Lindsay Fischer

Concurrent treatment with intravenous (IV) vitamin C and chemotherapy may benefit cisplatin-ineligible patients with locally advanced muscle-invasive bladder cancer, according to results presented at the 2022 AUA Annual Meeting.

The data specifically showed that patients who received vitamin C had more success with gemcitabine and carboplatin (GCa).

Overall, investigators observed a 30% rate of pathological downstaging (n = 4) among patients who underwent simultaneous treatment with GCa and IV vitamin C, which met the continuation criteria for a stage 2 study. 

Furthermore, among those who experienced a pathological response, 25% achieved a complete response. No treatment-related adverse events were reported.

Of those 12 patients who underwent simultaneous treatment with gemcitabine and carboplatin plus IV vitamin C, 11 underwent cystectomy following treatment, and 1 patient is pending surgery.

The standard of care for patients with locally advanced disease is neoadjuvant cisplatin-based chemotherapy. However, this treatment strategy is not appropriate for all patients; an estimated 40% to 50% of patients have either renal insufficiency, hearing loss, or poor performance status and are therefore ineligible for cisplatin.

The GCa regimen has demonstrated limited success as an alternative treatment for these patients. However, many patients progress directly to cystectomy without realizing the potential survival effect associated with neoadjuvant chemotherapy.

In other models, the IV administration of vitamin C has been found to safely and feasibly enhance outcomes with chemotherapy. For example, a phase 1 trial (NCT00954525) which assessed vitamin C in conjunction with gemcitabine, or gemcitabine plus erlotinib (Tarceva), elicited unexpected stable disease and prolonged survival in patients with advanced pancreatic cancer.

 The regimen was also reported to have good tolerability.

Similarly, a phase 1/2a trial (NCT00772798) not only reported that vitamin C substantially decreased grade 1/2 toxicities in patients with ovarian cancer who were receiving paclitaxel plus carboplatin, but also showed that the combination resulted in prolonged median progression-free survival (PFS). The difference in median PFS between those who did and did not receive IV vitamin C was 25.5 months vs 16.75 months, respectively.

This first-stage analysis (NCT04046094) enrolled 16 and ultimately treated 12 patients with muscle-invasive bladder cancer who were at least 18 years old.

 To be eligible, patients needed to have an ECOG performance status between 0 and 2, as well as adequate organ and marrow functions. Women of child-bearing potential and men whose partners had child-bearing potential needed to consent of prespecified forms of birth control.

Patients were ineligible for enrollment if they were enrolled in any other clinical trials, were currently or anticipating undergoing another investigational agent during the course of the study, diagnosed with any psychiatric or social illness which would inhibit their ability to comply with study requirements, pregnant or breast feeding, had a histology of pure adenocarcinoma, pure squamous cell carcinoma, or pure small cell carcinoma in a TURBT sample, had an uncontrolled or intercurrent illness, or had any prior systematic chemotherapy—not including priori intravesical therapy—or prior radiation to the urinary bladder.

In addition, current tobacco product consumption, as well as a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency, were criteria for exclusion.

Treatment consisted of a single cycle of GCa and IV vitamin C titrated to peak plasms concentration of 350 to 400 mg/dL (~20 mM) for 21 days followed by cystectomy. Patients underwent cystectomy about 4 to 6 weeks following treatment initiation.

Following therapy, patients were followed in accordance with National Comprehensive Cancer Network guidelines. This consisted of standard-of-care bloodwork, physical exams, and imaging studies until either progression or death. Quality of life is being evaluated by Functional Assessment of Cancer Therapy-Bladder (FACT-Bl).

At a mean follow-up of 10.8 months, 3 patients had experienced a recurrence, and 2 patients had died. FACT-BI analysis and clinical follow-up is still ongoing and will be reported at study completion.

Taylor J, Parikh R, Chen Q, et al. Interim analysis NCT04046094: IV vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients (CI-MIBC). Presented at: 2022 American Urological Association Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract LBA01-09. https://bit.ly/3FPQ99n

Monti DA, Mitchell E, Bazzan AJ, et al. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. 

. 2012;7(1):e29794. doi:10.1371/journal.pone.0029794

Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. 

. 2014;6(222):222ra18. doi:10.1126/scitranslmed.3007154

Intravenous (IV) vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients. ClinicalTrials.gov. Updated May 4, 2021. Accessed May 15, 2022. https://clinicaltrials.gov/ct2/show/NCT0404609

Articles

Concurrent treatment with intravenous vitamin C and chemotherapy may benefit cisplatin-ineligible patients with locally advanced muscle-invasive bladder cancer.

Vitamin C add-on may benefit MIBC patients receiving chemo

Findings presented at the 2022 AUA Annual Meeting suggest that immune-related adverse events (irAEs) may be a prognostic marker for improved survival and progression-free outcomes with pembrolizumab (Keytruda) in patients with metastatic urothelial carcinoma (mUC).1

Patients who experienced an irAE while receiving pembrolizumab achieved a median progression-free survival (PFS) of 28 months (95% CI, 11.7-not reached [NR]) compared with 5.4 months (95% CI, 4.0-8.9) among those who did not experience such an event (

<.0001). Furthermore, the median overall survival (OS) among patients who experienced an irAE was 44.3 months (95% CI, 15.9-44.3; 

= .0002) compared with 10.4 months (95% CI, 6.9-19.6) among those who did not (

“PFS was significantly longer in patients with irAEs than [in those] without irAEs,” Kazutaka Nakamura, Department of Urology, Tokiwakai Jyoban Hospital, said in a poster presentation of the findings. “In addition, OS was also significantly longer in patients with irAEs than [in those] without irAEs.”

Study authors noted that the relationship between irAE occurrence and disease prognoses in patients undergoing immune checkpoint inhibition has been observed across various cancer types. Furthermore, multiple studies have reported a positive relationship between irAE incidence and favorable prognoses in patients with mUC receiving pembrolizumab. However, there remains insufficient evidence regarding the prognostic impact of irAEs in this patient population.

Therefore, investigators conducted a retrospective analysis of 95 patients with mUC who received treatment with pembrolizumab as second-line or later-line therapy between January 2018 and February 2022. Patients received pembrolizumab at a dose of either 200 mg every 3 weeks or 400 mg every 6 weeks. Evaluable patients were classified according to their irAE development. Median PFS, OS, overall response rate (ORR), and disease control rate (DCR) were analyzed once the patients began treatment.

Among the 95 evaluable patients, 31 experienced an irAE (32%). Among these patients, a total of 43 irAEs occurred. Notably, there was a significant difference in ECOG performance status greater than 0 between those who did and did not experience an irAE (32% vs 56%, respectively; 

At a median follow-up of 15.1 months (interquartile range, 6.1-22.9), 62 patients (65%) had experienced disease progression and 52 (55%) had died.

Overall, univariate and multivariate analysis demonstrated that irAEs is an independent factor contributing to PFS (HR, 0.33; 95% CI, 0.17-0.62; 

 = .0006). Poor performance status greater than 0 (HR, 2.06; 95% CI, 1.22-3.46; 

 = .0065) and metastases across multiple organs (HR, 1.75; 95% CI, 1.04-2.94; 

 = .0343) were also predictive factors for PFS.

Similarly, these factors were also found to be independent factors for OS as well. The hazard ratio for irAEs was 0.32 (95% CI, 0.16-0.66; 

 = .0018) compared with 2.83 for poor performance status greater than 0 (95% CI, 1.59-5.05; 

 = .0004), 2.04 for modified Glasgow prognostic score greater than 0 (95% CI, 1.09-3.84; 

 = .0267), and 1.90 for multiple metastatic organs (95% CI, 1.07-3.39; 

Lastly, patients who experienced irAEs achieved significantly higher overall response rates than those who did not experience these events (35% vs 9%, respectively; 

= .0019). The difference in disease control rates were significant as well (61% vs 21%, respectively; 

“This multi-institutional study showed that [the] presence of irAE[s] was significantly associated with PFS, OS, ORRs, and DCRs in patients [with mUC] treated with pembrolizumab,” the study authors concluded. Moving forward they noted irAE occurrence may be used as a surrogate prognostic factor for pembrolizumab.

1. Nakamura K, Ishiyama Y, Nemoto Y, et al. Association between immune-related adverse events and survival of patients with metastatic urothelial carcinoma treated with pembrolizumab. Presented at: 2022 AUA Annual Meeting; May 13-16; New Orleans, LA. Abstract MP03-19.

Immune-related adverse events may be a prognostic marker for improved survival and progression-free outcomes with pembrolizumab in patients with metastatic urothelial carcinoma.

Immune-related adverse events linked to improved pembrolizumab outcomes in urothelial carcinoma

Next-generation sequencing (NGS) via urine cytology specimens may represent a valid, minimally invasive profiling tool for assessing genomic alterations in upper tract urothelial carcinoma (UTUC), according to a poster presented during the 2021 Society of Urologic Oncology Annual Meeting.

Specifically, researchers concluded that the overall success rate of NGS of urine cytology specimens from UTUC was 86% and that the derived genomic profiles were similar to those obtained via ureteroscopic biopsies and radical nephroureterectomies.

“Many times, genomic profiling is from tissue from FFPE cell blocks–obtaining tissue requires invasive surgical procedures, and DNA is often moderately degraded,” explained Wesley Yip, MD, urologic oncology fellow at Memorial Sloan Kettering, in a presentation of the findings. “Our group has previously shown that urine cytology specimens, at least in the context of [patients with] non-muscle invasive bladder cancer treated with BCG, present a potential source for genomic analysis. So, we asked the question: ‘Can genomic profiling upper tract tumors be performed through cytology specimens.’”

Researchers compared a total of 14 urine cytology specimens from UTUC tumors with paired tissue specimens including ureteroscopic biopsies and radical nephroureterectomies. The 20 most frequently altered genes in the urine cytology samples were consistent with the gene alterations present in the tissue samples. In both specimen groups, TERT (in cytology vs tumor specimen, 50% vs 67%, respectively), KMT2D (50% vs 67%), and FGFR3 (42% vs 58%) represented the most prevalent genomic mutations.

The tumor specimen findings yielded a total of 124 gene alterations, with TERT (67%), FGFR3 (58%), KMT2D (67%), and STAG2 (50%) as the most prominent mutations. The average tumor mutation burden was 12.3 (range, 2.6-61.4) in this collection of samples. Other prevalent mutations included CREBBP (33%), CCND1, FLT4, and KMT2C (all 25%), and ELF3, PRKD1, MAPKAP1 (all 20%).

Urine cytology specimen findings identified a total of 66 genomic alterations and the TMB average was 8 (range, 2.6–16.7). The most common alterations identified in this collection included FGFR3 (42%), KMT2D (50%), and TERT (50%). Other prevalent alterations included STAG2 (33%) and PIk3CA (25%).

“We demonstrate an 86% success rate of next generation sequencing of urine cytology specimens from upper track tumors. There are similar genetic profiles between the urine cytology, specimens and tissue specimens are there from biopsy or radical nephroureterectomy,” concluded Kip. “This demonstrates that urine cytology is actually a useful minimally invasive tool but has some room for improvement. Sequencing these specimens has the potential for risk stratification and treatment response monitoring.”

1. Yip W, Reisz P, Tracey A, et al. Feasibility and validation of genomic profiling of upper tract urothelial carcinoma from urine cytology specimens. Presented at: SUO 22nd Annual Meeting; December 1-3, 2021; Orlando, Florida. Poster 120.

Urine cytology specimen NGS was found to be a feasible and valid method of assessing genomic alterations in patients with upper tract urothelial carcinoma.


Urine cytology NGS comparable to tumor biopsy in identifying UTUC mutations

The majority of patients with prostate cancer adjusted their androgen deprivation therapy (ADT) post-scan management plan after receiving a 18F-fluciclovine PET/CT scan, according to findings presented at the 22nd Society of Urologic Oncology Annual Meeting.

Moreover, after the scans identified lesions, plans were commonly amended to target salvage therapy and spare patients the morbidity associated with ADT, said investigators.

Specifically, a total of 93 out of 146 patients (64%) had a change in management plan following their scans. The scan results also caused 55 patients (59%) to no longer have ADT included in their care plan. Furthermore, only 25% of patients who initially had a plan to receive ADT as a monotherapy still had a plan for ADT monotherapy post 18F-fluciclovine PET/CT.

“The advent of highly sensitive molecular imaging has allowed the identification of men with oligometastatic disease to may be more optimally treated with metastasis directed therapy than with systemic treatments, such as androgen deprivation therapy,” explained Gerald L. Andriole, Jr., MD, Division of Urologic Surgery, Department of Surgery, and the Alvin J. Siteman Cancer Center, Washington University School of Medicine, in a presentation of the findings. “So, the goal of this particular study was to evaluate the impact of 18F-fluciclovine PET scans on plans to use androgen deprivation therapy in patients with biochemical recurrence.”

Investigators performed a secondary analysis of 2 treatment alteration studies: LOCATE (NCT02680041) and FALCON (NCT02680041). Out of the 317 patients with biochemical recurrence (BCR) enrolled in these studies, 146 had ADT, either as a monotherapy or in combination with another treatment modality, included in their post-scan plan.

PET/CT detection rates for prostate/prostate bed region; pelvic and extra-pelvic lymph nodes (LN); and soft tissues and bones, were determined at a per-patient level. The post hoc analysis compared post-scan treatment plans with pre-scan treatment plans and used imagining findings to stratify the data.

Sixty patients in the study were initially planned to receive ADT as a monotherapy, while 86 were initially going to receive ADT with another modality. Overall, lesions were detected in 85 patients (58%) who were planning to receive ADT. Lesions were detected in prostate/bed, pelvic LN, extra-pelvic LN, and soft tissue and bones, at rates of 30%, 25%, 13%, 2.1% and 13%, respectively.

Findings revealed that 25 patients (17%) had positivity that was limited to the prostate/prostate bed, 21 patients (14%) had 18F fluciclovine–positive pelvic nodes, and 39 patients (27%) had positive detection beyond the prostate/bed and pelvic nodes.

Notably, patients with the most disseminated disease (extra-pelvic incolvenement,12/30; 40%) were the patients who were likely to have a post-scan plan for ADT monotherapy. In contrast, patients with a negative scan were most likely to have a modified post-scan plan which aborted ADT (14/54; 26%). Among those whose post-scan plan aborted ADT, local disease was common.

“So, in summary, data from two prospective trials indicate that 18F-fluciclovine significantly influences the management plans for a majority of patients who had a pre-scan plan that included androgen deprivation therapy,” concluded Andriole. “Androgen deprivation therapy was aborted in about 40% of the patients originally intended to receive that and management plans were commonly amended to target salvage metastasis directed treatment to 18F-fluciclovine PET/CT abnormalities, and this spared the patients the morbidity associated with androgen deprivation therapy.”

1. Andriole GL, Scarsbrook AF, Davis P, Chaglassian A, et al. Impact of 18f-fluciclovine PET/CT on plans for ADT in patients with biochemical recurrence of prostate cancer; data analysis from 2 prospective clinical trials. Presented at: Society of Urologic Oncology 22nd Annual Meeting; November 30-December 3, 2021; Orlando, FL. Abstract 144.

A secondary analysis of 2 treatment alteration studies demonstrated that 18F-fluciclovine PET/CT scans play a pivotal role in determining if androgen deprivation therapy is appropriate for patients with prostate cancer. 

Lindsay Fischer

Articles

Vitamin C add-on may benefit MIBC patients receiving chemo

Immune-related adverse events linked to improved pembrolizumab outcomes in urothelial carcinoma

Urine cytology NGS comparable to tumor biopsy in identifying UTUC mutations

18F-fluciclovine PET/CT significantly influences ADT plans for patients with prostate cancer