With a global age-adjusted incidence rate of 9.5 per 100,000 for men and 2.4 per 100,000 for women, bladder cancer (BC) is the most common urinary tract malignancy and the tenth most commonly diagnosed cancer (1). In muscle-invasive BC (MIBC), the tumor spreads into or through the muscle layer of the bladder. The prognosis of MIBC is poor, especially when there is metastasis to pelvic lymph nodes (LNs), termed locally advanced node-positive MIBC. This form is graded as at least stage III disease and carries a high risk of progression and mortality (2). Patients with node-positive BC have five-year disease-specific survival rates that are less than half those of patients without nodal involvement (31.2% vs. 66.7%) (3). Historically, patients with clinically node-positive BC have been treated similarly to those with distant metastases. However, recent studies reveal that this population is highly heterogeneous, and there is a lack of evidence-based guidance for their treatment, primarily due to their exclusion or underrepresentation in clinical trials (4).

Node-positive BC is widely regarded as a systemic disease with the probable presence of distant micro-metastases. As such, the management of clinically node-positive disease should ideally be multimodal, including a combination of systemic therapy, surgery, and/or radiation (4). According to international guidelines, the standard treatment for patients with node-positive MIBC includes radical cystectomy (RC) and pelvic lymph node dissection (PLND) before or after chemotherapy in selected patients (5–8). In the National Comprehensive Cancer Network (NCCN) guidelines, the primary treatment options for patients with radiologically suspicious node-positive (cN1) disease, classified as stage IIIA (9), include neoadjuvant chemotherapy (NAC) followed by RC and PLND for those eligible for cisplatin, or surgery alone for patients unfit for cisplatin-based chemotherapy (5). However, RC and PLND are associated with notable morbidity and high mortality risk and have a major impact on quality of life (QoL) (10). An alternative primary treatment approach, bladder preservation, involves maximal transurethral resection of the bladder tumor (TURBT) followed by concurrent chemoradiotherapy (cCRT). This bladder-sparing method is typically reserved for patients with smaller solitary tumors, absence of extensive or multifocal carcinoma in situ (CIS), no tumor-related hydronephrosis, and satisfactory pre-treatment bladder function (5–8). In contrast, the primary treatment for stage IIIB (cT1–T4a, N2–3) disease (9) includes either upfront systemic chemotherapy (with consideration of consolidative local therapy) or cCRT (5). The choice between these options should consider the patient’s clinical condition, surgeon and center experience, and patient preferences.

The goal of maintenance therapy is to extend the benefits achieved with first-line systemic therapy and prolong progression-free survival (PFS) and overall survival (OS). In the immunotherapy era, programmed death-ligand 1 (PD-L1) pathway targeting agent avelumab has shown promise as a “switch” maintenance therapy (11, 12). Starting avelumab maintenance therapy within 10 weeks of completing chemotherapy, irrespective of PD-L1 expression status, was shown to prolong PFS and OS in the Phase III JAVELIN Bladder 100 trial (12). In this trial, patients with unresectable locally advanced or metastatic urothelial carcinoma (UC) and no disease progression on first-line platinum-based chemotherapy received avelumab as first-line maintenance treatment along with best supportive care (BSC) (12). Avelumab plus BSC resulted in significantly higher one-year survival rates (58.4% vs. 71.3%) and longer median PFS (2 months vs. 3.7 months) than BSC, leading to accelerated Food and Drug Administration approval of avelumab as a first-line maintenance treatment in locally advanced or metastatic UC. Although the JAVELIN trial reported results for patients with non-visceral disease, it did not specifically analyze the subgroup of patients with clinically node-positive, non-metastatic disease. Therefore, the potential utility of avelumab maintenance therapy in this group remains unclear.

The cases presented here illustrate a bladder-sparing approach for node-positive MIBC, with upfront cisplatin-based chemotherapy and cCRT, followed by avelumab as maintenance therapy.

Until recently, node-positive MIBC was categorized as stage IV disease irrespective of the extent of nodal involvement and was often excluded from key clinical trials, limiting treatment guidance to small, observational studies (4). Now, it has been accepted that clinically regional node-positive BC is a heterogeneous entity, with some notable differences in prognosis and management approach depending on the extent of nodal involvement (4, 13). There is a general agreement that managing clinically node-positive disease should involve a multimodal approach, incorporating systemic therapy, surgery, and/or radiation. Current guidelines indicate that for patients with stage IIIA MIBC, the general approach includes RC coupled with NAC for those eligible for cisplatin. Alternatively, for patients suitable for a bladder-sparing approach, bladder preservation involving maximal TURBT followed by cCRT is an NCCN category 1 recommended option since 2022 (13). For stage IIIB MIBC patients, treatment typically involves either upfront systemic chemotherapy (with consideration of consolidative local therapy) or cCRT (5). Additionally, the use of avelumab as a “switch” maintenance therapy can be offered to patients with unresectable node-positive BC who achieved at least stable disease following initial chemotherapy (12, 14).

The two cases presented here illustrate the use of avelumab maintenance therapy as part of a bladder-preserving multimodal approach for patients with clinically regional node-positive, non-metastatic MIBC. At the time MIBC was discovered, both patients had clinically node-positive disease, albeit limited to multiple pelvic LNs without visceral or distant metastasis. Following multidisciplinary discussions and consultation with the patients, both patients expressed a preference for non-surgical management. Consequently, a bladder-preserving approach was pursued in both cases: upfront gemcitabine/cisplatin followed by potential consolidative cCRT based on the chemotherapy response, with the option for avelumab maintenance therapy thereafter. Both patients showed excellent responses after four cycles of gemcitabine/cisplatin, with their post-chemotherapy PET-CT scans showing remission of metabolic activity in bladder lesions and pelvic LNs, along with substantial shrinkage or disappearance of the tumors. Patient 1 started avelumab approximately 4 weeks after completing cCRT, and Patient 2 began treatment at around 3 weeks post-cCRT. Both timeframes were within the 10-week window indicated by the JAVELIN trial findings. Avelumab treatment (over two years for patient 1 and one year for patient 2) was well-tolerated by both patients, with no immune-related adverse events, and QoL was maintained. The most recent follow-up scans showed both patients remaining in a state of complete remission at 29 months and 16 months after chemotherapy, respectively, with no disease recurrence.

Close active surveillance after upfront systemic therapy is key for early detection of recurrence and evaluation of subsequent therapy options. Considering the presence of regional node-positive disease in both cases, we reasoned that following chemotherapy with consolidation cCRT would offer the best chance of local and systemic disease control. Moreover, analyses suggest a limited benefit of RC with PLND in patients with node-positive disease (15), which must be weighed against its notable negative impact on QoL and morbidity.

Finally, we explored the use of avelumab maintenance therapy, already a recommended post-chemotherapy option (5), in the context of consolidative cCRT. These two cases suggest that post-chemotherapy maintenance of remission with avelumab is still possible with the interposition of cCRT and that the resulting delay did not compromise disease control. Similarly, there has been an interest in establishing whether consolidative radiotherapy can provide additional benefits in the context of avelumab maintenance therapy (16).

The cases discussed here corroborate recent analyses that underscore the benefits of maintenance therapy in MIBC treatment paradigms, namely, prolonged survival without compromising QoL (11, 17). Data from the ongoing INSPIRE trial (the first prospective study dedicated to addressing node-positive MIBC) will provide insight into both short-term and long-term outcomes for bladder-preserving treatments in this patient population and has the potential to define new treatment strategies for stage III MIBC.

Observations from these cases provide support for extending the immune checkpoint inhibitor maintenance paradigm to encompass local consolidation therapy, which is potentially valuable for defining future bladder-preserving strategies in MIBC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

DP: Writing – review & editing, Conceptualization, Data curation. LH: Writing – review & editing, Data curation. YK: Writing – review & editing, Data curation.