Patients and
mucositis

Signs and symptoms of mucositis include:

• Red, shiny, or swollen mouth and gums
• Blood in the mouth
• Sores in the mouth or on the gums or tongue
• Soreness or pain in the mouth or throat
• Difficulty swallowing or talking
• Feeling of dryness, mild burning, or pain when eating food
• Soft, whitish patches or pus in the mouth or on the tongue
• Increased mucus or thicker saliva in the mouth

An extreme case of the condition is called confluent mucositis.  In a worst case, the mucous membrane of the patient’s entire mouth and tongue can be coated by a white mucus coating that is up to a millimeter thick.  The combination of mucus, excess saliva and pain can make it difficult or even impossible to eat.

The majority of oral cancer patients receiving chemotherapy in combination with radiation will experience at least some degree of mucositis. When caused by chemotherapy, mucositis is usually due to the low white blood cell count; when caused by radiation, mucositis is usually due to the necrotic and inflammatory effect of radiation energy on oral mucosa.

Factors that can increase the likelihood of developing mucositis, or that can make it worse if it does occur, include:

• Poor oral or dental health.
• Smoking or chewing tobacco and drinking alcohol.
• Gender (females appear to be more likely than males to develop mucositis)
• Dehydration.
• Low body mass index.
• Previous cancer treatment
•  Previous gastritis
• Diseases such as kidney disease, diabetes or HIV/AIDS.
• Previous cancer treatment.
• Chronic irritation from ill-fitting prostheses or faulty restorations can predispose patients to the development of oral mucositis due to local irritation and trauma.
• Generally, patients with hematologic malignancies have an increased rate of oral mucositis compared with those with solid tumors. This is to some extent related to the treatment regimens.
• Hyposalivation prior to and during treatment is associated with an increased risk of oral mucositis.
• The use of methotrexate for chronic GVHD prophylaxis may exacerbate lesions of oral mucositis, although this is less of a concern with newer prophylaxis regimens.
• Oral mucositis occurs independently of oral mucosal infections of viral and fungal etiology, but it may be exacerbated by such concomitant infections.

Younger patients tend to develop oral mucositis more often than older patients being treated for the same malignancy with the same regimen. This appears to be due to the more rapid rate of basal cell turnover noted in children. However, the healing of oral mucositis is also more rapid in the younger age group.

Prevalence of mucositis in cancer treatments

It is estimated that around 40% of people receiving chemotherapy will develop some degree of mucositis.(13)

In patients receiving very high doses of chemotherapy before haematopoietic stem cell transplant (HSCT) (bone marrow transplant), OM is seen in 80% of patients.(2)

It is estimated that up to 97% of people who have radiotherapy for head and neck cancer will develop some form of mucositis, which can include OM.(13)

Up to 90% of paediatric oncology patients may suffer from cancer treatment induced oral complications.(14)

It is important that cancer patients be on the lookout for signs of mucositis, which should be treated as soon as possible once diagnosed. The consequences of mucositis can be mild, requiring little intervention, but they can also be severe such as hypovolemia, electrolyte abnormalities, and malnutrition and even result in fatality.

Oral mucositis can:

• Cause pain
• Restrict oral intake
• Act as a portal of entry for organisms
• Contribute to interruption of therapy
• Increase the use of antibiotics and narcotics
• Increase the length of hospitalization
• Increase the overall cost of treatment.

Patients with oral mucositis and neutropenia (a type of white blood cell deficiency) have a relative risk of septicemia (a systemic, toxic illness caused by the invasion of the bloodstream by virulent bacteria coming from a local infection) more than 4 times that of patients with neutropenia only.

Mucositis is further complicated by the nausea and vomiting that often occur with treatment. Chemotherapy and radiation therapy can affect the ability of cells to reproduce, slowing healing of the oral mucosa, often extending the duration of present mucositis. Patients with damaged oral mucosa and reduced immunity are also prone to mouth infections.

Taste loss tends to increase in proportion to the aggressiveness of treatment. Nausea, pain, vomiting, diarrhea, a sore or dry mouth may make eating difficult. Thus, maintaining adequate nutrition is an important challenge for oral cancer patients. Reduction of caloric intake can lead to weight loss, loss in muscle mass strength and other complications, including a decrease in immunity and a longer healing time from treatments.

Measuring the severity of Oral Mucositis

Oral Mucositis is usually diagnosed with a description of symptoms and a physical examination.(20) Diagnosis is based on the clinical appearance, location, timing of oral lesions, and use of certain types of therapy known to be associated with OM.(20)

Patients receiving high-dose chemotherapy or radiotherapy will commonly receive regular assessments for mucositis until their risk of developing the condition has passed.(20)

Healthcare professionals use a grading system to determine how serious the symptoms of OM are.(20) There are several grading systems available, including systems presented by the World Health Organization Oral Toxicity Scale (WHO OTS).(21)

Who Oral Toxicity Scale

Radiation proctitis or radiation proctopathy is condition characterized by damage to the rectum after exposure to x-rays or other ionizing radiation as a part of radiation therapy. Radiation proctopathy may occur as acute inflammation called “acute radiation proctitis” (and the related radiation colitis) or with chronic changes characterized by radiation associated vascular ectasias (RAVE) and Chronic radiation proctopathy. Radiation proctitis most commonly occurs after pelvic radiation treatment for cancers such as cervical cancer, prostate cancer, bladder cancer, and rectal cancer. RAVE and chronic radiation proctopathy involves the lower intestine, primarily the sigmoid colon and the rectum, and was previously called chronic radiation proctitis, pelvic radiation disease and radiation enteropathy.

Signs and symptoms

Acute radiation proctopathy often causes pelvic pain, diarrhea, urgency, and the urge to defecate despite having an empty colon (tenesmus). Hematochezia and fecal incontinence may occur, but are less common. Chronic radiation damage to the rectum (>3 months) may cause rectal bleeding, incontinence, or a change in bowel habits secondary. Severe cases may lead to with strictures or fistulae formation. Chronic radiation proctopathy can present at a median time of 8-12 months following radiation therapy.

Diagnosis

Where chronic radiation proctopathy or RAVE is suspected, a thorough evaluation of symptoms is essential. Evaluation should include an assessment of risk factors for alternate causes of proctitis, such as Clostridium difficile colitis, NSAID use, and travel history. Symptoms such as diarrhea and painful defecation need to be systematically investigated and the underlying causes each carefully treated. Testing for parasitic infections (amebiasis, giardiasis) and sexually transmitted infections (Neisseria gonorrhoeae and herpes simplex virus) should be considered. The location of radiation treatment is important, as radiation directed at regions of the body other than the pelvis (eg brain, chest, etc) should not prompt consideration of radiation proctopathy.
Endoscopy is the mainstay of diagnosis for radiation damage to the rectum, with either colonoscopy or flexible sigmoidoscopy. RAVE is usually recognized by the macroscopic appearances on endoscopy characterized by vascular ectasias. Mucosal biopsy may aid in ruling out alternate causes of proctitis, but is not routinely necessary and may increase the risk of fistulae development. Telangiectasias are characteristic and prone to bleeding. Additional endoscopic findings may include pallor (pale appearance), edema, and friability of the mucosa.

Classification

Radiation proctitis can occur a few weeks after treatment, or after several months or years:

• Acute radiation proctitis — symptoms occur in the first 3 months after therapy.^[4] These symptoms include diarrhea and the urgent need to defecate.
• Radiation associated vascular ectasias (RAVE) and Chronic radiation proctopathy — previously known as “chronic radiation proctitis” occur 3-6 months after the initial exposure. RAVE is characterized by rectal bleeding, chronic blood loss and anemia. Chronic radiation proctopathy is characterized by urgency, change in caliber and consistency and increased mucus. Severe cases may present with fistulas and strictures which are rare.

Effect of radiotherapy on the gastrointestinal (GI) tract

The colon and rectum are commonly affected by abdominal and pelvic radiotherapy, because of their anatomical locations within the radiation field of various pelvic cancers.(1) The direct effects of radiation on the bowel mucosa can cause almost every patient to have some manifestation of acute radiation-induced injury of the GI tract in the form of burning pain sensations, abdominal cramping, tenesmus, urgency, bleeding, diarrhoea and incontinence.(2)

Injury to the GI tract due to radiotherapy depends on the type of radiotherapy given, the dose delivered to tissues, the way it is delivered, and how radiation energy dissipates through tissue.(3) Radiation injury of the rectum is attributed to the direct mucosal damage from radiation exposure characterised by inflammation or cell death.(4)

During external beam radiotherapy, ionising radiation enters and exits the body and therefore affects normal tissues surrounding the target tumour.(1)

Radiotherapy initially causes mucosal changes characterised by inflammation or cell death, but subsequently persistent cytokine activation in the submucosa leads to chronic effects such as progressive ischaemia, fibrosis and loss of stem cells. These ischaemic and fibrotic changes potentially cause chronic impairment of GI physiological functions.(5)

Acute changes in GI physiology can occur in any part of the GI tract that is exposed to radiotherapy, leading to clinical or subclinical symptoms.(3)

Radiation proctitis is radiation-induced rectal mucositis; and is defined as an inflammatory process of the rectal mucosa that occurs almost immediately after the initiation of therapy or up to 3 months after the onset of radiotherapy. Symptoms of acute radiation proctitis include burning pain sensations, diarrhoea, nausea, cramps, tenesmus, urgency, mucous discharge and minor bleeding.(6)

Acute radiation proctitis appears oedematous, beefy red, and may have ulceration of sloughing. Microscopically, there is a loss or distortion of the microvillus architecture with hyperaemia, oedema and ulceration. Colonoscopic biopsy of the inflammatory rectal mucosa is not usually recommended due to the increased risk of bleeding and fistula formation. Acute radiation proctitis does not increase the risk of chronic radiation proctitis, and is usually self-limiting with the discontinuation of radiation therapy.(6)

Acute radiation proctitis is caused by the death of rectal mucosal cells, and is confined to the lower 25cm of the large intestine.(7)

Cytotoxic chemotherapy agents have a direct effect on the GI mucosa, exerting chemotherapeutic damage to the epithelium, causing inflammation, oedema, ulceration and atrophy.(5) (8) Chemotherapy can cause small bowel bacterial overgrowth, bile acid malabsorption and pancreatic insufficiency, leading to chemotherapy-induced GI symptoms. In addition, patients may experience ongoing chronic GI problems with constipation, diarrhoea, flatulence, bloating and pain.(5)

The degree of damage to the mucosa, submucosa and GI stem cells may play a role in the development of chronic problems. In addition, chemotherapy increases the sensitivity of non-cancerous tissues to damage from radiotherapy.(5)

Risk factors for GI radiation injury include:

• Radiation techniques: Treatment volume, total dose, fractionation dose and schedules(1)
• Radiation dose is a major determinant of the severity of acute and late normal tissue toxicity(1)
• Radiation dose per fraction and altered fractionation schedules are important factors linked to increased risk of intestinal radiation toxicity(1)
• Treatment field size and intestinal volume irradiated are important factors and a key determinant of radiation toxicity(1)
• Combined modality therapies: Surgery or concurrent chemotherapy(1)
• Surgery could lead to an increased risk of radiation toxicity due to anatomical changes that increase intestinal exposure to radiation(1)
• Combining chemotherapy with radiation has been reported to increase the rate of acute intestinal toxicity(1)
• Medical co-morbidities: Vascular disease, connective tissue disease, inflammatory bowel disease, HIV(1)
• Genetic susceptibility: Single nucleotide polymorphism, ataxia, telangiectasia(1)

Prevalence of GI symptoms and radiation enteritis following cancer treatment.

In terms of acute radiation enteritis, almost all patients will experience signs and symptoms.(9)

GI symptoms are the most common of all the chronic physical side effects of cancer treatment, and have the greatest impact on quality of life. Yet, the prevalence of GI side effects following cancer treatment is reported to be underestimated.(5)

In 2013, Macmillan Cancer Support estimated that 90,000 people were living with chronic changes in lower GI function following treatment of pelvic cancers.(10)

In a UK study, chronic radiation enteritis was reported in up to 20% of patients receiving pelvic radiotherapy.(11) As cancer incidence continues to increase(12) it can be assumed that the number of people affected by GI consequences of cancer and its treatment will also increase.

The prevalence of GI symptoms following chemotherapy is less well reported than the prevalence of GI symptoms induced by pelvic radiotherapy. Some patients will not report GI symptoms, largely due to embarrassment or the belief that nothing can be done.(5)

The vaginal mucosa

The vagina is an elastic, muscular canal with a soft, flexible lining that provides lubrication and sensation, and connects the external vagina. The vulva and labia form the entrance, and the cervix of the uterus protrudes into the vagina, forming the interior end.(1)

The vaginal wall consists of three layers:

1. An inner mucous type stratified squamous cell epithelium supported by a thick lamina propria that undergoes hormone-related cyclical changes
2. The muscularis composed of outer longitudinal smooth muscle fibres and inner circular fibres
3. An outer fibrous layer, rich in collagen and elastin, which provides structural support to the vagina.(2)

Effect of chemotherapy on the vagina

Chemotherapy can damage the vaginal tissue, which can lead to ulcerations or disruption in the integrity of the mucosa, and increase the risk of infection.(3) Chemotherapy drugs that may cause mucositis can also cause vaginal irritation.(4)

Effect of radiotherapy on the vagina

The vaginal and vulval epithelium are highly sensitive to the effects of pelvic irradiation or pelvic radiotherapy due to rapid cell-turnover.(5)

Radiotherapy to the pelvic region can damage vaginal epithelium, connective tissues and small blood vessels, causing inflammation and cell death prior to resolution. The subsequent reduced blood supply, tissue hypoxia, loss of elastin, collagen deposition and hyalinisation and fibrosis leads to thinning of the vaginal mucosa, loss of lubrication, scarring and fibrosis.(6)

Acute effects of pelvic radiation in women

Following pelvic radiation, acute radiation effects include vaginal erythema, moist desquamation and a confluent mucositis. The mucosa may demonstrate severe congestion and submucosal haemorrhage.(5)

Radiation damage to the vaginal mucosa can cause inflammation, leading to pain. In addition, the damaged mucosa may lead to reduced vaginal secretions, causing vaginal dryness and itching.(7)

Significant vaginal, vulval and perineal changes may arise after radiotherapy and cause considerable pain during all phases of sexual interaction in the first months following radiotherapy. The acute effects of pelvic radiotherapy on the vagina may last for 2-3 months following radiotherapy.(5)

Pelvic cancers include: anal cancer; cervical cancer, uterine cancer, vaginal cancer, vulva cancer, ovarian cancer, bladder cancer and bowel cancer.(7)

Figure 1: Reported new cases of pelvic and abdominal cancers in females in 2013

Current UK guidelines for the acute effects of pelvic radiotherapy

Many current guidelines focus on the treatment of the long term effects of pelvic radiotherapy. However, Macmillan Cancer Support recommends that all women offered pelvic radiotherapy for a gynaecological cancer should receive and be guided to information on the potential side effects of treatment, including the potential for ovarian or uterine damage caused by pelvic radiotherapy.(16)

There are no specific guidelines for the management of the acute effects of pelvic radiotherapy.

Radiation therapy (RT) is a frequently used modality for cancer treatment. Acute and/or chronic skin changes may occur and carry risk of influencing quality of life during and after completion of RT. Radiation reactions may lead to delays in treatment, diminished cosmesis, and functional deficits. Lifestyle factors, treatment modalities, topical agents, and, in some cases, wound dressings may be utilized to help prevent or ameliorate radiation-induced skin reactions. While rigorous evidence supporting specific interventions may be lacking or contradictory, this article summarizes the current knowledge of the etiology, manifestations, and interventions available for prevention and management of radiation dermatitis.

Introduction

Radiation therapy (RT) remains an essential component of cancer treatment, with nearly 50% of cancer patients receiving RT at some point during the course of their illness. Of those receiving RT, as many as 95% may experience some form of radiation dermatitis, or radiation-induced skin injury.[1] Radiation dermatitis can manifest as acute erythema and desquamation, or as chronic effects including skin atrophy, telangiectasias, and fibrosis. These skin changes result from a combination of RT features and intrinsic patient risk factors. While a reduced total dose of radiation and use of an advanced mode of radiation delivery may help to mitigate the severity of radiation effects on the skin, radiation dermatitis remains one of the most common side effects of RT. This condition can affect a patient’s quality of life both during and after treatment. If severe, it carries the risk of limiting the dose of radiation or interrupting the treatment schedule, which could negatively impact treatment efficacy. Consequently, managing radiation-induced skin injury during and after treatment is an important aspect of cancer care.

Pathophysiology and Clinical Presentation

The high energy x-rays used in modern RT produce both direct and indirect ionization events that not only result in injury to cancer cells, but also pose a risk of injury to normal tissues (Figure 1). Most patients undergoing RT receive small, daily doses of radiation; the clinical goal is to achieve tumor killing after repeated exposure while minimizing harm to healthy surrounding tissue.[2] Inevitably, however, a small fraction of rapidly proliferating cells in the basal layer of the skin are injured or destroyed, precipitating a decrease in the population of differentiated epidermal keratinocytes; this can result in desquamation-ie, the peeling and shedding of the epidermis-depending on the total dose of radiation delivered. Impairment of the skin barrier function carries the risks of wound formation, loss of immune function, and infection. Further, radiation can also damage the microvascular system, increasing the risk of tissue hypoxia and fibrosis, and activating an inflammatory cascade, leading to acute and chronic skin changes.

The acute phase of radiation dermatitis is often defined as the changes seen within 90 days following RT. The development of acute radiation dermatitis follows a predictable course. While multiple systems exist for the grading of skin effects from RT, the ones most commonly referenced are the Radiation Therapy Oncology Group grading scale and the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03  Transient, mild erythema can occur within hours of RT, likely due to capillary dilation shortly after patient exposure to radiation. However, the more conventional, sustained hyperpigmentation or erythema associated with RT typically does not occur until 2 to 4 weeks into treatment. Hair follicles and sebaceous glands can be affected early in the course of RT, leading to dry skin and hair loss. As erythema develops, a sunburn-like reaction can ensue, with associated edema, pruritus, tenderness, and a burning sensation. Dry desquamation, which manifests as pruritus and flaking of the skin, may occur 3 to 6 weeks into the RT regimen, at cumulative doses above 20 Gy.[9] With increasing radiation doses above 30 to 40 Gy, patients may develop moist desquamation-a condition that is characterized by tender, red skin associated with serous exudate, hemorrhagic crusting, and the potential for development of bullae. Due to breakdown of the skin barrier, this stage is generally painful. It is characterized by increased susceptibility to contact injury, particularly in flexural areas prone to frictional stress; by infection; and by ulcer formation. In cases of extreme desquamation, clinicians may need to withhold RT for a period of time, to allow for sufficient re-epithelialization before the patient resumes treatment.

Figures 2 and 3 provide examples of different stages of dermatitis and illustrate how varying degrees of dermatitis can occur within the same radiation field. The acute skin reaction typically peaks at 1 to 2 weeks after completion of RT. As the epidermal keratinocytes repopulate and the immune response cascade reverses, the symptoms of acute dermatitis resolve in most patients. The time to resolution of any desquamation, erythema, and edema typically is 2 to 4 weeks following the end of treatment. It is not uncommon for residual postinflammatory hyperpigmentation to persist, but this typically wanes over subsequent months posttreatment.

Chronic radiation dermatitis is typically defined as changes that occur more than 90 days following a course of RT (Figure 4). Chronic skin changes may result from aberrant or dysregulated alterations in proinflammatory and profibrotic cytokines. These changes may include hypopigmented and/or hyperpigmented skin that persists or develops after resolution of the acute phase of dermatitis. There may be sustained loss of certain skin structures such as sebaceous glands, hair follicles, and nails, as well as textural changes to the skin.

Thinning or atrophy of the epidermis and dermis may be observed, although some patients may develop induration and thickening of the dermis. Telangiectasia may occur as a result of blood vessel dilation, while damage to blood vessels may also result in tissue hypoxia, predisposing the patient to development of skin ulceration and/or chronic wounds. Radiation-induced fibrosis is a potentially serious sequela of RT that may cause poor cosmesis, lymphedema, skin retraction, persistent hyperpigmentation, and joint immobility. In summary, depending on the severity and location of chronic skin changes after RT, there is potential for decreased quality of life due to pain, recurrent wounds, decreased range of motion, and cosmetic dissatisfaction.

Both the likelihood of developing radiation dermatitis and the severity of symptoms are dependent on a variety of factors. These include:

• The proximity of the radiation target to the skin.
• The energy of the radiation used.
• The radiation dose and fractionation schedule of treatment.
• The size of the skin surface area exposed to radiation.
• The presence or absence of radiosensitizing concurrent chemotherapy.

Thus, significant radiation dermatitis is most often seen in patients receiving treatment for sarcoma and cancers of the skin, breast, head and neck, vulva, and anus, since the target area of treatment is often close to the skin, with limited ability to spare the skin from higher doses of radiation exposure. Certain patient-specific factors can also increase the risk and severity of radiation dermatitis; these include malnutrition, smoking, excessive skin folds, elevated body mass index, underlying vascular or connective tissue disease, and genetic factors such as inherited DNA repair deficiencies (eg, as seen in Fanconi anemia and ataxia-telangiectasia syndromes)