The efficacy and safety of tislelizumab combined with gemcitabine plus cisplatin in the treatment of postoperative patients with muscle-invasive upper tract urothelial carcinoma
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SUBMITTER: Zhang J
PROVIDER: S-EPMC10863243 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundInvasive urothelial carcinoma (UC) with squamous and glandular differentiation is a highly malignant and complicated pathological subtype, and the standard care is radical cystectomy (RC). However, urinary diversion after RC significantly reduces patient quality of life, thus bladder-sparing therapy has become a research hotspot in this field. Recently, five immune checkpoint inhibitors have been approved for systemic therapy of locally advanced or metastatic bladder cancer by the Food and Drug Administration, but the efficacy of immunotherapy combined with chemotherapy for invasive UC is still unknown, especially for pathological subtypes with squamous and glandular differentiation.Case summaryWe report the case of a 60-year-old male who complained of repetitive painless gross hematuria and was diagnosed with muscle-invasive bladder cancer with squamous and glandular differentiation, defined as cT3N1M0 according to the American Joint Committee on Cancer, who had a strong desire to preserve the bladder. Immunohistochemical staining revealed that programmed cell death-ligand 1 (PD-L1) expression in the tumor was positive. Thus, a transurethral resection to maximize removal of the bladder tumor was performed under cystoscopy, and the patient subsequently received a combination of chemotherapy (cisplatin/gemcitabine) and immunotherapy (tislelizumab) treatment. No tumor recurrence in the bladder was observed following pathological and imaging examination after 2 cycles and 4 cycles of treatment, respectively. The patient achieved bladder preservation and has been tumor-free for more than two years.ConclusionThis case shows that the combination of chemotherapy and immunotherapy might be an effective and safe treatment strategy for PD-L1 expression positive UC with divergent histologic differentiation.
| S-EPMC9979306 | biostudies-literature
Project description:Although several programmed cell death (PD)-1 inhibitors are approved for the first-line treatment of advanced urothelial carcinoma, their efficacy remains unknown in cisplatin-ineligible patients with upper tract urothelial carcinoma (UTUC) compared with gemcitabine plus carboplatin. Data for patients with UTUC were retrospectively retrieved from the electronic medical records of nine institutions between 2018 and 2021. Patients considered ineligible for cisplatin who received either PD-1 inhibitors (n = 70) or gemcitabine plus carboplatin (n = 53) were included. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The objective response rate (ORR) was comparable between the PD-1 inhibitor and carboplatin-gemcitabine groups (38.6% versus 41.5%). Median PFS was 5.0 months (95% confidence interval [CI]: 2.0-8.0) in the PD-1 inhibitor group, versus 7.0 months (95% CI: 5.8-8.2) in the carboplatin-gemcitabine group (hazard ratio [HR] = 0.741, 95% CI: 0.485-1.132, p = .166). Median OS was 18 months (95% CI: 4.1-31.9) in the PD-1 inhibitor group, compared with 14 months (95% CI: 12.1-15.9) in the carboplatin-gemcitabine group (HR = 0.731, 95% CI: 0.426-1.256, p = .257). The duration of response was significantly longer in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (not reached vs. 9 months, p < .001). Treatment-related adverse events were less frequent in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (57.1% vs. 77.3%). In conclusion, PD-1 inhibitors displayed promising efficacy with less toxicity and longer DOR in the first-line treatment of UTUC in patients ineligible for cisplatin-based chemotherapy.
| S-EPMC9487735 | biostudies-literature
Project description:Introduction and importanceThe feasibility of combined tislelizumab with gemcitabine and cisplatin as a neoadjuvant regimen for muscle-invasive bladder cancer (MIBC) remains to be investigated.Case presentationThe neoadjuvant treatment not only shrunk tumours significantly but also lowered their stages from T4bN1M0, T3N0M0, and T3bN0M0 to pT1, pT0 and pTis, respectively. The treatment suppressed tumour cell proliferation and promoted luminal-to-basal transition.Clinical discussionMIBC is an aggressive bladder cancer with poor prognosis. All three patients with MIBC benefited greatly from the neoadjuvant regimen (tislelizumab + gemcitabine + cisplatin). It appears that the effect of the treatment is independent of the levels of programmed death-ligand 1 nor the subtype of urothelial bladder cancer.ConclusionCombination of tislelizumab with gemcitabine and cisplatin appeared to be a safe and efficacious neoadjuvant therapy for MIBC.
| S-EPMC10783357 | biostudies-literature
Project description:BackgroundGemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S-1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC.MethodsWe performed a mulitcenter, randomized phase III trial across 39 centers. Enrolled patients were randomly allocated (1:1) to either the GCS or GC arm. The GCS regimen comprised gemcitabine (1000 mg/m2 ) and cisplatin (25 mg/m2 ) infusion on day 1 and 80 mg/m2 of S-1 on days 1-7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778.ResultsBetween July 2014 and February 2016, 246 patients were enrolled. The median OS and 1-year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio [HR] 0.79, 90% confidence interval [CI]: 0.628-0.996; P = .046 [stratified log-rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577-0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms.ConclusionsGCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first-line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.
| S-EPMC10086809 | biostudies-literature
Project description:Chemotherapy drugs, such as gemcitabine and cisplatin (GC), are frequently administered to patients with advanced urothelial carcinoma, however the influence of the gut microbiota on their action is unclear. Thus, we investigated the effects of GC on the gut microbiome and determined whether oral supplementation with a probiotics mixture of Lactobacillus casei Shirota and Bifidobacterium breve enhanced the anti-tumor immune response. After subcutaneous inoculation with MBT2 murine bladder cancer cells, syngenic C3H mice were randomly allocated into eight groups. The gut microbiome cluster pattern was altered in both the GC and oral probiotics groups (p = 0.025). Both tumor-bearing conditions (no treatment) and GC chemotherapy influenced Pseudoclostridium, Robinsoniella, Merdimonas, and Phocea in the gut. Furthermore, comparison of the GC-treated and GC + probiotics groups revealed an association of four methyltransferase family enzymes and two short-change fatty acid-related enzymes with oral probiotics use. A significant difference in tumor volume was observed between the GC and GC + probiotics groups at week 2 of treatment. Additionally, decreased recruitment of cancer-associated fibroblasts and regulatory T cells, and activation of CD8+ T cells and dendritic cells were observed in the tumor microenvironment. Our findings reveal the positive effects of a probiotics mixture of Lactobacillus and Bifidobacterium in enhancing anti-tumor effects through the gut-tumor immune response axis. Future clinical trials are needed to evaluate the full benefits of this novel supplement with oral probiotics in patients with advanced urothelial carcinoma.
| S-EPMC9986082 | biostudies-literature
Project description:Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0-202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence.
| S-EPMC10859621 | biostudies-literature
Project description:This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.
| S-EPMC7935810 | biostudies-literature
Project description:BackgroundMetastatic upper tract urothelial carcinoma (mUTUC) is a malignant cancer associated with poor prognosis. Few studies have investigated the clinical outcome of a recently developed combination regimen of programmed cell death 1 (PD-1) inhibitor plus nab-paclitaxel in mUTUC.MethodsWe retrospectively retrieved data from the electronic medical records of cisplatin-ineligible or cisplatin-refractory mUTUC patients from five participating Chinese centers, who received treatment of PD-1 inhibitor plus nab-paclitaxel between April 2018 and January 2022. Clinical response was assessed according to Response Evaluation Criteria in Solid Tumors criteria version 1.1 (RECIST 1.1). Duration of response (DOR), overall survival (OS), and progression-free survival (PFS) were evaluated by the Kaplan-Meier method.ResultsThe confirmed overall response rate (ORR) was 14/34 (41.2%), and the disease control rate (DCR) was 24/34 (70.6%). Complete response (CR) was achieved in one case, partial response (PR) in 13 cases (38.2%), stable disease (SD) in 10 cases (29.4%), and progressive disease (PD) occurred in 10 cases (29.4%). After a median follow-up period of 16.0 months [95% confidence interval (CI): 9.9-22.1], 14 deaths were reported, with a median OS of 15.0 months (95% CI: 9.9-20.1); 22 progressions were reported, with a median PFS of 6.0 months (95% CI: 2.4-9.6). Patients with visceral metastasis had a similar PFS [hazard ratio (HR): 1.28, 95% CI: 0.53-3.09, P=0.574) and OS (HR: 1.94, 95% CI: 0.64-5.83, P=0.279] to patients with lymph node metastasis only.ConclusionsThis real-world study suggests that PD-1 inhibitor plus nab-paclitaxel is effective in cisplatin-ineligible and cisplatin-refractory mUTUC patients with acceptable toxicity, especially for patients with visceral metastasis.
| S-EPMC10560336 | biostudies-literature
Project description:BackgroundIntravesical recurrence (IVR) after surgery for upper tract urothelial carcinoma (UTUC) is a clinical problem. We investigated if preoperative invasive diagnostic modalities (IDM) such as antegrade/retrograde uretero-pyelography and/or selective urine cytology/barbotage, and URS with or without concomitant biopsy are associated with IVR after radical surgery for UTUC. Risk of death from urothelial cancer and all causes was investigated as secondary outcomes.MethodsWe investigated a population-based cohort of 1038 consecutive patients subjected to radical surgery for UTUC 2015-2019 in Sweden, using the Bladder Cancer Data Base Sweden (BladderBaSe 2.0), comprising all patients in the Swedish National Registry of Urinary Bladder Cancer. Risk estimates of IVR, death from urothelial cancer, and all causes was assessed using multivariable Cox regression models.ResultsThe study included 536 cases with and 502 without preoperative IDM. IDM was associated with increased risk of IVR (HR 1.24, 95% CI 1.03-1.52) and risk of urothelial cancer death (HR 1.56, CI 1.12-2.18), compared to no IDM after a median follow-up of 1.3 yrs. Stratified analysis for tumor location showed that IDM was associated with risk of IVR in ureteric cancer (HR 1.66, 95% CI 1.21-2.28) but not in renal pelvic cancer (HR 1.07, 95% CI 0.81-1.41). Limitations included the observational setting and the lack of variables such as tumour grade, multifocality and preoperative hydronephrosis.ConclusionsWorse outcomes for patients subjected to preoperative IDM highlight the need for carefully considering diagnostic decisions for UTUC patients, specifically in tumours located in the ureter.
| S-EPMC9894449 | biostudies-literature
Project description:Drug-induced hyponatremia is an adverse reaction with accelerated electrolyte disturbance. This study reported a rare case of delayed hyponatremia in a 68year-old female with recurrent upper tract urothelial carcinoma after Gemcitabine plus Cisplatin (GC) and Tislelizumab treatment. She had left ureter surgery, recurrence a year later with mildly abnormal kidney function (glomerular filtration rate (GFR) was 54.9 ml/min). After the first cycle of GC plus Tislelizumab, severe hyponatremia leading to life-threatening conditions occurred eight days later. Hypothesizing Cisplatin as the cause, its usage was modified in the second cycle (40mg/day for three days). No severe hyponatremia followed. CT showed partial remission. From the third cycle, due to grade IV bone marrow suppression, she had Tislelizumab alone. Now, she is on 21-day Tislelizumab maintenance with a stable tumor status. Low-dose continuous Cisplatin may suit patients with borderline or mildly abnormal renal function (GFR: 40-60mL/min) better than single full-dose use. Tislelizumab alone for maintenance may be an option for those intolerant of chemotherapy. But Na+ decrease may be related to Tirelizumab or Gemcitabine, needing more clinical observation and experiments.
| S-EPMC11769789 | biostudies-literature