前置式(手術前)輔助性以免疫檢查點抑制劑為主的治療

對於處理局部晚期上泌尿道上皮細胞癌有助益嗎？

李彥霓、陳冠州

台北醫學大學-部立雙和醫院泌尿科

Is Neoadjuvant Immune Checkpoint Inhibitors-Base Treatment Beneficial to Managements of Locally Advanced Upper Tract Urothelial Carcinoma (UTUC)?

An Ni Lee, Kuan-Chou Chen

Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan

Purpose:

In Taiwan, upper tract urothelial carcinoma (UTUC), which affects the renal pelvis or ureter, exhibits a 3.5% increase in incidence among men and a 5.3% increase among women. Currently, the NCCN guideline recommends radical nephroureterectomy (RNU) with bladder cuff excision as the gold standard treatment for UTUC. However, challenges arise due to potential declines in renal function post-nephroureterectomy, which may limit the feasibility of administering adjuvant systemic therapies.

Previous studies have indicated that UTUC patients’ survival after radical nephroureterectomy (RNU) depends on clinicopathological prognostic factors, notably lymphovascular invasion and the primary tumor size or extent (pT). Invasive UTUC is associated with a poor prognosis, with five-year survival rates of 73% for T2 disease, 40% for T3 disease, and a median six-month survival for T4 disease. One possible rationale for the stage-dependent worse survival is the micro- or macro- metastasis status at the time of RNU. This highlights the importance of considering preoperative systemic therapy to improve survival. Neoadjuvant systemic immunotherapy involves administering drugs before surgery to reduce tumor size and diminish metastatic lesions, ultimately leading to tumor downstaging and the less invasive surgical procedures.

However, consolidated data on the impact and efficacy of such therapy in UTUC prior to surgery remain scarce. We aim to share our institution’s experiences and insights regarding the advancement of preoperative immune checkpoint inhibitors-base treatment in locally advanced UTUC.

Methods and Results:

4 cases diagnosed with locally advanced upper tract urothelial carcinoma, who received either neoadjuvant immunotherapy (Pembrolizumab/Nivolumab) and/or antibody-drug conjugate (ADC) (Enfortumab vedotin) preoperatively, were retrospectively recruited. These patients had a median age of 65 years (range: 59-87 years), an ECOG performance status score of 1, and no evidence of distant metastasis. The baseline characteristics and outcomes of the patients are outlined in Table 1.

The first case involves a treatment-naïve male patient diagnosed with primary UTUC located at the right distal ureter, measuring 1.5cm in size, and radiographic lymphadenopathy. The patient underwent endoscopic ablation of partial tumors followed by six cycles of immunotherapy with Pembrolizumab (100mg Q3W). A partial response was observed during radiographic follow-up post three-months with regression of hydronephrosis.

The second case involves a 59-year-old male patient initially diagnosed with invasive high-grade papillary upper tract urothelial carcinoma (UTUC) at the right renal pelvis in 2019 and lost follow-up after radical nephroureterectomy was recommended. Three years later, he presented with disease progression characterized by the growth of the tumor at the right renal pelvis to a size of 9.1 cm accompanied by calyceal dilatation. Additionally, enlarged lymph nodes were noted at the retrocaval and aortocaval regions. Post neoadjuvant Pembrolizumab (200mg Q3W) for 9 cycles, CT imaging reveals in a reduction in tumor size and lymph node involvement despite low PD-L1 expression (CPS<1%). Subsequently, radical nephroureterectomy with bladder cuff excision and extensive lymph node dissection was performed. Surgical pathology revealed no evidence of residual carcinoma (Stage 0a, ypT0N0M0), indicating a complete response to neoadjuvant immunotherapy preoperatively. Post-operatively, maintenance Nivolumab (200mg Q2W) was prescribed for half year.

The third case pertains to a female patient who experienced stable disease following platinum-based adjuvant concurrent chemoradiation therapy (CCRT) for a prior right ureterovesical junction urothelial carcinoma. Disease progression was observed nine years later on the contralateral side, specifically in the left upper third ureter and lymadenopathy at the retrocaval and aortocaval regions. In consideration of preserving renal function and achieving tumor shrinkage to avoid RNU, adjuvant Nivolumab (100mg Q2W) therapy was administered consecutively. Radiographic follow-up revealed tumor shrinkage and partially subsided hydronephrosis and shrinkage of lymph nodes, indicating partial response.

The fourth case concerns an 87-year-old female who underwent left RNU in 2019 for left renal pelvis UTUC. Recently, recurrent disease was observed at the right uretero-vesical junction with distinct evidence of extravesical mass lesion and obstructive uropathy. Owing to patient’s condition of single-kidney and deterioration of renal function, neoadjuvant immunotherapy Pembrolizumab (100mg administered on day 1 of a 3-weeks cycle) plus Enfortumab Vedotin (50mg administered on day 1 and 8 of 3-weeks cycle) were prescribed for 10 courses. This treatment regimen resulted in nearly complete resolution of the tumor at the right uretero-vesical junction.

In the study, only one patient experienced Grade 1 skin rashes on the limbs following Nivolumab administration, which resolved with antihistamine use. No patients experienced severe adverse events (Grade 3 or above) following immunotherapy and ADC.

Conclusion:

All patients included in our study underwent neoadjuvant immunotherapy and/or ADC before radical nephroureterectomy surgery, regardless of platinum eligibility and PD-L1 expression. We hypothesize that neoadjuvant systemic immunotherapy offers beneficial effects on early micro- or macro-metastasis, alleviating obstructive symptoms and facilitating pathological downstaging of the primary tumor. Consequently, patients may experience reduced perioperative morbidity and a decreased the risk of radical nephroureterectomy (RNU). However, limitations may include the risk of overtreatment prior to obtaining an accurate pathological diagnosis. Hence, larger databases and longer follow-up durations are essential to thoroughly evaluate the outcomes of preoperative neoadjuvant immune checkpoint inhibitors-base treatment in patients with locally advanced UTUC.