Fungal Infections during Cancer Treatment

Fungal infections, particularly those in the mouth, can occur due to treatments for head and neck cancer. They may pose a particular threat to the health or life of the patients afflicted, due to the major arteries, structures and nervous tissues (e.g. the beginning of the spinal cord and the brain) contained in that region. These cancers are often treated with radiotherapy and chemotherapy in cases where surgery is not immediately necessary, however these therapies may be associated with an increased risk of other conditions and disorders. This is often due to the effects these treatments pose on the immune system. Tissue damage to the protective linings of parts of the head or neck, such as the mouth, may also be a factor.

Radio- and chemo-therapy may damage healthy cells as well as tumour cells, and may also depress immune mechanisms in other ways. Infection by micro-organisms such as fungi and/or bacteria is a common complication associated with head or neck cancer treatments.

A common example of this is the fungal infection of the mouth, mostly associated with fungi types such as:

• Aspergillus
• Candida
• Geotrichum
• Penicillium

This condition is often diagnosed as oral thrush. Symptoms of these infections may include:

• Pain on the surface of the tongue and mouth tissue
• Difficulty in swallowing
• Decreases in the sense of taste
• Itchiness within the mouth

Treatments of fungal infections

This condition may be addressed with the administration of anti-fungal drugs, or drugs that eradicate fungal infections. These include:

• Amphotericin B
• Fluconazole
• Itraconazole
• Ketoconazole
• Miconazole
• Natamycine
• Nystatin
• Posaconazole
• Voriconazole

Antifungal therapy may be administered empirically (i.e. based on the detection of fungus in the mouth and/or which specific type of fungus is present) or prophylactically (preventatively). Antifungal prophylaxis may be given before or during therapies to combat against the probability of fungal infection due to immune system impairment. However, these strategies may have some disadvantages.

Disadvantages of prophylactic anti-fungal treatments

Fungal drug resistance

Many species of Candidia may be involved in the development of oral infections. The most prominent of these tend to be albicans and C. glabrata. C. glabrata is associated with a high rate of resistance to many drugs used to treat fungal mouth infections, particularly ketoconazole and fluconozole.

This increases the risk of recurrent infections that are not affected by these drugs. Some drug-resistant fungi may take the opportunity to infect cancer patients while their immune systems have been affected by treatment. This may render some prophylactic measures ineffective. In some cases, multiple drugs of different types may be required to eradicate some fungal strains. This may result in the increased use of healthcare resources, the increased risk of side-effects and/or an increased financial burden.

Side-effects

Antifungal medications may be associated with many side-effects and adverse events. Examples include:

• Gastrointestinal effects, including diarrhoea
• Kidney damage
• Liver damage
• Toxicity

A trial evaluating the toxicity of voriconazole also found incidences of hallucinations and photosensitivity in a minority of its subjects (human patients). In addition, antifungal therapies may interact with chemotherapeutic drugs to enhance their availability in the body. This may lead to an increased risk of toxicity associated with these drugs. Drug interactions with chemotherapy agents may also lead to decreases in the efficacy of antifungal treatment.

Strategies to improve the effectiveness of anti-fungal treatments

Side effects and interactions may also affect the adherence to treatment, thus reducing the overall point of antifungal therapy during chemo- or radio-therapy. This may be addressed by:

• Novel applications such as oral/topical administration of the antifungals in question, and timing this optimally relative to mealtimes. This is thought to reduce the risk of some side-effects.
• Ensuring adequate hydration levels
• Therapeutic monitoring (i.e. through laboratory tests for drug concentrations in the blood, evidence of toxicity or organ damage, etc.)
• Electrolyte supplementation
• Dose modification

How effective are these treatments?

It may not be completely clear whether antifungal therapy is necessary during radiotherapy or chemotherapy.

A review of 25 studies (including over 2900 participants) on the prophylactic administration of these drugs to cancer patients found no significant effect on the rate or risk of death. On the other hand, some studies have found significant reductions in these in response to intravenous amphotericin B therapy. This drug is cheaper than newer therapies such as fluconazole. However, amphotericin B may be poorly absorbed, and thus potentially less effective. This may be due to the simple fact that it is administered in a way that releases the drug into many tissues, not just those of the mouth.

Newer forms of antifungal therapy for oral infections include lozenges, which provide much more localised delivery, and thus potentially more effective treatment. Micozanole, in tablet form, is associated with comparatively reduced durations of antifungal therapy, and decreases in other consequences of tissue damage as a result of chemotherapy. These include the need for painkilling drugs and an increase in the length of hospital stay.

Untreated fungal infection

An untreated fungal infection may lead to serious consequences. Advanced infections may lead to the migration of fungi into the blood, or fungaemia. This may lead to systemic infection, which is thought to be a prominent cause of death in patients. Therefore, the use of antifungal therapy in patients also receiving treatment for cancer may be influenced by factors such as:

• Considerations of efficacy: This may include verifying the presence of a fungal infection beforehand and/or which specific species is causing the infection (i.e. in the case of empirical therapy).
• Cost (i.e. as a result of multidrug therapy for resistant strains, additional pain treatment, etc.)
• Potential harm (i.e. from drug interactions, side-effects, etc.)

There is a possibility that some novel cancer treatments may also address fungal infections, and vice versa. Licochalcone-A is a compound found in liquorice that has been found to have anti-bacterial, anti-inflammatory and anti-fungal properties. A recent trial concluded that licochalcone-A can also induce death in human oral cancer cells, while sparing normal cells. This is based on data from cell culture studies, but indicates the potential for dual anti-fungal/cancer treatments. Dual therapy may be necessary, as recent research indicates that there is a correlation between infection with Candida and the increased progression of oral cancer.

References

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