Upper tract urothelial carcinoma (UTUC), including renal pelvis cancer and ureteral cancer, is highly prevalent in people aged 70 ~ 90 years. In relevant European and American reports, its incidence accounts for only 5% –10% of urothelial carcinoma. The preliminary survey results of hospitalized patients in 32 large hospitals in China in 2018 showed that it accounted for 9.3% –29.9% of urothelial carcinoma, with an average of 17.9%. Smoking, occupational exposure, analgesics, chronic inflammation, and genetics are possible causes and risk factors. Although UTUC is rare, compared with other urothelial cancers, the prognosis is poor and the recurrence and metastasis rate is high . The 5-year survival rate of T3 patients is less than 50%, while the 5-year survival rate of T4 patients is less than 10%. Therefore, effective neoadjuvant and adjuvant therapies are critical for locally advanced or locally progressive UTUC. A study of postoperative pathological subgroup analysis of patients with locally advanced (stage T3 – T4) UTUC confirmed that neoadjuvant chemotherapy can reduce the postoperative pathological stage of such UTUC patients and is associated with postoperative pathological complete response (CR) , however, there is no relevant report on the application of neoadjuvant immunotherapy in the treatment of UTUC. In this paper, we report a case of immunization combined with chemotherapy in neoadjuvant therapy for locally advanced renal pelvis cancer. This case report has been reported in line with the SCARE Criteria .
A 66-year-old male patient presented on July 2, 2021, with a 3-month history of left-sided abdominal pain and a 2-month history of gross hematuria. Patient had no other associated co-morbidities, any significant past history and family history. He had repeatedly visited a local hospital and was given anti-infective treatment, which was still recurrent, and he visited our hospital for further diagnosis and treatment by himself. Outpatient abdominal ultrasound revealed a renal mass, so he was admitted to our department. The main clinical symptoms were gross hematuria without obvious inducement, initial hematuria, occasionally accompanied by cord-like blood clots, intermittent left abdominal pain, no frequent urination, urgent urination, no fever, chills, high fever, etc., the general condition was good, and no significant weight loss was observed. He had no history of surgery, allergies, smoking, hypertension, diabetes, or coronary heart disease, and drug history and family history are unremarkable. Special examination revealed percussion pain in the left renal area, and the rest showed no significant abnormalities.
The auxiliary examination was perfected after admission, and abdominal ultrasound demonstrated space-occupying lesions in the middle and upper segments of the left kidney, 5.3 * 4.8 cm with slight hypoechogenicity. Perfection of CTU revealed space-occupying lesions in the left kidney, mostly considering: 1) renal carcinoma (papillary renal cell carcinoma?) with the invasion of the renal pelvis, 2) renal pelvis carcinoma with invasion of the renal parenchyma, (Figure 1a); multiple enlarged retroperitoneal lymph nodes, considering metastases (Figure 1b). Chest CT showed no significant abnormality. Urine exfoliative cytology: No suspicious tumor cells were found in any of the three tests.
To confirm the diagnosis, the treatment of cystoscopy + left ureteroscopy (Figure 1c) was performed under general anesthesia on July 7, 2021, during which ureteroscopy indicated neoplasms in the left renal pelvis, and pirarubicin 30 mg was immediately instilled into the bladder for chemotherapy within 24 hours after surgery. Biopsy pathology revealed urothelial carcinoma, low grade, invading the lamina propria, PD-L1 tumour proportion score (TPS) ≈ 10% (Figure 2a&b). Combined with the disease condition, the initial diagnosis was: malignant tumor of the left renal pelvis invading the renal parenchyma (invading the perirenal adipose tissue was not excluded), clinical stage cT3-4N1M0, high-risk.
Because the disease was locally advanced, 4 cycles of neoadjuvant therapy were preoperatively administered with immunotherapy combined with chemotherapy, specifically: PD-1 inhibitor (Tislelizumab 200 mg, D0, every 21 days), GC chemotherapy (gemcitabine 1000 mg/m2, D1, D8, cisplatin 70 mg/m2, D2, every 21 days). On November 9, 2021, reexamination of CTU include space-occupying lesions in the left kidney, which were smaller than before, as shown in Figure 1d; multiple slightly larger retroperitoneal lymph nodes, which were smaller than before, as shown in Figure 1e, and efficacy evaluation (RECIST1.1): partial response (PR). During neoadjuvant therapy, no grade 3–4 adverse reactions such as rash, severe myelosuppression, bleeding, infection, hypothyroidism, pulmonary fibrosis, myocarditis, vasculitis, or neurological damage occurred.
The patient underwent ‘radical nephroureterectomy (RNU) + bladder cuff excision (BCE) + lymphadenectomy (LND)’ under general anesthesia on November 11, 2021. Postoperative pathology revealed: 1. gross specimen: left renal pelvis mass, size: 3 × 2 × 2 cm; 2. microscopic: (left kidney and ureter) renal pelvis invasive urothelial carcinoma, cancer tissue invading the renal cortex. No cancer was found in the renal dorsal membrane, renal sinus fat, ureter, and vascular stump. (renal hilar lymph nodes) showed no cancerous tissue (0/7) (Figure 2c&d). (Paraaortic lymph nodes) No cancer tissue was observed (0/21); 3. immunohistochemistry: Ki67 (index ≈ 30%), c-erbB-2 (2 +), TP53 (–); 4. PD-L1 TPS ≈ 70%. Postoperative diagnosis: left renal pelvis cancer, pT3N0M0, high risk.
Adjuvant therapy was continued after surgery with 4 cycles of GC chemotherapy without grade 3–4 adverse reactions. After chemotherapy, CTU reexamination on June 23, 2022, revealed: 1. postoperative left renal pelvis cancer: no significant abnormal soft tissue density was observed in the surgical area (Figure 1f). 2. abnormal enhanced nodules in the left medial lobe of the liver, mostly considering small hemangiomas, without significant change compared with before; 3. multiple cysts in the liver; 4. bladder wall thickening, mostly considering chronic cystitis, without significant change compared with before; 5. benign prostatic hyperplasia. Cystoscopy was performed and the bladder mucosa was smooth with no significant abnormalities, and a random biopsy was grasped, which showed chronic inflammation of the bladder (Figure 2e&f).
It is difficult to accurately diagnose the clinical stage of UTUC patients before surgery, so UTUC patients were divided into high-risk and low-risk groups according to whether the tumor was single, the diameter of the tumor, the pathological grade of exfoliative cytology or ureteroscopy, the presence of hydronephrosis, and whether there were multiple tumors suggested by preoperative CT examination. According to risk groups, surgical treatment, adjuvant chemotherapy, neoadjuvant chemotherapy, and immunotherapy can be used clinically .
Neoadjuvant therapy is anti-tumor therapy performed before surgery, after neoadjuvant therapy, the tumor shrinks, downstaging, giving more patients the opportunity for surgical treatment and surgical resection. According to different tumor types, neoadjuvant therapy has different degrees of benefit for patients with various types of tumors through chemotherapy, radiotherapy, endocrine therapy, targeted therapy, immunotherapy, and other means. At the same time, neoadjuvant therapy can be used to understand the sensitivity of tumors to this treatment through preoperative treatment, to better develop subsequent treatment strategies. Neoadjuvant therapy can also prevent the formation of drug-resistant cell lines and reduce postoperative recurrence and metastasis. After neoadjuvant therapy, some tumors can regress to varying degrees and achieve PR, and a small proportion of patients can even achieve CR after neoadjuvant therapy, thereby achieving a better prognosis.
Clinically, the standard treatment regimen for UTUC is surgical resection (RUN + BCE), and LND can be selected for patients above T2. However, surgical resection alone has a recurrence rate of 30 to 50%, while the 5-year survival rate is only 0 to 34% [5, 6]. Quhal et al  showed that preoperative neoadjuvant chemotherapy can reduce the postoperative pathological stage of UTUC patients, especially locally advanced UTUC patients. Matin et al  also showed that overall survival (OS) was associated with neoadjuvant chemotherapy in all patients with UTUC as well as in patients with locally advanced UTUC, and neoadjuvant chemotherapy followed by surgery could not only reduce the recurrence rate but also reduce the mortality of patients.
In recent years, people have a further comprehension of the immune system, the efficacy of immunotherapy for a variety of tumors has been gradually recognized, and the scope of immunotherapy for cancer patients has been greatly broadened. The PD-1/PD-L1 inhibitors pembrolizumab and atezolizumab have been approved by the FDA since 2017 for the first-line treatment of metastatic UC in patients who are not eligible for cisplatin chemotherapy. After years of groping practice, immunotherapy has now been shown to significantly improve OS in patients with advanced UC, and five PD-1/PD-L1 inhibitors have been approved by the FDA as second-line drugs for the treatment of locally advanced or metastatic UC after the failure of platinum-based chemotherapy. However, there are no current guidelines regarding the use of immunotherapy in neoadjuvant therapy for UTUC.
Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This single-arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD-L1-positive urothelial carcinoma who progressed during/following platinum-containing therapy and had no prior PD-(L)1 inhibitor treatment. Patients were considered PD-L1 positive if ≥25% of tumor/immune cells expressed PD-L1 when using the VENTANA™ PD-L1 (SP263) assay .
At present, the effectiveness of immunotherapy combined with chemotherapy for lung cancer, esophageal cancer, gastric cancer, and breast cancer has been demonstrated [10, 11, 12, 13]. There are few reports on neoadjuvant therapy with preoperative immunotherapy combined with chemotherapy, and a phase II clinical study  showed that neoadjuvant gemcitabine and cisplatin combined with pembrolizumab met the primary endpoint of pathological downstaging and were generally safe. In the present case, the patient was initially diagnosed with carcinoma of the left renal pelvis, cT3-4NxM0, high risk. For this patient with locally advanced, PD-L1 positive, high-risk UTUC, based on full communication with patients and their families, combined with the patient’s general condition, underlying diseases, personal wishes, family and economic status, and other factors for comprehensive consideration, preoperative neoadjuvant PD-1 inhibitor immunotherapy combined with GC chemotherapy was selected for 4 cycles. After neoadjuvant therapy, patients were reexamined for tumor shrinkage, further radical surgery was performed after assessing the disease stage as PR, and adjuvant chemotherapy was performed after surgery to achieve better efficacy, indicating that the application of immune combined chemotherapy in PD-L1-positive locally advanced UTUC is feasible.
Another aspect of assessing the treatment effect is medication safety. Immunotherapy-related adverse events can occur in any organ and tissue, common skin toxicity, gastrointestinal toxicity, hepatotoxicity, endocrine toxicity, and pulmonary toxicity. Previous studies of lung cancer  and gastric cancer  have shown that immunotherapy has a lower overall incidence of adverse events compared with chemotherapy. In the field of UC treatment, the KeyNote052 study  also demonstrated the safety of immunotherapy. Regarding related studies of immunotherapy combined with chemotherapy, the BLASS-1 study  demonstrated the safety of nivolumab combined with GC regimen chemotherapy in the treatment of UC. A further systematic review of the available data did not find sufficient evidence that immunotherapy combined with chemotherapy increases the severity of adverse events or leads to unexpected toxicity. In the present case, we did not find significant grade 3/4 adverse reactions during treatment either.
Chemotherapy can deplete immunosuppressive cells and have immune sensitization. After the completion of first-line chemotherapy, the continuation of maintenance therapy with PD-1/PD-L1 inhibitors may enhance anti-tumor activity and avoid potential interactions including cross-resistance and cumulative toxicity. In this context, a phase III study, JAVELIN Bladder 100 study  demonstrated that first-line maintenance therapy with avelumab in advanced patients can prolong overall survival by about 7 months. Therefore, this patient could continue to be maintained with immunotherapy after the completion of subsequent treatment regimens with postoperative chemotherapy.
In a conclusion, it’s feasible and safe in PD-L1-positive locally advanced UTUC patients that preoperative neoadjuvant PD-1 inhibitor immunotherapy combined with GC chemotherapy was selected for 4 cycles, after neoadjuvant therapy, further radical surgery was performed, and adjuvant chemotherapy was performed after surgery.
With the continuous progress of research, the emergence of antibody-drug conjugate (ADC) brings new opportunities to patients with locally advanced or metastatic UC. The EV103 study of pembrolizumab in combination with ADC drugs was reported at the 2020 ASCO meeting, which showed excellent efficacy in platinum-intolerant patients with advanced uroepithelial cancer and is now in phase III clinical studies that may transform the treatment of advanced uroepithelial cancer in recent years. In the present case, we found that postoperative pathology suggested c-erbB-2 (2 +), and therefore, immunotherapy combined with ADC may be an option for follow-up after further disease progression.
Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor in Chief of this journal on request.
This work was supported by the Science and Technology Program for Gansu Province of Youths(CN): 21JR11RA015. We would like to thank KetengEdit(www.ketengedit.com) for its linguistic assistance during the preparation of this manuscript.
The authors have no competing interests to declare.
Liuting Xu, Dongxing Wang contributed equally to this work and shared first authorship. They contributed to write the manuscript, to gather the clinical data as well as the relevant imaging information; Youyou Wu, Chunlei Zhang collected data, Pathology review, help editing manuscript; Pengcheng Miao, main operating surgeon, designed and mentoring original draft, writing and editing.
Not commissioned, externally peer-reviewed.
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