Radiotherapy plays a crucial role in the treatment of various cancers. Depending on the tumour site it is either delivered before or after surgery or as a definitive treatment. Even though novel technical advances in treatment delivery have enabled more selective irradiation of the region of interest or tumour, normal tissue radiation toxicity remains the most important dose limiting factor of radiotherapy. Injury to the gastro-intestinal tract is oft the most important cause of radiation-induced side effects in patients being treated for abdominal and pelvic tumours.
Symptoms of intestinal radiation injury may occur during and/or after treatment. Depending on the time of onset intestinal radiation injury is divided into acute and chronic injury. Acute radiation toxicity occurs during and shortly after the treatment period. It may affect quality of life during treatment and may even require treatment interruption or alteration. The most important symptoms of acute gastro-intestinal toxicity include: diarrhoea, nausea, increased stool frequency, bleeding, abdominal and rectal/anal pain, decreased food uptake, and fluid and electrolyte loss. The severity of the symptoms may vary from mild discomfort to severely disabling and requiring hospital admission.
Chronic intestinal radiation injury is generally defined as injury present or occurring at least 3 months after treatment. The latency period of chronic radiation toxicity may be months up to years. Chronic gastro-intestinal injury may reduce quality of life in long term cancer survivors. Again the symptoms are various, including change in bowel habit, diarrhoea, faecal incontinence, pain, and intestinal blood loss.
In contrast to the earlier belief that acute and chronic injury are two unrelated phenomena, it now has been recognized that part of the chronic effects is consequential to early toxicity.
Cancer patients could greatly benefit from pharmacological agents that are able to prevent or reduce gastro-intestinal radiation injury. Unfortunately, to date, there are no effective pharmacological interventions to prevent the development of gastro-intestinal radiation toxicity after abdominal or pelvic irradiation. There is some evidence from phase I and II trials that the thiol-containing compound amifostine may reduce rectum toxicity when either administered systemically or topically. However, in contrast to head and neck cancer, the usefulness of amifostine in radiotherapy for abdominal or pelvic cancer has not been confirmed in a phase III trial [1
]. Moreover, systemic amifostine treatment may cause severe side effects [5
]. Therefore, the use of amifostine is not widely implemented in clinical practice. Currently, intestinal radiation toxicity can only be managed symptomatically with analgesic, anti-emetic agents or drugs to reduce diarrhoea.
Hence, novel substances that can prevent or reduce intestinal radiation injury in cancer patients are urgently needed. During the last few years it is become clear that these agent do not necessarily need to be radioprotectants, i.e. agents administered before radiation exposure that protect the cell at the moment of exposure. Agents may also reduce radiation injury by targeting pathways more downstream in the pathogenesis of radiation injury [6**
]. Administration of these substances may be started after radiation exposure. These agents are called radiation mitigators opposed to protectants. Recently, various novel target pathways to mitigate radiation injury have been discovered.
Remarkably, many of the recently indentified candidate agents to reduce radiation injury were initially not investigated to reduce radiation injury in cancer patients, but to reduce toxicity after radiation exposure in non-clinical situations. Lately, the socio-political climate has been supportive towards research programmes to develop novel radiation countermeasures for emergency situations such as nuclear accidents and terrorist attacks with radioactive material. This trend has not only provided novel opportunities and funds to develop interventions for non-clinical radiation exposure, but may also benefit cancer treatment. The newly discovered drug may develop as “dual utility” drugs that can both be used as radiation countermeasure and in patients undergoing radiotherapy. The field of radiotherapy may therefore benefit from novel advances made in the development radiation countermeasures.
This review will discuss several promising novel drugs emerging from the lab that that may be able to prevent or reduce intestinal radiation injury in cancer patient. The discussed agents appear to exert their effect by protection or stimulation of the intestinal epithelium, endothelium or immune system.