SCBC is a rare tumor variant, accounting for approximately 1% of all bladder cancers; SCBC exhibits the same pathological features of SCLC and is characterized by an aggressive behavior [1, 2]. However, treatment guidelines have not yet been established due to its rarity. Its treatment algorithm was derived from the SCLC guidelines and retrospective studies [3]. Given its high malignancy, a multimodal approach was recommended as a treatment option for localized SCBC [7]. A previous retrospective study by Lynch et al. demonstrated that neoadjuvant chemotherapy before cystectomy resulted in pathological downstaging and improved prognosis compared to cystectomy without neoadjuvant chemotherapy [8]. A platinum-based regimen was recommended according to the SCLC guidelines [3, 9]. In our patient, examination of the TURBT specimen revealed muscle invasive bladder cancer, but we did not evaluate the pathological variant. Since the diagnosis of SCBC was confirmed after cystectomy, the patient did not receive neoadjuvant chemotherapy. Contrastingly, Choong et al. demonstrated that adjuvant chemotherapy after cystectomy should be considered for patients with stage III/IV disease [7]. Our patient received adjuvant chemotherapy (often used for urothelial carcinoma) due to lymph node metastasis. However, disease progression could not be prevented, even when the regimen included cisplatin
It has been well documented that SCBC has a high risk of recurrence and metastasis and is often diagnosed at an advanced stage [1, 2]. While platinum-based chemotherapy used for extensive-disease SCLC has been recommended as a treatment option for metastatic SCBC, prognosis has still been poor [3]. Ismaili et al. demonstrated that the median overall survival of metastatic SCBC is 7.6 months [3]. Horn et al. revealed that the carboplatin, etoposide, and atezolizumab regimen followed by maintenance atezolizumab monotherapy was more effective compared to the traditional regimen (carboplatin and etoposide) as a systemic therapy for extensive-disease SCLC [4]. Atezolizumab induces a blockade of PD-L1 that is expressed on the surface of tumor cells in many cancer types; PD-L1 binds to its receptor, programed death 1, and suppresses T-cell immunity against cancer [10]. Atezolizumab restores T-cell activity by inhibiting PD-L1 [10]. In our case of pure SCBC, chemotherapy combined with atezolizumab achieved a complete response. Moreover, unlike our patient, the cases of SCBC mixed with urothelial carcinoma are more frequently seen than pure SCBC in clinical practice [3, 11]. Galsky et al. demonstrated that addition of atezolizumab to platinum-based chemotherapy also improved prognosis of patients with metastatic urothelial carcinoma [12]. Chemotherapy combined with atezolizumab may also be efficacious as a treatment option for patients with SCBC of mixed pathological variants. In our case, PD-L1 expression was slightly found in the tumor-infiltrating immune cells, but not in the tumor cells. Unlike non-small cell lung cancer, small cell carcinoma has been demonstrated to exhibit PD-L1 expression more frequently in tumor-infiltrating immune cells than in tumor cells [13]. Moreover, Liu et al. revealed that patients with extensive-disease SCLC benefited from the addition of atezolizumab to chemotherapy, regardless of PD-L1 immunohistochemistry [14]. Their findings are inconsistent with our experience in this case. Comparable to our findings, Hossain et al. reported that SCBC with muscle metastasis treated with a similar therapy achieved at least four months of disease control [5]. However, only a few cases have reported similar findings. It remains unclear what biomarkers are associated with the response to atezolizumab. Furthermore, maintenance immunotherapy has attracted attention. Powles et al. revealed that maintenance monotherapy with avelumab, a PD-L1 inhibitor, following platinum-based first-line chemotherapy improved prognoses of metastatic urothelial cancer [15]. Our patient with SCBC did not derive benefits from adjuvant platinum-based chemotherapy, which is often used for urothelial cancer, but greatly responded to chemotherapy combined with atezolizumab, which is often used for extensive-disease SCLC. Based on the study protocol of extensive-disease SCLC, following atezolizumab maintenance monotherapy was administered and it achieved long-term progression free survival [4]. Further studies are required to establish the optimal maintenance therapy for SCBC.
Additionally, Horn et al. documented that the combined regimen with carboplatin, etoposide, and atezolizumab was as safe as the traditional regimen (carboplatin and etoposide) for extensive-disease SCLC because the rates of side effects were comparable in the two groups [4]. Nausea (31.3%), vomiting (12.6%), and loss of appetite (19.7%) are commonly observed adverse events of grades I/II [4], whereas neutropenia (22.7%), anemia (14.1%), and thrombocytopenia (10.1%) are commonly observed adverse events of grades III /IV [4]. Our patient only experienced grade II neutropenia. He continued to receive maintenance immunotherapy in an outpatient setting, without any serious adverse events.
In conclusion, the present report describes a case of metastatic SCBC successfully managed with carboplatin, etoposide, and atezolizumab. The regimen may be useful as a treatment option for SCBC, which is highly aggressive. However, further studies are required to evaluate the efficacy and safety of this treatment regimen at a population level and establish additional treatment strategies for SCBC.
