Currently, treatment recommendations for small-cell urothelial cancer (SCUC) are based on anecdotal case reports and small retrospective series. We now report results from the first phase II clinical ...trial developed exclusively for SCUC, to our knowledge.
From 2001 to 2006, 30 patients with SCUC provided consent and were treated with alternating doublet chemotherapy. Patients with surgically resectable disease (< or = cT4aN0M0) received a total of four cycles of neoadjuvant chemotherapy, whereas those with unresectable disease (> or = cT4b, N+, or M+) received two cycles beyond maximal response.
Eighteen patients with surgically resectable SCUC received neoadjuvant treatment with a median overall survival (OS) of 58 months; 13 of these patients remain alive and cancer free. For patients with cT2N0M0 SCUC, the 5-year OS rate is 80%; only one of four patients with cT3b-4aN0M0 remains alive (median OS, 37.8 months). For 12 patients with unresectable or metastatic SCUC, the median OS was 13.3 months. Chemotherapy was well tolerated, with transfusion, neutropenic fever, and infection remaining the most frequent grade 3 and 4 toxicities. There was only one postsurgical death. Brain metastases were strongly associated with more advanced-stage disease, developing in eight of 16 patients with either bulky tumors (> or = cT3b) or metastatic disease (P = .004).
These clinical trial results are consistent with previously reported retrospective data demonstrating long-term survival with four cycles of neoadjuvant chemotherapy for surgically resectable SCUC. Once metastases develop, the prognosis remains poor. The strong positive association between disease stage and brain metastases highlights a patient subset that may potentially benefit from prophylactic cranial irradiation.
Whole-genome analyses have revealed that muscle-invasive bladder cancers (MIBCs) are heterogeneous and can be grouped into basal and luminal subtypes that are highly reminiscent of those found in ...breast cancer. Basal MIBCs are enriched with squamous and sarcomatoid features and are associated with advanced stage and metastatic disease at presentation. Like basal breast cancers, basal bladder tumours contain a claudin-low subtype that is enriched with biomarkers characteristic of epithelial-to-mesenchymal transition. The stem cell transcription factor ΔNp63α controls basal MIBC gene expression, just as it does in basal breast cancers. Luminal MIBCs are enriched with activating FGFR3 and ERBB3 mutations and ERBB2 amplifications, and their gene expression profiles are controlled by peroxisome proliferator activator receptor γ (PPARγ) and possibly also by oestrogen receptor activation. Luminal bladder cancers can be further subdivided into two subtypes, p53-like and luminal, which can be distinguished from one another by different levels of biomarkers that are characteristic of stromal infiltration, cell cycle progression, and proliferation. Importantly, basal bladder cancers are intrinsically aggressive, but are highly sensitive to cisplatin-based combination chemotherapy. Although the luminal subtypes are not as intrinsically aggressive as basal cancers, p53-like tumours are resistant to chemotherapy and might, therefore, represent a problem for treated patients.
Treatment with lenvatinib plus pembrolizumab had a manageable safety profile and did not show superior antitumor efficacy to treatment with pembrolizumab plus placebo. First-line pembrolizumab ...monotherapy remains a standard of care for certain patients who are ineligible for cisplatin-based or any platinum-based chemotherapy.
Pembrolizumab plus lenvatinib has shown antitumor activity and acceptable safety in patients with platinum-refractory urothelial carcinoma (UC).
To evaluate pembrolizumab plus either lenvatinib or placebo as first-line therapy for advanced UC in the phase 3 LEAP-011 study.
Patients with advanced UC who were ineligible for cisplatin-based therapy or any platinum-based chemotherapy were enrolled.
Patients were randomly assigned (1:1) to pembrolizumab 200 mg intravenously every 3 wk plus either lenvatinib 20 mg or placebo orally once daily.
Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). An external data monitoring committee (DMC) regularly reviewed safety and efficacy data every 3 mo.
Between June 25, 2019 and July 21, 2021, 487 patients were allocated to receive lenvatinib plus pembrolizumab (n = 245) or placebo plus pembrolizumab (n = 242). The median time from randomization to the data cutoff date (July 26, 2021) was 12.8 mo (interquartile range, 6.9–19.3). The median PFS was 4.5 mo in the combination arm and 4.0 mo in the pembrolizumab arm (hazard ratio HR 0.90 95% confidence interval {CI} 0.72–1.14). The median OS was 11.8 mo for the combination arm and 12.9 mo for the pembrolizumab arm (HR 1.14 95% CI 0.87–1.48). Grade 3–5 adverse events attributed to trial treatment occurred in 123 of 241 patients (51%) treated with lenvatinib plus pembrolizumab and in 66 of 242 patients (27%) treated with placebo plus pembrolizumab. This trial was terminated earlier than initially planned based on recommendation from the DMC.
The benefit-to-risk ratio for first-line lenvatinib plus pembrolizumab was not considered favorable versus pembrolizumab plus placebo as first-line therapy in patients with advanced UC.
Lenvatinib plus pembrolizumab was not more effective than pembrolizumab plus placebo in patients with advanced urothelial carcinoma.
Bempegaldesleukin plus nivolumab was well tolerated and showed antitumor activity in this preliminary investigation of first-line treatment in patients with locally advanced or metastatic urothelial ...carcinoma in a phase 2 cohort from the open-label, multicohort phase 1/2 PIVOT-02 study.
Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients.
To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study.
This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41).
Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk.
The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8+ tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response.
The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval CI 2.1–8.7) and median OS was 23.7 mo (95% CI 15.8–not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design.
BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC.
We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients.
This trial is registered at ClinicalTrials.gov as NCT02983045.
The inherent toxicity associated with cisplatin-based therapy in the typical urothelial cancer population of elderly and frail patients ensures that it is unlikely to be given to a substantial ...proportion of patients. ...recommendations about adjuvant chemotherapy will remain highly relevant either until a non-toxic curative therapy is discovered, or until the patients who truly benefit from these potentially toxic regimens can be accurately identified. Zephyr/Science Photo Library AOS-R has received grants from the US National Institutes of Health, Genentech, Michael and Sherry Sutton Fund for Urothelial Cancer, Dendreon, Bristol-Myers Squibb, and Millenium, and has received other financial support from Dendreon, Bristol-Myers Squibb, Janssen, Celgene, Threshold, Merck, and the US National Comprehensive Cancer Network.
Summary Urachal carcinoma is a rare tumor that has not been well studied. To determine the pathologic and clinical features of this disease, we retrospectively evaluated 46 cases from our surgical ...pathology files. The patients included 16 women and 30 men, with a mean age of 53.4 years (range, 28-82 years). Forty patients had undergone cystectomy, and the remaining 6 had undergone transurethral bladder biopsy. Most tumors were located at the dome (n = 44); only 2 were located at both the dome and anterior wall. All tumors consisted of adenocarcinoma, including mucinous (n = 36), enteric (n = 7), not otherwise specified (n = 2), and signet ring cell (n = 1) types. Focal areas of signet ring cell features were present in 23 cases, but urothelial carcinoma in situ was not identified in any cases. The tumors invaded the muscularis propria (n = 8), perivesical adipose tissue (n = 27), and abdominal wall (n = 3). Twenty-five patients had died of cancer at a mean of 32 months (range, 12-74 months), and 21 patients were alive at a mean of 65 months (range, 7-230 months). The median cancer-specific survival time of urachal adenocarcinoma patients was 45 months, which was significantly longer than that of bladder urothelial carcinoma patients with similar-stage disease ( P = .047). Patients' cancer-specific survival was associated with tumor stage according to the Sheldon, Mayo, and TNM staging systems. In conclusion, urachal carcinomas are predominantly composed of invasive adenocarcinomas, which commonly demonstrate mucinous features. Most tumors present at advanced stages but are still associated with a better survival rate than bladder urothelial carcinomas.
Urachal carcinoma is a rare non-urothelial malignancy frequently involving the midline or dome of the bladder due to direct extension from the urachal ligament, the structure from which this tumor ...arises. Nearly always an adenocarcinoma, it is important to recognize the diagnosis upfront due to the differences in surgery and chemotherapy as compared to traditional urothelial cancer. For patients with surgically resectable tumors, a partial cystectomy with en-bloc resection of the urachal ligament with the bladder dome and umbilicus is required to appropriately control the tumor. Leaving the umbilicus in place provides inadequate control and has been associated with a higher risk of relapse. A lymph node dissection also may help in the control of this cancer. While there is yet no proven role for neoadjuvant or adjuvant chemotherapy, combinations of 5-fluoruracil with cisplatin are active in those with metastases. Since the activity of this combination also has lead to surgical consolidation of node-positive disease, one might consider the potential for benefit from perioperative chemotherapy. A higher risk of relapse following surgery has been reported in those with positive margins, lymph node involvement, involvement of the peritoneal surface, or where the umbilicus was not resected en-bloc, and may predict a group of patients where the risk of relapse is sufficiently high enough to consider adjuvant chemotherapy. A recent clinical trial of 5-fluorouracil, leucovorin, gemcitabine, and cisplatin has recently completed accrual in metastatic urachal carcinoma, with patients now in long-term follow-up.
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