Photodynamic Therapy For Bladder Cancer

We all know that light is very essential for survival, but do you know light can be used for destruction too? Yes, for therapeutic purposes against various diseases like psoriasis, vitiligo and cancer. It is widely called nowadays as photodynamic therapy - when a specific wavelength of light along with photosensitising agents is used to selectively target and destroy abnormal cells in the human body.

Cancer is a quickly spreading disease-causing increased morbidity and deaths worldwide. Early detection and advanced treatment strategies are the major factors that positively impact cancer prognosis. Photodynamic therapy is one of the potential non-invasive treatment options for most of the cancer types including bladder cancer.

Overview - bladder cancer

Bladder cancer develops when any uncontrollable, abnormal cell growth begins in the inner lining of the urinary bladder. It is one of the fatal diseases of the urinary system as it has non-specific symptoms and high rates of relapse after treatment. Bladder cancer is broadly classified into non-invasive (superficial) and invasive (possibly metastatic) based on how far the disease has been spread into deep muscle layers and/or around the bladder wall. 

The non-invasive bladder cancer types are suitable candidates for photodynamic therapy as cancer cells can be specifically targeted without any harm to healthy cells in the organ. Nearly 70% of the bladder cancers diagnosed are non- invasive which suggests photodynamic therapy is a potential effective treatment option for them.¹

What is photodynamic therapy?

How does it work?

Photodynamic therapy is performed in combination with a photosensitiser (light sensitive drug) and light. If the disease is superficial (for example, skin cancer), the patient gets a cream containing the photosensitising drug, otherwise the drug is given intravenously to gain access to the affected area via bloodstream. 

The photosensitisers are known for its selective accumulation in much larger amounts in cancer or any pathologically altered cells compared to healthy cells. The increased expression of receptors of blood proteins, lipoproteins and several growth factors on the abnormal cell membranes favours this selective binding. When these cells are exposed to a light of a certain wavelength that specifically activates the photosensitisers, they generate high levels of reactive oxygen species leading to cellular toxicity and eventual cell death.² It also damages the blood vessels that nourish tumour cells.

Photosensitizers used for bladder cancer

Different types of photosensitisers and different wavelengths of visible light spectrum, usually in the form of laser, for appropriate activation of photosensitisers are currently in clinical use.

Photofrin

Photofrin or porfimer sodium is the first clinically approved photosensitising drug for bladder cancer. Photofrin is given intravenously and after hours or days (40- 50 hours) of administration, the drug is found to be selectively accumulated in the bladder tumour cells. Then, a fibre optic tip is positioned in the middle of the bladder and used to deliver laser light of 630 nm for uniform photofrin activation among tumour cells.³

However, photofrin is no longer in use for bladder cancer due to its slow clearance from the body leading to prolonged eye and skin photosensitivity. Another major disadvantage is that photofrin damages the structural alignment of bladder tissue as it can go to deep layers at 630 nm exposure and may cause permanent damage to bladder function.⁴

5‐Aminolevulinic acid 

Aminolevulinic acid is an amino acid which naturally synthesises protoporphyrin IX, a precursor for haemoglobin formation in our body. In tumour cells, the protoporphyrin IX gets accumulated due to impaired haemoglobin production.⁵ This accumulated protoporphyrin IX acts a photosensitiser which can be used for both visualisation and treatment of cancer.

In bladder cancer patients, aminolevulinic acid is administered intravesically (through a catheter directly into the bladder via urethra) resulting in high levels of protoporphyrin IX in tumour cells. When illuminated under blue light (375 - 445 nm), protoporphyrin IX helps to identify tumour cells, whereas, under green light (450 - 580 nm) and red light (600 - 740 nm), protoporphyrin IX forms reactive oxygen species which leads to programmed bladder tumour cell death.⁵

Aminolevulinic acid is known for precise, local, direct effect on superficial, non-invasive bladder tumours and no structural damage to the bladder itself evidenced in treated patients.  However, when aminolevulinic acid is externally (topical application) or internally (intravenous or oral) administered, the bioavailability of this photosensitiser is found to be very less.

Hexyl aminolevulinate

To overcome reduced bioavailability via routes other than intravesical, the ester derivative of aminolevulinic acid, known as hexyl aminolevulinate has been evaluated for cancer treatment. Hexyl aminolevulinate exhibits enhanced effect of photosensitising agent due to its high lipophilicity and also therapeutic effects are seen when used just at lower concentration (< 20 folds) than aminolevulinic acid. 

While mechanism of action of hexyl aminolevulinate is similar to aminolevulinic acid via synthesis of protoporphyrin IX, the effective activation of this photosensitiser occurs only when exposed to green light wavelength. This limits deep penetration making it not an effective treatment option for tumours of size greater than 1mm among non-invasive bladder cancer patients.⁶

TLD1433

TLD1433 is a ruthenium-based photosensitizer. When intravesically administered, TLD-1433 is readily taken up by tumour cells and when exposed to green light , it induces generation of reactive oxygen species which destroys the tumour cells. TLD-1433 is found to be safe and effectively regresses non-invasive bladder tumours. Also, it is not found to have a negative effect on the bladder structure when activated under a green light.⁷

In addition, there are many herbal photosensitisers such as hypericin, chlorophyllin, chlorin e6 and palladium bacteriochlorophyll derivatives are under investigation for clinical testing as they show promising results in inhibiting tumour growth in the laboratory. 

Combination therapies

The traditional therapies to treat non-invasive bladder cancer include transurethral resection of bladder tumour (surgical removal) and/or intravesical chemotherapy (drugs that inhibit rapid division of cancer cells) or immunotherapy using BCG (to boost immune response against cancer cells). However, non-specific toxicity and tumour recurrence are a serious problem in more than 70% of the treated patients.

Generally, in a clinical setting, photodynamic therapy is suggested as a second-line of treatment for non-invasive bladder cancer patients who were unsuitable or non-responsive to the above-mentioned common approaches. Integrating photodynamic therapy with traditional methods of treatment may improve efficacy and aid in total eradication of cancer. The potential synergistic effects of combination therapies can overcome the issues related to multidrug resistant tumour growth and enhance tumour-free survival rate of cancer patients.⁸

Clinical applications

In general, the urinary bladder is easily accessible due to its translucent nature through fibre optic tools. This feature makes photodynamic therapy the most suitable option for bladder cancer for a fast and direct effect. Moreover, patients in early stages of superficial (non-invasive) bladder cancer are best suited for high efficiency without any negative effect on the organ.

In a clinical setting, a single photodynamic treatment procedure is scheduled in two sessions. The first one involves direct, targeted irradiation of the tumour with a heavy light dose, whereas the second session involves irradiation through a diffuser throughout the bladder to eradicate residual tumour lesions with a lower light dose.⁹  

Effectiveness and considerations

The effectiveness of photodynamic therapy is primarily based on the type of photosensitiser used and accurate delivery of light. Also, the effectiveness of the therapy can vary according to position of the tumour and wavelength of the light used. Furthermore, accurate dosing and duration of the light, light source positioning and manoeuvring in the bladder determines the safety and efficacy of this therapy. Any small displacement of the fibre optic cable can significantly affect the treatment outcome.

Benefits and advantages

The clinical efficacy of the photodynamic therapy is high because of the following:

• Safe and well-tolerated compared to the standard intense treatment regime 
• Highly feasible as the bladder is easily accessible through fibre optics
• Minimally invasive
• Can be performed as an out-patient procedure
• Minimal scarring and thus protects the organ’s structure and function 
• Effective tumour selectivity
• Low systemic toxicity 
• Cost-effective 
• An excellent alternate choice for patients with inoperable tumours, refractory to radiation and chemotherapy 
• The synergistic effect when used in combination with standard therapies

Potential side effects and risks

Although the therapy is highly advantageous, it is associated with some risks too.

• Possible thermal burns if the light diffuser comes in contact with the bladder wall.
• Skin and eye photosensitivity
• If intravesical delivery was chosen, the urine may dilute the photosensitisers before light activation.
• Limited selectivity to early-stage and superficial bladder tumours

Numerous advancements are being currently made to expand the scope of photodynamic therapy in bladder cancer. Improving the permeability of photosensitisers without risking the organ could aid in the treatment of malignancies in bladder cancer. The new generation photosensitisers are being developed to enhance targeting by conjugating to nanomolecules that easily bind to tumour-specific biomarkers.¹⁰

Summary

Bladder cancer has a high recurrence rate. Photodynamic therapy is a safe and effective treatment modality with increased tumour selectivity, especially if used against superficial bladder tumours. The therapy exerts effective anti-tumour effect either as a stand-alone treatment option or in combination therapies. Long-term recurrence free survival after photodynamic therapy plays a crucial role in improving the quality of life of bladder cancer patients. However, there is a lot of room for potential advancements to widen the prospect of the therapy.