Bladder cancer: a cancer in crisis

AMONG Australia’s 15 most common malignancies, bladder cancer remains the only one with survival rates that have deteriorated over the past 30 years. From 2010 to 2014, Western Australian data showed that the 5-year relative survival for bladder cancer had fallen to an all-time low of 53.9%, while the comparative survival for all cancers combined rose to 68.6%. In 2019 it is the 9th most commonly diagnosed malignancy in Australia.

Despite a falling age-standardised incidence of bladder cancer from 17.8 per 100 000 in 1982 to a projected 10.1 per 100 000 in 2019, mortality–incidence ratio has increased from 0.28 to 0.38 over the past two decades. Unfortunately, many Australian health care practitioners remain unaware of this bladder cancer survival crisis.

Table 1: Data from AIHW Cancer data in Australia report

Why is survival deteriorating?

Our nation’s worsening bladder cancer survival rate is likely multifactorial, and although clinical coding issues may explain a small part of this decline, the probable major contributor is Australia’s ageing population. The percentage of patients diagnosed with bladder cancer aged over 80 years has gradually increased (from 15.7% in 1982 to 36.5% in 2015). In Western Australian data from 2014, bladder cancer was the fifth highest cause of cancer mortality for men aged over 65 years, exceeding that of malignant melanoma. In this older cohort, radical treatment options are reduced, as patients are frequently unsuitable for cystectomy or chemoradiotherapy. Other disadvantaged groups are rural, Indigenous and female patients, as demonstrated in a South Australian study. Delayed presentation is thought to contribute significantly (here and here). The male survival advantage in bladder cancer is a consistent finding internationally and is unusual because females tend to demonstrate a survival advantage for most other malignancies. Reasons for this are poorly understood, but the phenomenon cannot be purely explained by delayed presentation, as the survival matched by stage at presentation is also inferior.

Current referral and treatment pathways for bladder cancer

Bladder cancer typically presents with haematuria, or storage lower urinary tract symptoms such as frequency, urgency or dysuria. Early identification and referral of all patients with visible haematuria is of paramount importance to a timely diagnosis. Bladder tumours are detected with cystoscopy and urinary tract imaging (computed tomography intravenous urogram or ultrasound of urinary tract) and affected patients proceed to rigid cystoscopy with bladder biopsy or transurethral resection of bladder tumour (TURBT). Immediately after TURBT, a single instillation of intravesical chemotherapy is recommended for patients with non-muscle invasive bladder cancer (NMIBC) to reduce the risk of recurrence.

For high grade NMIBC, treatment with adjuvant intravesical immunotherapy (Bacille Calmette Guerin [BCG]) has been the standard of care for the past three decades. Up-front radical cystectomy can also be offered, but overtreats a large proportion of patients. Neo-adjuvant chemotherapy plus radical cystectomy is the gold standard for curative treatment of muscle invasive bladder cancer (MIBC); however, trimodal treatment with maximal TURBT and chemoradiotherapy is a viable alternative that is perhaps underutilised. Platinum-containing combination chemotherapy is active in patients with metastatic disease. Immunotherapeutic checkpoint inhibitors appear highly active, with less toxicity, and are currently licenced in the second-line setting.

How can we improve bladder cancer outcomes?

A nationwide improvement in bladder cancer mortality requires action at multiple levels. Visible haematuria is the single most predictive symptom of malignancy, with as many as one in five patients referred for specialist assessment being diagnosed with cancer. Improved awareness of the significance of visible haematuria in patients and primary care clinicians promotes early presentation, diagnosis and improved outcomes. All patients with visible haematuria warrant referral to a urologist. When available, referral to a rapid-access haematuria clinic with a streamlined “one-stop” urological assessment, including flexible cystoscopy, is encouraged. Non-visible haematuria has a much lower association with malignancy, although as many as one in 20 patients are diagnosed with bladder cancer after referral with non-visible haematuria (here and here).

Better treatment of bladder cancer starts with a high quality TURBT, and re-resection if indicated according to the initial pathology. The majority of elective operations are performed in Australia’s private sector, which, for a number of reasons, may restrict access to administration of intravesical therapy, multidisciplinary team management or radical cystectomy in a high volume centre. Centralisation facilitates the integration of enhanced recovery after surgery protocols and is associated with better post-operative mortality outcomes, reduced hospital length of stay, lower re-intervention rates and improved overall survival (here, here, here and here). Centralisation of cystectomy should be the standard of care. When possible, neo-adjuvant chemotherapy should be offered to patients requiring cystectomy, and has been associated with pathological downstaging, improved positive margin rates and improved long term survival data (here and here).

Multiple phase 1–3 clinical trials of systemic immunotherapy in metastatic disease have demonstrated promising results relating to survival and disease progression and survival. Agents with proven efficacy include targeted immune checkpoint inhibitors, such as the programmed cell death protein 1 (PD-1) receptor or the programmed cell death ligand 1 (PD-L1). These include pembrolizumab (PD-1), nivolumab (PD-1), durvalumab (PD-L1), atezolizumab (PD-L1), and avelumab (PD-L1). As BCG has been an immunotherapeutic mainstay in NMIBC for over three decades, the urological community is excited to see what role these novel immunotherapeutic agents will play in the management of non-metastatic disease including MIBC and high risk NMIBC.

The latest in bladder cancer research

There are several groundbreaking bladder cancer trials currently underway in Australia, largely under the auspices of the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. ANZUP is a cancer cooperative clinical trials group that was established in 2008 to improve multidisciplinary collaboration regarding clinical trial research into the management of urological cancers; its bladder cancer subcommittee now has more than 320 members.

High risk NMIBC

One such study is the BCG Mitomycin (BCG+MM) trial, a national randomised phase 3 trial of combined BCG plus mitomycin versus BCG alone in the treatment of high risk NMIBC. BCG+MM is now the largest bladder cancer trial undertaken in Australia, with higher accrual to date than many of the previous international studies that determined its conception.

The patient-reported outcomes associated with the diagnosis and treatment of NMIBC are being further investigated in a University of Sydney and ANZUP co-badged, multicentre longitudinal cohort study entitled “Developing a patient-reported symptom index for non-muscle invasive bladder cancer” (NMIBC-SI), primarily assessing the patient-reported symptoms and quality of care through their treatment journey.

BCG-refractory NMIBC is challenging to manage, especially in patients unfit for cystectomy. Device-assisted therapies (thermo-chemotherapy and electromotive drug administration) may have a role, and systemic immunotherapy is being investigated in this space by industry-sponsored trials, such as the phase 2 KEYNOTE-057 (pembrolizumab) and phase 3 KEYNOTE-676 (pembrolizumab plus BCG).

MIBC

PCRMIB (Pembrolizumab with Chemoradiotherapy as Treatment for Muscle Invasive Bladder Cancer) is a novel phase 2 trial of bladder-preserving treatment for MIBC. All participants receive curative intent chemo-radiotherapy plus concurrent 3-weekly pembrolizumab.

The NIAGARA trial is an international industry-sponsored phase 3 randomised controlled trial that aims to determine the efficacy and safety of durvalumab in combination with gemcitabine and cisplatin as pre-cystectomy neo-adjuvant therapy.

Metastatic bladder cancer

There are numerous ongoing national and international industry-sponsored studies investigating the exciting role of immunotherapeutic checkpoint inhibitors as both first- and second-line agents in the metastatic bladder cancer setting. An ANZUP contribution in this space is the now accrued BL12 trial, which randomised 199 patients between nab-paclitaxel and paclitaxel as second-line therapy.

Conclusion

Despite these research efforts and the arrival of new immunotherapeutic agents, we are still seeing deteriorating outcomes. In addition to the promotion of rapid access diagnostics and best possible clinical management at each and every stage of the disease, novel approaches are clearly required to reverse these unacceptable trends in this current cancer crisis.

Dr Andrew Moe is a urology registrar at Fiona Stanley Hospital in Perth, and is also affiliated with the University of Western Australia’s School of Medicine and ANZUP.

Professor Dickon Hayne leads the urological research team at UWA and chairs the ANZUP Bladder Urothelial and Penile Cancer Sub-committee.

The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.