Benjamin P. Saylor is associate editor of Urology Times, an Advanstar Communications publication.

Benjamin P. Saylor

Investigators have reported an association between high urinary cotinine (UC) levels and non–muscle invasive bladder cancer (NMIBC) recurrence in smokers, with a 4-fold greater risk of recurrence in patients with high levels of the nicotine metabolite.

The research was presented at the 2021 European Association of Urology Annual Congress by Maher Abdessater, MD, MPH, of Notre Dame de Secours University Hospital in Lebanon.

“[Cotinine is] the best marker for tobacco exposure, but little is known about its carcinogenic effect. Additionally, little is known whether the recurrence of bladder cancer can be related to the nicotine metabolites eliminated in urine,” Abdessater explained. To this end, the investigators sought to evaluate the association between UC level and NMIBC recurrence.

The investigators performed a cross sectional study between January 2018 and June 2019. The study enrolled patients who were smokers, received a diagnosis of NMIBC that was treated with resection only, and who were presenting for a follow-up cystoscopy. Cotinine was measured on a sample of voided urine prior to cystoscopy. Patients with a UC level less than 550 ng/mL were considered moderate smokers, whereas patients with a UC level greater than 550 ng/mL were considered heavy smokers. Tumor recurrence was evaluated via cystoscopy. A Fisher Exact Test was used for statistical analysis.

The cohort included 135 patients aged 36 to 78 years (mean age, 64). All patients were Caucasian and had a similar profile of exposure to carcinogens related to bladder cancer. Eighty-two percent of patients were male, and 12% were female.

The investigators found that 40.74% of the cohort were moderate smokers and 59.26% were heavy smokers. Overall tumor recurrence rate was 51.85%.

“Specifically, tumor recurrence was observed in 75% of heavy smokers and 18% of moderate smokers. This result was statistically significant,” Abdessater said, with a relative risk of 4.16 (

In a news release about the results, Abdessater discussed the ease of use and low cost of using cotinine levels to detect bladder cancer recurrence.

“One of the major advantages of using cotinine is that it can be detected using a simple urine test, which is a cheaper and less invasive alternative to cystoscopy. It can also pick up where patients are not accurately reporting their smoking levels, or where passive smoking combined with active smoking is pushing them into the heavy smoker category."

“Additional prospective studies are needed to better understand the relation between urinary cotinine levels and bladder cancer and to evaluate its usefulness in bladder cancer surveillance,” Abdessater said in his concluding remarks.

Although the data reported by the investigators were from the period between January 2018 and June 2019, the study is ongoing, and the investigators are seeking additional institutions to collaborate on the effort, according to the news release.

Commenting on the results in the news release, EAU Secretary-General Adjunct Professor Arnulf Stenzl said, “This study definitely gives food for thought, although as yet the findings are only in a small number of patients. We now need to test this in a larger trial, and also look at more precise indications of smoking levels and the type of cigarettes involved—particularly whether they are filtered or not. It would be interesting as well to look at whether cotinine levels are higher in patients with other risk factors for bladder cancer, such as exposure to arsenic or industrial benzole."

1. Abdessater M, Kanbar A, El Khoury J, et al. Role of urinary cotinine level in the recurrence of non-muscle invasive bladder cancer. Paper presented at: 2021 European Association of Urology Annual Congress. July 8-12; virtual. Abstract P0726

2. Nicotine by-product can predict recurrence of cancer. News release. European Association of Urology. July 8, 2021. Accessed July 12, 2021. https://www.eurekalert.org/pub_releases/2021-07/eaou-nbc070721.php

Articles

Investigators report that high urinary cotinine levels are associated with a greater risk of recurrence in smokers.

Nicotine metabolite linked to NMIBC recurrence

Several abstracts presented at the 2021 ASCO Annual Meeting highlighted how integrating immune checkpoint inhibitors into bladder-sparing approaches may enhance the efficacy of these strategies in patients with bladder cancer.

“The biggest impact from studies at ASCO this year in the bladder cancer field had to do with bladder-sparing approaches, and the studies really mark a ‘new dawn’ in bladder-sparing approaches in bladder cancer in terms of integrating immune checkpoint blockade with radiation or even without radiation to achieve bladder sparing,” Matthew Galsky, MD, said in an interview with 

“This is an approach that has, of course, been used for decades—it is a standard of care and there is level 1 evidence for the approach—although it is not practiced as frequently in some parts of the world as others. And it could be that the integration of a new treatment modality into the bladder-sparing arena is a tipping point that is needed to really have the community [as a whole] embrace this as a reasonable option for patients with bladder cancer,” added Galsky, a professor of Medicine and acting chief of the Division of Hematology and Medical Oncology for the Mount Sinai Health System.

The following 3 ASCO abstracts in particular demonstrated the emergence of immune checkpoint inhibitors as a major component of the bladder-sparing treatment paradigm.

Findings from the phase 2 HCRN GU16-257 trial showed that combining transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy is a promising bladder-sparing approach in patients with muscle-invasive bladder cancer (MIBC).

The study enrolled 76 patients with cisplatin-eligible cT2 to T4aN0M0 clinically localized urothelial bladder cancer.

Patients initially received 4 cycles of gemcitabine plus cisplatin plus nivolumab. Following these 4 cycles, all patients underwent clinical restaging, including MRI/CT of the bladder (unless otherwise contraindicated), urine cytology, and cystoscopy with bladder/prostatic urethral biopsies. Patients with a clinical complete response (CR) could then opt to proceed with cystectomy or proceed without cystectomy and instead receive an additional 4 months of single-agent nivolumab. For patients without a clinical CR, a cystectomy was recommended.

At the time of the data cutoff, 64 patients had completed clinical restaging. Of these patients, 31 (48%) achieved a clinical CR. Thirty of these patients chose not to undergo cystectomy and instead receive an additional 4 months of nivolumab monotherapy. Only 1 patient opted for immediate cystectomy. On surgical pathology, that patient had a low-grade papillary tumor. The remaining 33 patients did not reach a clinical CR and cystectomy was recommended.

All 31 patients who achieved a clinical CR were still alive at the cutoff and, at the time of the data reporting, there were a number of patients who were 12 months out since treatment initiation who had no recurrence and whose bladders remained intact.

An early analysis of pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) for MIBC found that the protocol demonstrated safety and efficacy.

The phase 2 trial included patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic RT or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m

 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve patients (25%) had dose reductions of gemcitabine. One patient (2%) discontinued RT/gemcitabine, 3 (6%) discontinued gemcitabine only, and 4 (8%) discontinued pembrolizumab.

Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort.

The investigators reported a 1-year bladder-intact disease-free survival (DFS) rate in the efficacy cohort of 88%. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

Durvalumab, tremelimumab, and radiotherapy

The phase 2 IMMUNOPRESERVE-SOGUG trial showed that a regimen combining transurethral resection followed by duel immune checkpoint blockade with durvalumab (Imfinzi) and tremelimumab along with concurrent RT was effective at inducing responses and leading to bladder sparing in patients with localized MIBC.

The study enrolled 32 patients with clinical stage cT2 to 4aN0M0 disease with an ECOG performance status of 0 to 1 who were either medically ineligible for radical cystectomy or refused to receive the procedure.

All patients received transurethral resection, after which they were administered durvalumab plus tremelimumab. Two weeks following the start of immunotherapy, patients initiated normofractionated external-beam RT. Salvage cystectomy was offered to patients with residual or relapsed MIBC.

Overall, 81% (n = 26) of patients achieved a CR. Two patients did not respond and 4 patients were not evaluable (rejection, clinical impairment, COVID-19–related death, and death related to peritonitis). The 12-month DFS and overall survival rates were 76% and 87%, respectively.

At a median follow-up of 12.7 months (range, 5.3-24.5), the 12-month bladder intact DFS rate was 73%. Two patients received salvage cystectomy (both late, not immediate).

1. Galsky MD, Daneshmand S, Chan KG et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257. 

 39, 2021 (suppl 15; abstr 4503). doi: 10.1200/JCO.2021.39.15_suppl.4503

2. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. 

, 2021 (suppl 15; abstr 4504). doi: 10.1200/JCO.2021.39.15_suppl.4504

3. Garcia del Muro X, Valderrama BP, Medina A, et al. Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy (RT) in patients (pts) with localized muscle invasive bladder cancer (MIBC) treated with a selective bladder preservation approach: IMMUNOPRESERVE-SOGUG trial. 

 39, 2021 (suppl 15; abstr 4505). doi: 10.1200/JCO.2021.39.15_suppl.4505

Integrating immunotherapy into bladder-sparing approaches may enhance the efficacy and uptake of these strategies in bladder cancer. 

Can immunotherapy propel bladder sparing–approaches to prime time?

Findings of a study examining comprehensive genomic profiling shed more light on disparities in prostate cancer care.

Among the notable findings were that patients with African ancestry are less likely to receive comprehensive genomic profiling earlier in their treatment course, and are also less likely to be treated on clinical trials.

For the study, which was presented at the 2021 ASCO Annual meeting by Brandon A. Mahal, MD, 11,741 patients with prostate cancer with comprehensive genomic profiling done as part of routine care were evaluated, of whom 12% had African ancestry. A single-nucleotide polymorphism-based approach was used to infer predominant ancestry. In addition, the investigators queried a de-identified clinico-genomic database (CGDB) of 897 evaluable patients with prostate cancer to examine trends in comprehensive genomic profiling utilization, treatment patterns, and clinical trial enrollment.

In the larger cohort, the median age was 67 years and 98% had adenocarcinoma histology. The median age of patients with African ancestry was 64 years vs 67 years for patients with European ancestry (

<.001). In addition, 4.2% of patients with African ancestry were younger than 50 years of age vs 2.5% of patients with European ancestry.

Several gene alterations were significantly enriched in patients with African ancestry versus patients with European ancestry in 

Gene alterations that occurred less frequently in patients with African ancestry versus European ancestry included 

rearrangements also occurred less frequently in patients with African ancestry (15% vs 33%).

When comparing targetable gene alterations, the investigators found similar rates of actionable genes (22.1% in patients with African ancestry vs 22.4% in patients with European ancestry) as well as DNA damage response-associated genes (17.8% in patients with African ancestry vs 18.7% in patients with European ancestry). Mahal noted, however, that 

alterations were slightly enriched in patients with African ancestry (5.0% vs 3.2%; 

Turning to the CGDB cohort, Mahal reported that 91% of patients with African ancestry were treated in the community versus 63% of patients with European ancestry.

“Notably, less than 10% of individuals with African ancestry were treated in an academic setting, whereas 37% of individuals with European ancestry were treated in an academic setting,” said Mahal, assistant professor of radiation oncology and assistant director of community outreach and engagement, University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.

Eighty-five percent of patients with African ancestry had castration-resistant prostate cancer versus 72% of patients with European ancestry.

Also in the CGDB cohort, it was noted that patients with African ancestry received a median of 2 lines of therapy prior to undergoing comprehensive genomic profiling, compared with 1 line of therapy in patients with European ancestry.

“While there were no significant differences in the use of targeted therapies, including PARP inhibitors or other therapies, only 11% of African-ancestry patients received a clinical study drug compared with 30% of European-ancestry patients,” Mahal said. This was observed both for patients treated in the academic setting as well as for patients treated in the community.

“Please note that these findings are from a small cohort, and in particular, in the academic setting, there were only 5 individuals with African ancestry that were treated at academic centers and therefore, these findings must be interpreted within these limitations,” Mahal noted as a caveat.

“Ultimately, equitable use of comprehensive genomic profile testing, clinical trial enrollment, and subsequent precision medicine treatment pathways could lead to a major reduction in disparities,” Mahal concluded.

1. Sivakumar S, Lee JK, Moore JA, et al. Ancestral characterization of the genomic landscape, comprehensive genomic profiling utilization, and treatment patterns may inform disparities in advanced prostate cancer: A large-scale analysis. 

 39, 2021 (suppl 15; abstr 5003). doi: 10.1200/JCO.2021.39.15_suppl.5003

Patients with African ancestry were also less likely to be treated on clinical trials versus patients with European ancestry, the investigators reported.

Men with African ancestry less likely to receive early genomic profiling in prostate cancer

An early analysis of pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) for muscle-invasive bladder cancer (MIBC) found that the protocol demonstrated safety and efficacy.

Findings from the phase 2 trial (NCT02621151) were reported at the 2021 ASCO Annual Meeting1 by lead author Arjun V. Balar, MD, an associate professor of medicine at the NYU Grossman School of Medicine and genitourinary medical oncology program director at NYU Langone’s Perlmutter Cancer Center, New York.

The trial included patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic radiotherapy or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

The median age of the entire population was 74 years (range, 51-97). Thirty-nine patients (72%) were male, and the majority of patients (n = 38; 70%) had T2N0 disease at baseline, with T3N0 and T4N0 disease present in 14 (26%) and 2 (4%) men, respectively. Regarding histology, 34 patients (63%) had conventional urothelial carcinoma, 20 (37%) had divergent differentiation, and 14 (26%) had carcinoma in situ. Hydronephrosis was present in 6 patients (11%). Fifteen patients (28%) were not candidates for surgery, whereas 39 patients (72%) declined radical cystectomy.

The primary end point of the study was 2-year bladder-intact disease-free survival (BIDFS), which was defined as muscle-invasive recurrence, regional or distant metastases, need for cystectomy, or death. The key secondary end points were safety, 12 weeks’ complete response rate, metastases-free survival, and overall survival.

Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort. The investigators reported a 1-year BIDFS rate in the efficacy cohort of 88%, “which is quite encouraging, but obviously this is at a median follow-up of 14.6 months for the population here,” Balar said. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

In the efficacy cohort, the majority of treatment-related toxicities were grade 1 and 2, with fatigue, nausea, diarrhea, urinary urgency, maculopapular rash, decreased platelets, and anorexia observed in 20% or more of the efficacy cohort. Grade 3 and 4 treatment-related toxicities included diarrhea, decreased lymphocyte count, colitis, fatigue, anemia, urinary tract pain, hypokalemia, hyponatremia, urinary tract infection, neutropenia, febrile neutropenia, protein-losing enteropathy, immune-related polyneuropathy, and colonic perforation. Balar noted that 1 patient died of fungemia that was not related to study treatment.

Regarding toxicities suspected to be related to pembrolizumab, grade 1 and 2 fatigue, maculopapular rash, alanine aminotransferase, and pruritis were seen in 10% or more of the efficacy cohort. Grade 3 toxicities suspected to be related to pembrolizumab included immune-related protein-losing enteropathy, immune-related polyneuropathy, neutropenia, and urinary tract infection. One grade 4 case of colonic perforation was observed. In addition, 9 patients (19%) were treated with systemic corticosteroids for the management of an immune-related adverse event.

In his concluding remarks, Balar said, “Trimodality bladder preservation therapy is an effective nonsurgical option for patients with muscle-invasive bladder cancer and with curative intent.”

Balar also noted that correlative studies on serially collected tumor tissue and blood are underway; these studies will evaluate the local and systemic impact of pembrolizumab added to chemoradiation on antitumor immunity.

“What we need are randomized studies…and the ongoing studies SWOG 1806 [NCT03775265] and KEYNOTE-992 [NCT04241185] will better define the role of immunotherapy added to bladder preservation therapy,” Balar said.

1. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. 

A 1-year bladder-intact disease-free survival rate of 89% was observed across the entire phase 2 study cohort.

Benjamin P. Saylor

Articles

Nicotine metabolite linked to NMIBC recurrence

Can immunotherapy propel bladder sparing–approaches to prime time?

Men with African ancestry less likely to receive early genomic profiling in prostate cancer

Bladder-sparing, trimodal pembrolizumab-based regimen shows promise in MIBC