disease continued to progress (Fig.
1E,F), and the patient developed pain and swelling in the left leg
.
Coincidentally, pembrolizumab was just approved in Japan at the time, so pembrolizumab was started
.
After 6 courses of treatment, computed tomography (CT) showed that the tumor had shrunk by 50%, achieving a partial response (Fig.
2A)
.
After 9 courses of treatment, frequent bladder irrigation was required due to recurrent urinary retention due to tissue necrosis (Fig.
2B)
.
Because of the palliative treatment of urinary retention, the investigators performed only a ureterocutaneous fistula and no total cystectomy
.
After surgery, the necrotic tissue disappeared
.
After 6 courses of treatment, the tumor shrank completely, confirming complete remission
.
After a total of 20 courses of treatment, treatment was discontinued due to ACTH deficiency and rash due to pembrolizumab treatment-related adverse reactions
.
The patient remained in CR more than 24 months after discontinuation of pembrolizumab (Figure 2C-E)
.
We used the Ventana sp263 assay to detect PD-L1 expression in TURBT samples at three time points
.
The initial TURBT samples showed negative PD-L1, the PD-L1 in TURBT samples before chemoradiation was 5%, and PD-L1 expression became more than 10% after chemoradiation (Fig.
3A-C)
.
Figure 1 Imaging and pathological findings before and after chemoradiation
.
(A) MRI imaging results from 12 years ago
.
Arrows indicate bladder diverticulum; no obvious tumor in the bladder; (B) pathology results of TURBT samples 12 years ago; (C) MRI imaging results
.
Arrows indicate that the cancer is located in the bladder diverticulum and has invaded the pelvis and left iliac artery; (D) TURBT sample pathology results before chemoradiotherapy; (E) CT scan results of chemoradiotherapy, arrows indicate disease progression; (F) TURBT sample disease after chemoradiotherapy Physiological results
.
Figure 2 Imaging and cystoscopy findings during pembrolizumab treatment
.
(A) CT scan results, arrows indicate partial response; (B) cystoscopy; (C) CT scan results 2 years after treatment discontinuation, arrows indicate atrophic bladder and fluid accumulation in diverticula; (D) treatment discontinuation 2 MRI results 2 years later, arrows indicate the atrophic bladder and fluid accumulation in the diverticulum; (E) Cystoscopy results 2 years after cessation of treatment
.
Figure 3 (A) The first TURBT sample showed no PD-L1 expression; (B) TURBT sample before chemotherapy showed low PD-L1 expression by 1%-5%; (C) TURBT sample showed up-regulated PD-L1 expression after chemotherapy (10% -20%)
.
Discussion Pembrolizumab was approved by the FDA in 2017 for the second-line treatment of locally advanced or metastatic bladder cancer after cisplatin resistance
.
The KEYNOTE-045 subgroup analysis showed that the median OS of patients with PD-L1 >10% and <1% was 8.
0 months vs 5.
2 months, respectively
.
In addition, the CR rates in PD-L1>1% and PD-L1<1% subgroups were 9.
1% (10/110) and 7.
3% (11/151), respectively
.
The results suggest that PD-L1 expression may be a predictor of immune checkpoint efficacy
.
In this case, dynamic changes in PD-L1 expression were found during treatment
.
Figure 3 shows that PD-L1 is not expressed in the initial TURBT samples, the PD-L1 expression is low (1%-5%) in the pre-chemotherapy samples, and PD-L1 expression is up-regulated (10%-20%) after chemoradiotherapy
.
In July 2020, avelumab was approved by the FDA for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma in remission or stable disease after chemotherapy
.
Therefore, clinicians need a biomarker to determine the need for continued chemotherapy or maintenance therapy with immune checkpoint inhibitors
.
If possible, assessment of PD-L1 expression in tumor tissue after chemotherapy may predict the response of immune checkpoint inhibitors
.
Conclusions In this case report, a patient with stage T4 locally invasive bladder cancer achieved CR with pembrolizumab after progression on chemoradiotherapy
.
After discontinuation of pembrolizumab, the patient had not relapsed for more than 2 years
.
The researchers found that PD-L1 expression changes dynamically with chemotherapy use, and PD-L1 expression may be a predictor of treatment response before the use of immune check inhibitors
.
References: Horibe Y, Nakata W, Tsujimura G, et al.
A case of long-term complete remission of locally advanced T4 bladder cancer treated with pembrolizumab, Urology Case Reports (2021), doi: https://doi.
org/ 10.
1016/j.
eucr.
2021.
101959.
