Paper Alert

Dear Readers,

The Paper Alert section of Bladder Cancer reviews new publications (usually published within the prior 6 months) that will be of interest to most clinicians and scientists in the bladder cancer field, but which may have been overlooked by many super specialists (clinicians and researchers). They are selected not only because they are important in their own right but also because they may influence how we care for patients, and because they may give us new perspectives on common problems. The selection is done by myself and approved by the Editors-in-Chief before publication.

Edward Messing MD, FACS
Professor of Urology and Oncology
University of Rochester School of Medicine
Rochester, NY, USA

Paper Alert 27

The Y-chromosome until recently had not been regarded to be as consequential as other chromosomes in mammalian development. However, it is needed for male sex determination and spermatogenesis [1], and a variety of other functions [2]. This work has been facilitated greatly by advances in molecular genetic methodologies, particularly the development of CRISPR/Cas9- mediated knockout of parts, or all of entire chromosomes [3]. Indeed, loss of the Y chromosome (LOY) has been identified in many cancer types and as many as 10–40% of human bladder cancers [4–8]. Now a recent publication sheds some light on how LOY potentially drives cancer growth and progression and focuses on bladder cancer [9].

Paper Alert 26

Immediate post transurethral resection of bladder tumor (TURBT) intravesical chemotherapy with a variety of agents is considered the standard of care for treating non-muscle invasive bladder cancers (NMIBC). However, at times it cannot be administered because of depth of resection and fear of extravesical extravasation or there is too much hematuria to safely clamp a catheter for an hour dwell time.

Paper Alert 25

Since the landmark publication by Grossman et al. neoadjuvant chemotherapy (NAC) with a combination of Methotrexate, Vinblastine, Adriamycin (doxorubicin) and cisplatin (MVAC) demonstrated a 5% advantage in overall survival (OS) compared with radical cystectomy (RC) alone, NAC followed by RC has become standard of care for managing muscle invasive bladder urothelial cancer (MIBC) in patients “able” and willing to undergo RC and cisplatin containing NAC.

Paper Alert 24

Robotic surgery has spread rapidly, both in the United States (US) and elsewhere. In 2020 it was estimated that 86% of radical prostatectomies for prostate cancer were performed robotically in the US compared with 22% in 2003, and nearly similar rises have been seen in surgery for benign and malignant renal diseases and abdominal and pelvic surgeries in other specialties. Much of this increase has been driven by several factors including presumed lower morbidity, shorter lengths of stay during the initial hospitalization, more rapid recovery, and less blood loss.

Paper Alert 23

It should probably be considered shameless self-advertising for the author of Paper Alert to highlight a clinical trial and subsequent articles related to it that he was study chair and senior author on, but there is some justification for doing this (for the first time since I’ve written Paper Alert), and I have received the “green light” from one of the editors (SPL) of Bladder Cancer.

Paper Alert 22

Intravesical instillation of Bacillus Calmette Guerin (BCG) has long been a critical means to treat intermediate and particularly high risk, non-muscle invasive (NMI) urothelial cancer (UC) of the bladder [1]. These cancers recur frequently after transurethral resection (TURBT) and may progress to muscle invasive or more extensive UC.

Paper Alert 21

So what does the patient with high grade, non-muscle invasive bladder cancer who has disease that is unresponsive to (or has quickly recurred after) adequate intravesical therapy with Bacillus Calmette Guerin (BCG) do, particularly if he (she) does not want to lose his (her) bladder? Two agents that received priority, fast track priority review by the Food and Drug Administration (FDA) for such patients, Vicinuim [1] and Nadofaragene (rAd-If Na/Syn 3) [2], which have efficacy in this circumstance have experienced production problems and are not available [3, 4].

Paper Alert 20

The bladder and the upper urinary tract (UUT) are both lined by urothelium, and have cancer characteristics that are histologically and molecularly similar. Aside from inherited (e.g. Lynch family tumor syndrome) [1] or unusual exposures (e.g. phenacetin or herbal remedies with Aristolochia fanchi) [2, 3], upper tract urothelial cancer (UTUC) represents 5–10%of all UCs [4] (Sountoulides) and presents with concomitant UC of the bladder (BC) in 20%of cases [5].

Paper Alert 19

Patients with newly diagnosed high risk (see below), high grade (HG) non-muscle invasive bladder cancer (NMIBC) have a significant likelihood of disease recurrence, progression and eventual death from BC [1, 2].

Paper Alert 18

The management of upper tract urothelial cancer (UC) remains challenging; standard care being nep-hroureterectomy and bladder cuff excision (NU). However in the face of a solitary kidney or significant chronic kidney disease, NU will result in severe or total kidney dysfunction and likely need for dialysis. In this scenario, endoscopic therapies have often been utilized. However, ipsilateral local recurrence rates approaching 60% have been reported for endoscopic management alone [1].

Paper Alert 17

Patients with metastatic (M1) Urothelial cancer (UC) have an extremely ominous prognosis, with a 5 year survival rate of <5% after receiving cisplatin- based combination chemotherapy [1–3]. Thus, it is highly welcome news that within a year, two publications of Phase II (or I– II) trials of novel agents, erdafitinib [4] and enfortumab vedotin (EV) [5], have reported their efficacy and toxicity in patients with previously treated metastatic or unresectable UC.

Paper Alert 16

Bladder cancer (BC) is known to be a carcinogen induced malignancy with cigarette smoke, industrial chemicals and certain fungal exposures (e.g. Aristolichia frangi) being among the best appreciated carcinogens [1].

Paper Alert 15

Non-muscle invasive (NMI) urothelial cancer (UC) of the bladder has been responsive to intravesical therapy with live microorganisms (e.g. BCG) for well over 40 years [1] through mechanisms that induce direct cytotoxicity and more importantly, stimulation of the innate and adaptive immune systems.

Paper Alert 14

Hematuria, both macroscopic and microscopic, is the most common finding leading to a diagnosis of bladder cancer. The American Urological Association (AUA) defines microhematuria as having >3 red blood cells (RBCs) per high-powered field on a microscopic urinalysis [1].

Paper Alert 13

Bladder recurrences of urothelial cancer after nephroureterectomy and bladder cuff excision (NU) for upper tract (UC) occur in about 30% of patients who’ve not had prior bladder cancers, with most of these occurring in the first year after surgery [1–4]. A single intravesical instillation of chemotherapy immediately after a transurethral resection of bladder tumor (TURBT) can significantly reduce the likelihood of tumor recurrence using a variety of agents (summarized in ref # 5) [5], but does it help after NU for UT UC? And if so, what agent should be used and when should it be administered?

Paper Alert 12

Cigarette smoking remains the greatest preventable risk for developing bladder cancer (BC), with roughly 75% of patients with newly diagnosed BC having a strong smoking history, and roughly 25% still being active smokers [1]. As physicians we all ask about current and former smoking histories, but rarely do urologists (or medical oncologists or radiation oncologists) actually initiate the conversation about stopping smoking, and make appropriate referrals to smoking cessation programs.

Paper Alert 11

There are many reasons to restrict administration of allogeneic perioperative blood transfusions (PBTs) including avoiding transfusion reactions, transmission of infections, sensitization against future transfusions and organ transplantations, and of course, “waste” of a precious and scarce resource. However, the one that concerns bladder cancer surgeons the most is having worse oncologic outcomes, particularly reducing cause specific (CSS) and overall survival (OS) for patients undergoing radical cystectomy.

Paper Alert 10

Bladder cancer is the most expensive malignancy to treat over the lifetime of patients [1, 2]. What is not often recognized, particularly by treating physicians, is that these costs are frequently a source of great concern and anxiety among patients with the disease and their families – a condition termed “financial toxicity“ (FT). This was emphasized in a recent article by a team at the University of North Carolina’s Lineberger Comprehensive Cancer Center [3].

Paper Alert 9

The diagnosis of any cancer is a very serious event. It is thus not surprising that the response to such a diagnosis in many patients is despair, fear and concern. As one might expect, as a reflection of this psychological stress, the rate of suicide among patients receiving a new diagnosis of any cancer (except non-melanoma skin cancer) is 2 to 3 times higher than in the age and gender matched general population, being minimally higher with advanced age, slightly higher (1.28 times – but with overlapping 95% confidence intervals) in men than women, and higher yet in patients with pre-existing serious (requiring psychiatric hospitalization) psychiatric conditions.

Paper Alert 8

The molecular alterations of muscle-invasive (MI) urothelial cancer (UC) have been studies extensively by the Cancer Genome Atlas (TCGA) [1]. A consensus classification not dissimilar to that used for breast cancer, with luminal and basal subtypes, among others, reflecting various degrees of tumor aggressiveness and responsiveness to systemic chemotherapy, has been developed.

Paper Alert 7

Between 15 and 20% of patients with newly diagnosed urothelial cancer (UC) of the bladder will have high grade (HG) non-muscle invasive (NMI) disease including carcinoma-in-situ (CIS) and stage Ta and T1 tumors [1]. After transurethral resection of the cancer (TURBT), patients may undergo re-TURBT, but if no muscle invasive (MI) cancer is found most will receive an induction course of 6 weekly intravesical instillations of Bacillus Calmette Guerin (BCG).

Paper Alert 6

In 2014, I was on the Board of Directors of the Society of Urologic Oncology (SUO) when Merck announced having shortages of Tice strain Bacillus Calmette Guerin (BCG), a critical “drug” for treating intermediate and particularly high risk non-muscle invasive (NMI) urothelial cancer (UC) of the bladder, including carcinoma-in-situ (CIS) and high-grade (HG), stage Ta and T1 disease after transurethral resection.

Paper Alert 5

The standard initial treatment for urothelial cancer and other tumors of the bladder is a complete transurethral resection (TURBT). This is, of course, also a diagnostic and staging procedure and the information gained from both the endoscopic and histologic examinations have huge prognostic and management implications. But the hallmark of this procedure, particularly for non-muscle invading (NMI) urothelial cancers (UCs) is that all VISIBLE tumor is resected/ablated.

Paper Alert 4

Roughly 25% of patients at diagnosis of urothelial cancer (UC) have at least muscle invasive disease [1] and about half of these have extravesical extension or more advanced disease at that time. Additionally 10–15% of patients who initially have non-muscle invasive UC will subsequently develop muscle invasive or more advanced cancer. The outlook for patients with advanced or metastatic UC, particularly those who do not respond to Cisplatin-based combination chemotherapy regimens is very poor.

Paper Alert 3

Radical cystectomy is the gold standard treat-ment for muscle invasive (stage T2 – T4a) bladder cancer, but is associated with a high incidence of complications, readmissions, and mortality [1–3] partially because of the magnitude of surgery and partially because of the significant comorbidity bur-dens patients who develop this disease have [4, 5].