A metachronous bilateral upper urinary tract urothelial carcinoma achieved partial remission by multiple treatment modalities: A case report and literature review

doi:10.21203/rs.3.rs-3585370/v1

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Case Report

A metachronous bilateral upper urinary tract urothelial carcinoma achieved partial remission by multiple treatment modalities: A case report and literature review

https://doi.org/10.21203/rs.3.rs-3585370/v1

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Background: Upper tract urothelial carcinoma (UTUC) is less common but more aggressive than bladder urothelial carcinoma in China. Bilateral UTUC is even rarer. Managing bilateral UTUC is a great challenge, especially when patients request kidney sparing and refuse hemodialysis. Besides robot-assisted laparoscopic radical nephroureterectomy (RNU) and chemotherapy, immune checkpoint inhibitor therapy is a promising strategy. We present a case of metachronous bilateral UTUC that benefited from multiple treatment modalities.

Case Description: We report a special case of a 68-year-old woman with metachronous bilateral UTUC. She underwent robot-assisted laparoscopic radical nephroureterectomy (RNU) due to an occupied lesion in the middle segment of the right ureter. Pathological findings indicated muscle-invasive high-grade urothelial carcinoma (on the right), clinical stage T3N1M0, high-risk. Adjuvant gemcitabine/cisplatin chemotherapy for three cycles every 21 days was administered. To prevent tumor recurrence in bladder, sapylin (OK-432) was used for intravesical instillation, made from a low-virulence strain (Su) of Streptococcus pyogenes (group A) incubated with penicillin. Twenty-nine months later, a left renal pelvis-occupied lesion was found. Pathological examination by ureteroscopy suggested that the tumor was non-invasive high-grade papillary urothelial carcinoma. The patient requested kidney sparing and declined radical surgery. The tumor was too large for complete endoscopic resection. The patient underwent neoadjuvant chemoimmunotherapy followed by retrograde intrarenal surgery (RIRS). After surgery, adjuvant immunotherapy was continued as before. The patient finally achieved partial remission.

Conclusions: We present a rare case of metachronous bilateral UTUC. The patient had radical surgery for the right UTUC and requested kidney sparing for the subsequent left UTUC. The patient received neoadjuvant chemoimmunotherapy followed by RIRS and adjuvant immunotherapy for the left UTUC. The patient achieved a stable state with no disease progression and partial remission of the left UTUC. Our report suggests a new approach for the treatment of bilateral UTUC.

upper tract urothelial carcinoma

chemotherapy

Immune checkpoint inhibitors

neoadjuvant therapy

adjuvant therapy

Upper tract urothelial carcinoma (UTUC) is more insidious, malignant, and recurrent than bladder cancer. The EAU guidelines stratified the risk of patients with UTUC: low-risk patients were characterized by a single tumor with a diameter < 2cm, low-grade cytology or pathology, and non-muscular invasion by imaging; High-risk patients were those with hydronephrosis, multiple tumors, diameter ≥ 2cm, a cytological or pathological indication of high-grade bladder tumors, previous history of high-grade bladder tumors, and pathological types other than urothelial carcinoma ^[1].

The preferred treatment for high-risk non-metastatic UTUC is radical nephroureterectomy (RNU) with sleeve cystectomy. This surgical procedure involves resection of the kidney, the full length of the ureter, and part of the bladder surrounding the ureter orifice. RNU is associated with the risk of renal insufficiency after surgery. For low-risk UTUC, there is no significant difference in long-term survival between RNU and renal-sparing surgery ^[2]. Surgical methods for renal preservation include segmental ureterectomy, ureteroscopy, and percutaneous laser nephrectomy. Renal-sparing surgery may be considered for patients with isolated kidneys and high-risk UTUC after adequate assessment.

However, endoscopic therapy has a significantly higher recurrence rate for high-risk UTUC. Previous studies have shown that for high-risk UTUC, preoperative neoadjuvant chemotherapy and RNU can reduce the tumor recurrence rate and mortality compared with RNU alone^[3]. The efficacy of adjuvant chemotherapy after RNU has also been demonstrated repeatedly: a population-based study showed chemotherapy after RNU improved overall survival in patients with pT3/T4 and/or pN+^[4]. A systematic review and meta-analysis showed that adjuvant chemotherapy after RNU may improve disease-free survival and cancer-specific survival in patients with locally advanced UTUC^[5]. The chemotherapy regimen is mainly platinum-based, and the first-line regimen is cisplatin-based chemotherapy. The dose of cisplatin needs to be adjusted according to the patient’s renal function because of its nephrotoxicity. It is important to note that bladder recurrence is common after UTUC (22%-50%), and intravesical epirubicin can prevent it ^[6].

Immunotherapy, especially immune checkpoint Inhibitors (ICI), such as programmed death-Ligand 1 (PD-L1) inhibitors, have achieved good effects in malignant melanoma, such as lung cancer, renal cell carcinoma, and digestive tract tumors. The NCCN guidelines indicate that atezolizumab (a PD-L1 inhibitor) and pembrolizumab (a PD-1 inhibitor) can be used as first-line therapy for locally advanced or metastatic bladder cancer that is not suitable for platinum-based chemotherapy^[7]. However, there are no clinical trials of ICI in UTUC.

Managing bilateral UTUC is a great challenge, especially when patients request kidney sparing and refuse hemodialysis. We report a rare metachronous bilateral UTUC case in which multimodality therapy helped this patient reached a stable state with no disease progression.

A 68-year-old female patient was hospitalized on December 4, 2018, due to "right lower back pain for 20 days and uninterrupted gross hematuria for half a month". She had not consumed alcohol nor smoked cigarettes, and there was no cancer history in her family. CT examination of the urinary system showed a space-occupying (31.7mm*13.4mm) lesion in the right middle ureter and effusion in the right kidney (Fig. 1A-D). On December 12, 2018, she underwent robot-assisted laparoscopic RNU and lymph node dissection combined with bladder sleeve resection was performed. The pathology report showed muscle-invasive high-grade urothelial carcinoma (on the right), pT3N1M0 (lymph node metastasis in the mesangial ureteral). Three cycles of postoperative adjuvant chemotherapy (21-day GC regimen: gemcitabine 1000mg/m², d1 and d8; Cisplatin 70mg/m², d2) were administered on January 11, 2019. Postoperative intravesical instillation with sapylin (OK-432), made from a low-virulence strain (Su) of Streptococcus pyogenes (group A) incubated with penicillin, was performed regularly (once a week, eight times plus once a month, ten times). Cystoscopy, pelvic and abdominal CT and lung CT were reviewed regularly. By May 6, 2021, the plain CT scan of the urinary system suggested slight dilation of the left renal pelvis (Fig. 1E). CTU examination revealed a left renal pelvis space-occupying lesion (23.1*12.4mm) (Fig. 1F-H). A left ureteroscopy was performed, finding that the tumor could not be completely resected due to its deep tumor infiltration. So a small part of tumor tissues were biopsied without any resection operation on May 18, 2021. The pathology report indicated that it was a high-grade papillary urothelial carcinoma, with negative immunohistochemical staining for PD-L1. The patient was in an isolated kidney state with renal insufficiency and she strongly requested kidney sparing instead of dialysis. The strategy of neoadjuvant chemotherapy and immunotherapy followed by endoscopic surgery was introduced to the patient. Given the adverse reactions of chemotherapy, such as nausea, vomiting and myelosuppression, the patient requested priority in immunotherapy. So Tislelizumab (a PD-1 inhibitor) 200mg (Q3W) alone was regularly used from May 20, 2021. After the third cycle of immunotherapy (July 19, 2021), MRU showed the carcinoma was obviously smaller than before (Figure I-J). But it was a pity that after the sixth cycle (Sep 16, 2021), MRU showed that the lesion of the left renal pelvis was enlarged (Fig. 1K). Considering the poor effect of immunotherapy alone, immunotherapy combined with chemotherapy was proposed. The GFR of the left kidney was 50.56 mL/min/1.73m^2. Tislelizumab (200mg, Q3W) combined with a 21-day GC chemotherapy regimen was used. After the third and sixth cycle of neoadjuvant chemoimmunotherapy, MRU showed a significant shrinkage of the carcinomas (Fig. 1L and 1M). And then the patient received RIRS operation with laser ablation for the residual tumor on Mar 30, 2022. Considering the deep infiltration of the tumor, adjuvant immunotherapy was continued until now after RIRS. Follow-up in three months later, MRU showed the tumor continued to shrink (Fig. 1N).The timeline of this case is shown in Fig. 2. According to RECIST V1.1 evaluation criteria, the patient achieved PR status.

The epidemiology, etiology, and prognosis of UTUC in China differ from those in other countries. UTUC in China is primarily found in females, but the prognosis of females is better than that of males ^[8]. The incidence of bilateral UTUC is lower, accounting for only 1%-2.8% of all UTUC, which can be manifested as simultaneous or metachronous bilateral UTUC. This case describes an older woman with metachronous bilateral UTUC. The pathology report on the right was T3N1M0, and radical surgery followed by postoperative adjuvant chemotherapy was performed. The patient's UTUC on the left renal pelvis was larger than 2cm and the pathology indicated high-grade urothelial carcinoma. According to the EAU guidelines, the UTUC on the left side also belongs to the high-risk stratification, like the right side, which indicates a RNU surgery. Due to the patient's strong desire for kidney preservation and refusal of hemodialysis, neoadjuvant immunotherapy and chemotherapy followed by endoscopic resection surgery were performed, and the tumor on the left achieved partial response (PR). However, since there are no more cases of UTUC, the effect of chemoimmunotherapy on PD-L1 negative UTUC still needs to be confirmed. One of the limitations was that UTUC tissues on each side should have performed high-throughput gene sequence, to give a precise guide for subsequent therapy.

For patients with locally advanced or metastatic UTUC, the first-line treatment is mainly a cisplatin-based chemotherapy regimen (such as a GC regimen) with a high objective response rate (ORR) of about 50%. In a systematic review and meta-analysis, adjuvant chemotherapy was superior to immunotherapy in patients after radical surgery for UTUC and bladder carcinoma (n = 2444) ^[9]. Therefore, chemotherapy is still recommended as first-line treatment for patients who can tolerate platinum chemotherapy.

Immune checkpoint inhibitors (ICIs), are approved for patients with locally advanced or metastatic UTUC who cannot tolerate platinum-based chemotherapy and have high PD-L1 expression. ICIs have shown lasting efficacy as first- and second-line therapy in patients with advanced urothelial carcinoma ^[10]. ICIs were associated with a lower incidence of adverse reactions than chemotherapy ^[11]. Based on the reported multicenter randomized controlled clinical results of IMvigor210 and Keynote-052, ICIs demonstrated efficacy in locally advanced or metastatic urothelial carcinomas, with overall response rate (ORR) of 39% (Mvigor210) and 22%(Keynote-052) in subtype UTUC, respectively ^{[12, 13]}. Chemotherapy and immunotherapy are complementary to a certain extent. However, the multi-center, randomized controlled clinical trials Mvigor130, Keynote-361, and DANUBE have been carried out in UC. The results showed that chemotherapy combined immunotherapy failed to significantly improve patients' OS time and PFS time ^[14–16]. One of the factors leading to these differences may be the expression status of PD-L1 of patients. But curiously in this case, the sensitivity of her left tumor, which was negative for PD-L1, to immunotherapy varied at different stages, with initial benefit and poor follow-up. In the future, how to activate PD-L1 expression of tumors may be a solution for improving the OS time and PFS time of PD-L1 negative patients to immunotherapy.

We reported a rare metachronous bilateral UTUC case. After radical surgery of the right UTUC, for kidney sparing request from the patient, neoadjuvant chemoimmunotherapy followed by RIRS and adjuvant immunotherapy of the left UTUC, this patient reached a stable state with no disease progression and partial remission of the left UTUC. Our report provides new ideas for the treatment of bilateral UTUC.

Acknowledgements

Author Contributions: (I) Conception and design: Haohao Huang, Tiejun Pan; (II) Administrative support: Chunhui Yan and Jiarong Yang; (III) Provision of study materials or patients: Wei Liu and Qintao Hu; (IV) Collection and assembly of data: Hongzhe tian and Wei Liu; (V) Data analysis and interpretation: Jiarong Yang and Chunhui Yan; (VI) Manuscript writing and revising: Hongzhe tian and Haohao Huang; (VII) Final approval of manuscript: All authors.

Funding: Natural Science Foundation of Hubei Province (No.2020CFB215), and supporting plan of postdoctoral Workstation in China (No.BSH021). Natural Science Foundation of Hubei Province (2022CFB883). China Postdoctoral Science Foundation (2021MD703960). General Hospital of Central Theater Command of Chinese People’s Liberation Army Foundation (ZZYCZ202107). General Hospital Of Central Theater Command and Hubei Key Laboratory of Central Nervous System Tumor and Intervention Foundation (ZZYKF202202).

Availability of data and materials: Not applicable

Ethics approval and consent to participate

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013).

Consent for publication: Written informed consent was obtained from the patients for the publication of this case report.

Competing interests: The authors declare no competing interests.

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No competing interests reported.

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A metachronous bilateral upper urinary tract urothelial carcinoma achieved partial remission by multiple treatment modalities: A case report and literature review

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