I. Problem/Condition

Radiotherapy is used in half of cancer patients, and this is expected to increase as the population continues to age. Despite its effectiveness, it has been associated with multiple complications, ranging from mildly troubling to life-threatening. A complete discussion of all the possible complications of radiotherapy is beyond the scope of this chapter. However, the most common acute side effects which might lead to hospitalization – cytopenias, radiation esophagitis/mucositis, radiation pneumonitis, and radiation enteritis – will be discussed.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The most important consideration when attributing a symptom or clinical finding to radiation is that radiation side effects are local. If the area is not being irradiated, do not expect to see a complication from radiation in that area.

Attributing a complication to radiotherapy requires knowledge of the radiotherapy treatment plan/area, and may be best assessed by the radiation oncologist. As the side effects of radiotherapy, unlike chemotherapy, are almost entirely local, knowing exactly where the treatment is delivered is helpful in assessing the likelihood that the given symptoms are indeed caused by radiation. Therefore, patients getting radiation to one part of the body are not at risk for getting a radiation-induced complication to another part of the body.

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Likewise, radiotherapy side effects correlate to certain dose volume parameters calculated for the individual patient. There is a tendency to attribute untoward symptoms to radiation in patients undergoing treatment. This should be avoided as it may mask another underlying process that needs medical attention. For example, if a patient receiving whole brain radiation is found on endoscopy to have an erosion at the gastroesophageal junction, this is not radiation esophagitis, as the esophagus is not receiving radiation, and therefore, not at risk. Another etiology (steroid-induced gastritis) should be sought and treated.

Radiation pneumonitis is always a diagnosis of exclusion. Before treating with high dose steroids, one should eliminate infectious etiologies, as steroids would most often worsen those conditions. Pneumocystis carinii pneumonia, community-acquired pneumonia, drug-induced pneumonitis, metastatic disease to the lungs or lymphangitic carcinomatosis should also be considered.

Radiation enteritis is clinically indistinguishable from other causes of diarrhea. It is typically a secretory diarrhea, and pathologically results from radiation-induced damage of the intestinal crypt cells with loss of absorptive ability. It can also take an exudative form, with both blood and pus present in the stool.

Radiation oral mucositis can often coexist with oropharyngeal candidiasis, and both should be sought out and treated.

B. Describe a diagnostic approach/method to the patient with this problem

Diagnostic approach to the patient with a suspected radiation-induced complication

The ideal approach investigates the relationship of the symptoms with the start of the radiation, the location of the symptoms with the location of the radiation and the likelihood of alternate causes.

Review of the dose-volume histogram (a report generated by the radiation oncology team specifying what volume of each nearby organ received what dose of radiation) is helpful in predicting the likelihood of a radiotherapy-related complication to that organ.

1. Historical information important in the diagnosis of this problem.

Diagnosis of radiation-induced toxicity

The interview should focus on what treatment the patient received, how long ago and how many total treatments were delivered. Radiation mucositis, esophagitis, gastritis, enteritis, and cytopenias typically occur during treatment or immediately (2-3 weeks) following treatment.

Side effects and their severity are cumulative with the accumulated dose – so a patient receiving standard fractionation (i.e., standard dosing schedule between 1.8 grays (Gy) and 2 Gy given daily, 5 days each week for 5 to 8 weeks) is unlikely to have any significant skin or mucosal reactions until sometime after the 10th treatment.

Meanwhile, patients being treated palliatively who receive hypofractionated courses (3-8 Gy per day for 5-10 treatments) may experience delayed dermal and mucosal reactions, which do not appear until the first or second week following the completion of treatment. Generally speaking, palliative courses are given in fewer, larger doses, and definitive courses are given in a more protracted fashion (6-8 weeks). Importantly, patients receiving palliative hypofractionated radiotherapy have limited survival and are not likely to experience the more long-term side effects associated with this therapy.

Concurrent chemotherapy can lead to earlier and more severe symptoms.

Radiation pneumonitis typically presents as low-grade fevers, dry cough and mild dyspnea within 12 weeks after radiation therapy. Pneumonitis during radiation is exceedingly rare, although there are situations in which there can be an acute respiratory distress syndrome (ARDS) type presentation following even a single dose of radiation to very large volumes of lung (hemi-lung or whole lung).

Radiation esophagitis presents as any esophagitis, in that the predominant symptom is odynophagia, first to solids, then to liquids. In the early stages, patients may experience awareness of food’s passage or a feeling of food almost “getting stuck” in the throat before true pain is perceived.

It is most commonly seen in thoracic radiotherapy (when the mediastinum is included, like for stage III non-small cell lung cancer, or in palliative treatment of cervical thoracic spine metastases). In patients undergoing a 6-week or longer course of radiation, esophagitis emerges after week 2-4, and gradually increases in severity. Patients who have sudden onset severe esophagitis should raise suspicion of a candidal infection.

Radiation enteritis begins as an increase in bowel movements, with gradually soft bowel movements progressing into frank diarrhea over days to weeks. Of note, the intestines are highly sensitive to radiation. As such, nearly every patient receiving abdominal, pelvic, or rectal radiotherapy will experience symptoms of radiation enteritis. Symptoms usually start during the first course of radiation, but can occur up to 8 weeks following treatment.

Patients who report sudden-onset explosive diarrhea are more likely to have an alternate cause (e.g., infectious or chemotherapy-induced, like capecitabine). This can be associated with crampy abdominal pain, malaise, nausea, and anorexia. It should subside within 2-6 weeks following cessation of radiation therapy, with a large majority resolved to minimal side effects within 2 weeks.

Certain chemotherapeutics can cause a “radiation recall” phenomenon, most commonly as recall dermatitis, but also as a recall pneumonitis. This is most associated with taxanes and anthracyclines, and has been associated with gemcitabine, erlotinib, and etoposide. “Radiation recall” can also occur with cefazolin, tamoxifen, simvastatin, azithromycin, and antituberculosis agents. Patients remote from radiation who exhibit signs of pneumonitis or dermatitis but have recent exposure to a new drug should be considered for having a recall phenomenon.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Examination of the skin will often demonstrate tattoo demarcation of the treatment field. With time, treatment portal hyperpigmentation can develop as an indication on physical exam of where treatment is being delivered. This is dose dependent, so changes may not appear until the second or third week of treatment as a barely perceptible blush erythema, which may progress to brisk erythema or even moist or dry desquamation (skin peeling).

There may be no perceptible skin changes when treatment is delivered through greater than three approaches, or fields, per day, such as with intensity modulated radiation therapy (IMRT) or some 3D conformal approaches.

Radiation pneumonitis classically has crackles in the affected lung(s). Hypoxia may be noted in more severe cases.

Radiation esophagitis often shows no discernible mucosal changes in the oropharynx, as the inflammation and mucosal damage is at the site of radiotherapy delivery, which may be much further down in the gastrointestinal tract.

Presence of thrush may be a coexistent problem, even in patients not receiving chemotherapy. Mucositis, however, is usually easily visualized in the oropharynx/oral cavity. The severity of the mucositis (patchy versus confluent ulceration) will be discernible and correlates with the severity of symptoms. Hypotension often accompanies esophagitis and mucositis, and is from dehydration.

Radiation enteritis physical exam can be notable for borborygmi, although this does not distinguish it from other causes.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Complete blood count should be obtained. High white blood cell may indicate infection (coexistent or solitary), whereas profoundly neutropenic (absolute neutrophil count (ANC) less than 500) patients with diarrhea should be considered for neutropenic typhlitis/enterocolitis. Leukopenia need not be present for candidal infections of the esophagus/oropharynx to be seen.

Radiation pneumonitis classically appears on computed tomography scan of the chest as inflammation and ground glass opacification within the radiation portal. Often, there is a straight line on the scan correlating to the definition of the treatment portal rather than any anatomic delineation. This is diagnostic of radiation-induced lung injury, although such changes can occur radiographically without clinical symptoms. Spirometry with diffusing capacity testing can help characterize the severity of radiation pneumonitis and fibrosis, though the 6-minute walk test can also assess for radiation pneumonitis.

More complicated techniques (intensity-modulated radiation therapy, stereotactic body radiation therapy, multi-field 3D conformal radiation), which throw a wider low dose halo around the treated area may not show defined lines, and are more difficult to recognize.

However, when one compares the diagnostic scan with the superimposed dose distribution from the treatment, there is often excellent correlation. There is excellent data regarding the prediction of radiation pneumonitis based on certain dose-volume parameters (V5, V10 , V20 of the total lungs, mean lung dose).

Computed tomography of the abdomen in radiation enteritis often shows diffuse bowel wall thickening, which is supportive but not diagnostic. Endoscopy should be avoided unless other causes are considered likely.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

There are no laboratory tests that can definitively diagnose a radiation-related complication. The diagnosis is made through review of the radiotherapy treatment administered, the timing of the complication in relationship to radiation dose and absence of other causes.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

In the appropriate clinical scenario, investigation with invasive techniques is inappropriate if a radiation-induced cause is suspected. Patients receiving definitive treatment for lung cancer with targeting of the mediastinum, or head and neck cancer patients, are routinely expected to experience esophagitis, which can take 2 (or rarely 3) weeks to resolve following cessation of radiation. Pursuing endoscopy in such patients, provided they show signs of improvement with time, is inappropriate and unnecessary.

Likewise, radiotherapy-induced skin effects, provided they are confined to the treatment area, do not require skin biopsies, topical antimicrobials or consideration of a drug rash.

Radiation enteritis does not require endoscopy for diagnosis.

Radiation pneumonitis requires bronchoscopy only when another cause is considered likely. The temptation to do a positron emission tomography (PET) scan to determine if consolidation is tumor recurrence or pneumonitis should be evaluated with the knowledge that pneumonitis is a fluorodeoxyglucose-avid (FDG-avid) process, and the intensity of the uptake correlates with the severity of the pneumonitis.

III. Management while the Diagnostic Process is Proceeding

A. Management of acute complications of radiation.

Radiation enteritis should be managed initially with loperamide (4 mg after first loose stool, then 2 mg every loose stool thereafter to a maximum of 16 mg/day). As this loses it efficacy, diphenoxylate hydrochloride plus atropine sulfate (2.5 mg/0.025 mg tablets, 2 tablets 4 times daily) can be used.

Tincture of opium (6 mg orally 4 times daily) is also effective in severe cases, and there is some data that octreotide (100 micrograms subcutaneously 3 times daily) is efficacious. Prophylaxis with a probiotic containing live lactobacillus acidophilus plus bifidobacterium bifidum can be considered.

Radiation esophagitis is managed with topical anesthetics (viscous lidocaine on its own or combined with liquid diphenhydramine or liquid Maalox), analgesics (opioids, such a oxycodone or hydrocodone elixir preparation, with or without a fentanyl patch) and antacid therapy.

Analgesics without acetaminophen are preferred, since accidental acetaminophen overdose can occur as patients increase their dose to treat pain. Topical anesthetics, when prescribed for oral mucositis, are often given with the instruction to swish and swallow. In the setting of esophagitis rather than oropharyngeal mucositis, this is unnecessary, and patients may prefer to take the drug via a straw to bypass the unpleasant numbness within the oral cavity.

Sucralfate has been shown to be ineffective, although once commonly prescribed. Diet modification is suggested with a switch to bland, soft or pureed foods. Extremes of temperature, acidic foods (coffee, citrus or tomato juices), hard foods (chips, dry bread), or spicy foods should be avoided. Nutritional supplements are useful to boost calorie intake in the setting of weight loss.

Radiation mucositis is often profound and severe in definitive radiation of the head and neck, particularly in the setting of concurrent chemotherapy. Aside from limited circumstances (e.g., radiation alone for T1 or T2 N0 glottic carcinomas), most patients have a large volume treated and experience significant mucositis. Meticulous oral care is needed, and most radiotherapy centers recommend baking soda and saline rinses (1 liter of water with 1/2 teaspoon sodium bicarbonate and 1/2 teaspoon salt) 3-4 times daily. Gentle tooth brushing and flossing should occur, being careful not to inflict further mucosal trauma.

Topical anesthetics are rarely useful for long. The switch to opioid analgesia should be made early on to prevent treatment breaks, which are detrimental for tumor control. Patients should strongly consider prophylactic percutaneous endoscopic gastrostomy (PEG) tube placement, as morbidity tends to be less and quality of life may be improved, although data regarding equivalence of longterm outcomes and necessity of tube placement have recently been questioned.

Basic oral care is the first step in maintaining oral mucosal health. Multiple expert panels have recommended against the use of particular products, including mouthwashes containing sucralfate, chlorhexidine, and misoprostol and antimicrobial containing products. Adequate pain control is important and patient controlled analgesia may be needed. Radiation esophagitis is managed similarly to mucositis in terms of symptomatic agents (topical analgesia, narcotics). Intravenous hydration is often required.

The viscid secretions that go along with the xerostomia often seen with head and neck radiation are often well managed with the simple salt and sodium bicarbonate rinses. Elevation of the head of the bed to 30 degrees can be useful, and some patients can require portable suction to remove the secretions manually from the mouth. In patients in whom a cycle of gagging can develop from the thickness of the secretions, lorazepam is useful. A cool mist vaporizer can also help, although if used at home proper cleaning must occur to prevent pseudomonas contamination. Scopolamine can be used when secretions are large volume, however in many patients the issue is that secretions are already too dry, and as such further drying is detrimental.

Radiation pneumonitis, when very mild and consisting only of a cough, can be initially managed with nonsteroidal anti-inflammatory drugs. More severe cases should warrant steroids, typically 60 mg of prednisone daily for two weeks followed by a slow for a total of 12 weeks of therapy. Some patients require a more protracted taper. Consistent with the pathologic hyperactivation of the immune system, there are case reports regarding the efficacy of cyclosporine and azathioprine.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

The most important measure that is taken is the proper diagnosis of a radiotherapy complication. Overlooking other causes due to inappropriately attributing a complication to radiotherapy delays appropriate treatment. Symptom management is the most important maneuver.

IV. What's the evidence?

Kim, JH, Jenrow, KA, Brown, SL. “Mechanisms of radiation-induced normal tissue toxicity and implications for future clinical trials”. Radiation Oncology Journal. vol. 32. 2014. pp. 103-115. (This article discusses the clinical and pathological manifestations of radiation injury and notes therapeutic strategies for treatment.)

Moleiro, J, Faias, S, Fidalgo, C, Serrano, M. “Usefulness of Prophylactic Percutaneous Gastrostomy Placement in Patients with Head and Neck Cancer Treated with Chemoradiotherapy”. Dysphagia. vol. 31. 2016. pp. 84-89. (This is a prospective evaluation of PEG tube placement in patients with head and neck cancer.)

Hauer-Jensen, M. “Late radiation injury of the small intestine. Clinical, pathophysiologic and radiobiologic aspects”. A review. Acta Oncol. vol. 29. 1990. pp. 401-15.

Lutz, ST, Chow, EL, Hartsell, WF, Konski, AA. “A review of hypofractionated palliative radiotherapy”. Cancer. vol. 109. 2007 Apr 15. pp. 1462-70. (This article reviews differences between standard and hypofractionated radiotherapy and reviews indications for its use.)