Bladder cancer is the 9th most common cancer worldwide, the 5th most common in Europe, the 6th most common in the US and the 11th most common in the UK.
Around 70-75% of cases are NMIBC, where the tumour is confined to the tissues lining the bladder wall. In high-risk grades, where there is the greatest chance of recurrence or progression, the standard of care is TURBT followed by intravesical BCG. Even so, 40-50% of these patients relapse, with 10-20% developing muscle-invasive or metastatic disease.
For BCG-unresponsive bladder cancer, treatment options are limited, with radical cystectomy the current standard of care. Yet many NMIBC patients do not want radical cystectomy because of the significant, lifelong changes it brings, while many others are unfit for such major surgery.
The Global Burden of Bladder Cancer
Bladder cancer remains one of the most challenging cancers to manage, not only due to its prevalence but also because of its high recurrence and progression rates.
According to GLOBOCAN data, it accounts for approximately 570,000 new cases and 210,000 deaths each year. The impact of bladder cancer across the world often goes unnoticed, mainly because it competes for attention with other, more publicised malignancies such as lung, breast, and colorectal cancers.
In many countries, the rate of diagnosis is rising, not necessarily due to an increase in the disease itself, but due to improvements in diagnostic techniques and increased awareness. Ageing populations and exposure to risk factors like smoking and industrial chemicals have also contributed to the continued prevalence of this disease.
What Makes NMIBC Unique?
While NMIBC is generally not life-threatening in its early stages, it poses a persistent threat due to high recurrence and progression rates.
What makes NMIBC particularly frustrating for doctors and patients alike is that while it’s initially more manageable than muscle-invasive disease, it often behaves unpredictably. Many patients undergo repeated resections and therapies over the years, and for a subset, the disease progresses despite aggressive treatment.
High-risk NMIBC, which includes high-grade Ta, T1, and CIS lesions, is particularly aggressive and requires prompt and effective treatment.
Patients with high-risk NMIBC are therefore treated more aggressively due to their increased chance of progression to muscle-invasive disease, which carries a much poorer prognosis.
Current Standard of Care: TURBT and BCG Therapy
TURBT remains the first-line intervention for diagnosing and treating NMIBC. The procedure involves inserting a resectoscope into the bladder via the urethra to remove the tumour and obtain tissue for histopathological examination. TURBT serves a dual purpose: therapeutic and diagnostic. However, it’s rarely curative on its own, particularly in high-risk cases.
While TURBT can clear visible tumours, microscopic cancer cells often remain, especially in aggressive or multifocal cases. Therefore, it is usually followed by intravesical therapy to reduce the risk of recurrence. Despite being minimally invasive, TURBT must often be repeated, and the risk of complications like bleeding or bladder perforation remains, especially in elderly or frail patients.
BCG Therapy: Mechanism and Challenges
For decades, Bacillus Calmette-Guérin (BCG) has been the mainstay of intravesical therapy for high-risk NMIBC. BCG is an attenuated live strain of Mycobacterium bovis, and when instilled into the bladder, it stimulates a robust immune response that targets residual cancer cells.
While effective for many, BCG therapy has its limitations:
- 40-50% of patients relapse despite treatment.
- 10-20% progress to muscle-invasive or metastatic disease.
- Side effects can range from irritative bladder symptoms to severe systemic BCG infections.
- There’s also an ongoing global shortage of BCG, further limiting accessibility.
This leaves a large number of patients in need of alternative therapies – especially those who are BCG-unresponsive.
Recurrence and Progression Despite Standard Care
Patients whose disease recurs or progresses after adequate BCG therapy are labelled as BCG-unresponsive. This classification includes individuals with persistent high-grade disease, recurrent high-grade tumours within 6-12 months, or progression to muscle-invasive bladder cancer. BCG-unresponsive NMIBC is notoriously difficult to manage, as few effective treatments are available that match BCG’s historical efficacy.
The emotional and physical toll on these patients is substantial. Many are caught in a therapeutic limbo – too advanced for conservative treatments, but either unwilling or unable to undergo radical surgery.
The Limitations of Radical Cystectomy
Radical cystectomy unfortunately remains the standard of care for BCG-unresponsive NMIBC. While effective in eliminating the disease, it carries significant drawbacks, which are:
- Major surgical risks, particularly in elderly or comorbid patients.
- Lifelong alterations in urinary function, requiring a stoma or neobladder.
- Psychological impact from loss of bladder function and body image changes.
Because of these factors, many patients either refuse this surgery or are medically unfit to undergo such an invasive procedure in the first place. This gap in care necessitates alternative treatments that are both effective and bladder-sparing.
The Promise of HIVEC: Bladder-Sparing Treatment for NMIBC
Combat’s HIVEC® (Hyperthermic Intravesical Chemotherapy) system is designed specifically for high-risk NMIBC patients, including those unresponsive to BCG or ineligible for surgery. The HIVEC® system delivers heated Mitomycin C (MMC) directly into the bladder using a recirculating system, maintaining optimal temperature and drug concentration throughout the treatment session.
Unlike traditional intravesical chemotherapy, HIVEC® introduces a thermal element, which enhances the drug’s cytotoxic effect while improving penetration into the bladder wall. It’s a bladder-sparing, outpatient-compatible option that provides both patients and clinicians with a much-needed alternative.
Check out our ongoing HIVEC HEAT trial, led by the University of Leicester: https://www.isrctn.com/ISRCTN49174478
