Small cell bladder carcinoma treated with nivolumab as adjuvant maintenance therapy

Abstract

We report using the programmed death-1 immune checkpoint inhibitor (ICI) antibody, nivolumab, as part of a multimodal treatment strategy in small cell bladder carcinoma (SCBC). The patient presented with gross haematuria and was diagnosed with urothelial carcinoma with SCBC. He received neoadjuvant chemotherapy (NAC; carboplatin plus etoposide) according to the small cell lung cancer regimen. After three cycles of NAC, there was no progression of local disease, and a robot-assisted radical cystectomy with ileal conduit was conducted. Post surgery, the patient was treated with nivolumab (240 mg) every 2 weeks as a maintenance therapy after adjuvant cisplatin plus etoposide therapy. After more than 1.5 years post surgery, no tumour recurrence or metastases are present. The patient was treated with nivolumab, which was curative after radical cystectomy. Further research is required to elucidate the potential role of ICIs in SCBC.

Background

Small cell bladder carcinoma (SCBC) is a rare and aggressive malignant tumour, accounting for 0.5%–0.7% of all bladder tumours.¹ No agreement is recommended, and most data are extrapolated from small cell lung cancer (SCLC) where chemotherapy and radiation therapy (RT/CRT) are a commonly used algorithm, but surgical resection, specifically radical cystectomy, remains a widely used treatment modality.²,³ The National Comprehensive Cancer Network (NCCN) Guidelines also recommend concurrent chemoradiotherapy or neoadjuvant chemotherapy (NAC), followed by local treatment, for patients with small cell component histology, and the regimen for systemic therapy has been recommended in the Small Cell Lung Cancer Guidelines.⁴ Compared with urothelial carcinoma of the bladder, SCBC tends to be more aggressive and has a poorer prognosis. Typically, patients with SCBC present with locally advanced disease, and the median survival period is reported to be 10–21 months for all patients.³ Most commonly, treatment approaches are surgical resection together with strategies that appear to have the best outcomes, including NAC followed by radical cystectomy.⁵ The efficacy of the programmed death-1 immune checkpoint inhibitor (ICI) antibody, nivolumab, as adjuvant therapy, has been reported in patients with muscle-invasive urothelial carcinoma following radical surgery; however, the efficacy of adjuvant maintenance therapy for variant histology bladder cancer remains uncertain.⁶,⁷ We report a unique case of a patient with advanced SCBC treated with nivolumab as adjuvant maintenance therapy.

Case presentation

A man in his late 50s presented at our institution with macroscopic haematuria. He had hypertension and was on anticoagulant medication for deep vein thrombosis, as well as a history of alcohol consumption, and had never smoked. A urine analysis confirmed haematuria with pyuria, and urine cytology showed class 5 (positive for urothelial carcinoma). The serum level of the tumour marker neuron-specific enolase (NSE) was slightly elevated (19.1 µg/L; normal range 0–16 µg/L).

Investigations

MRI T2-weighted image revealed a tumour protruding from the left of the bladder region with a suggestion of extramural infiltration. The left obturator lymph node was enlarged, but no distant metastases were observed (figure 1). Due to a large tumour size, complete transurethral resection was difficult, so a tumour biopsy was performed and haemostasis achieved. The pathological diagnosis was bladder cancer composed of urothelial carcinoma and small cell carcinoma. A histology (H&E staining) showed a solid sheet of poorly differentiated tumour cells with a high nuclear/cytoplasmic ratio (figure 2A). Immunohistochemistry staining in SCBC is often used to support the diagnosis of small cell carcinoma and typically includes chromogranin A (22%–89% positive), synaptophysin (66%–76% positive) and NSE (25%–100% positive).⁸ For this patient, diagnostic investigations using immunohistochemistry were strongly positive for neuroendocrine markers CD56, synaptophysin (figure 2B) and chromogranin antigens.

Figure 1.

MRI: T2-weighted image revealing the bladder tumour protruding from the left of the bladder region with a suggestion of extramural infiltration. The left obturator lymph node was enlarged.

Figure 2.

(A) Tumour cross-section: urothelial carcinoma with small cell carcinoma (H&E staining, magnification ×200). (B) Immunohistochemical tests were strongly positive for synaptophysin markers.

Treatment

Given the patient’s clinical staging (T3aN2M0), three cycles of etoposide-carboplatin NAC were planned according to the SCLC regimen (etoposide 100 mg/m² on days 1, 2 and 3 and carboplatin area under the curve 5 on day 2). After two NAC cycles, CT imaging showed a reduction in left obturator lymphadenopathy and no distant metastases. After one additional NAC cycle, the patient showed no progression of local SCBC, and a robot-assisted radical cystectomy (RARC) with ileal conduit was performed. Subsequent pathological examination of the removed tissue revealed degeneration of urothelial carcinoma and the presence of small cell carcinoma; however, the tumour cells were viable and lymph node metastases were observed (staging: ypT2aN2M0).

Outcome and follow-up

Two months after surgery, the patient was treated with two cycles of adjuvant chemotherapy (cisplatin 75 mg/m² and etoposide 100 mg/m²). After completion of adjuvant chemotherapy, a positron emission tomography-CT scan confirmed the absence of metastases. We started the administration of nivolumab (240 mg) every 2 weeks as adjuvant maintenance therapy which was continued for 1 year. After more than 1.5 years post surgery, the patient is still alive and no tumour recurrence or metastases are evident.

Discussion

Although SCBC is a rare disease associated with an aggressive malignant behaviour, poor prognosis and efficacious treatment are poorly established. In previous reports, the survival period for SCBC is about 10–13 months, and the 5-year survival rate for stage III or higher is about 10%–15% of patients.^{9 10},¹¹ Fischer-Valuck et al reported that in a modern cohort of patients with limited-stage disease, patients treated with chemotherapy alone had significantly worse overall survival (OS) outcomes compared with patients treated with radical cystectomy plus chemotherapy or radiation.³ In a report by Baralo et al, the absence of surgical intervention was reported as one of the factors that worsened the prognosis.¹² The NCCN Guidelines recommend systematic chemotherapy with agents used for SCLC in patients with SCBC with distant or lymph node metastases.⁴ Chemotherapy and radiation therapy are recommended for the treatment of limited-stage SCLC; however, despite cancer present in the lymph nodes (N2 staging) in this patient, NAC resulted in tumour shrinkage, and RARC was chosen in this case. Pathological findings showed tumour degeneration, so additional adjuvant chemotherapy was performed. Zhu et al reported that only patients with neuroendocrine variant bladder cancer histology who received adjuvant chemotherapy showed a treatment benefit compared with patients who underwent surgery alone.⁷ Treatment algorithms have been extrapolated from the treatment of small cell cancer arising in the lung and often involved chemotherapy regimens using a platinum agent. Since the treatment efficacy of cisplatin-based or carboplatin-based chemotherapy in the first-line treatment of SCLC remains contentious, a meta-analysis of individual patient data was performed to compare the two treatments, which suggests no differences in efficacy between cisplatin and carboplatin in the first-line treatment of SCLC, but there are differences in the toxicity profile.¹³ Since surgery after chemotherapy was being considered for this case, carboplatin was selected because of its minimal effect on renal function.

No standard treatment exists for SCBC, but since it shares many clinicopathological features with SCLC, it is reasonable to expect a similar response to an ICI as shown in SCLC. For advanced-stage or extensive-stage SCLC, combined chemotherapy (platinum-etoposide) and immunotherapy (atezolizumab or durvalumab during and after chemotherapy) has become the new standard first-line treatment.¹⁴ An abundance of preclinical data suggests a synergistic benefit to limited-stage SCLC treated with ICIs and radiation therapy.¹⁵ Immunohistochemical staining of neuroendocrine bladder tumours, including SCBC, has shown less expression of Programmed cell Death ligand 1 and density of CD8+ T lymphocyte infiltration.¹⁶ A double-blind, phase III trial (Checkmate 451) of nivolumab and ipilimumab (combination therapy) and nivolumab monotherapy did not show a prolongation of OS with combination therapy used as a maintenance therapy versus placebo; however, trends toward greater improvement in progression-free survival were observed.¹⁷ Given the high risk of tumour regrowth in SCLC, some patients may have experienced disease progression before initiating maintenance treatment. In line with this, OS appeared to improve with nivolumab monotherapy versus placebo when maintenance treatment was initiated sooner after the last dose of first-line chemotherapy. In Checkmate 451, the median time between the last chemotherapy dose and the first dose of study drug was 5.6 weeks study-wide.¹⁷ In this case, the time since the last dose of chemotherapy was 5 weeks, a time period not different from that of Checkmate 451. In patients with high-risk muscle-invasive urothelial carcinoma after radical surgery with curative intent, disease-free survival was shown to be significantly longer with adjuvant nivolumab versus placebo. The treatment effect size was also larger in patients previously treated with NAC compared with that of patients who had not received it.⁶ There are additional factors that may have influenced treatment response in this patient, including the following: the tumour was initially sensitive to platinum-based therapy, and the time from the last dose of adjuvant chemotherapy was 5 weeks. In conclusion, this report describes a patient with metastatic SCBC managed with NAC followed by RARC in which the patient responded to nivolumab as a maintenance therapy. A combination of ICIs and chemotherapy has the potential to improve outcomes in patients with SCBC and merits consideration as a future treatment option.

LEARNING POINTS.

• Small cell bladder carcinoma (SCBC) with lymph node metastases is a rare and aggressive malignant tumour with no established treatment guidelines.

• This case shows that NAC and radical cystectomy may have some benefits for patients with SCBC and lymph node metastases.

• No standard treatment exists for SCBC, but since it shares many clinicopathological features with small cell lung cancer, it is reasonable to expect a similar treatment response to immune checkpoint inhibitors.

• Patients with SCBC and patients with high-risk muscle-invasive urothelial carcinoma undergoing radical surgery may have longer disease-free survival when adjuvant nivolumab is used.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).