Complications of Chemoradiotherapy for Locally Advanced Non-Small-Cell Lung Cancer

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Introduction

Approximately one-third of patients with non-small cell lung cancer (NSCLC) present with locally advanced disease, the majority of whom are treated with concurrent chemotherapy and thoracic radiation therapy. Concurrent chemoradiation therapy is superior to sequential chemotherapy followed by thoracic radiation therapy or thoracic radiation therapy alone.^1-3 However, this improvement in survival is achieved at the expense of increased toxicity. As a significant proportion of patients treated with chemoradiation therapy develop acute and delayed complications, skillful management of these problems is essential. This article summarizes the diagnosis and management of unique complications associated with chemoradiation therapy for locally advanced NSCLC.

Acute Complications

Esophagitis

The incidence of acute severe esophagitis varies from 1.3% with radiation therapy alone to 14%-52% with concurrent chemoradiation therapy.^4,5 The definition of moderate and severe esophagitis (grade 3 and 4) has been defined variously. The most current version of the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) definition emphasizes the need for nutritional requirement and complications in the grading of esophagitis. Those who require a gastrostomy tube would be designated as having grade 3 esophagitis and those with complications such as perforation and stricture would be defined as having grade 4 esophagitis. Patients with grade 1 esophagitis are diagnosed incidentally when endoscopy is performed for other reasons. The reported incidence of severe esophagitis (grades 3 and 4) varies from 1% with standard once-daily radiation therapy to 52% with chemotherapy (cisplatin, gemcitabine [Gemzar]) and radiation therapy.⁵

Factors predisposing patients to develop severe esophagitis include radiation dose, fractionation (a twice-daily regimen poses a higher risk than a once-daily regimen), use of concurrent chemotherapy, and the volume of the esophagus receiving at least 55 Gy (Table 1). Advanced age (70 years or older) may increase the likelihood of severe esophagitis as well.

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The Radiation Therapy Oncology Group (RTOG 9410) conducted a randomized study  comparing sequential chemotherapy (cisplatin and vinblastine) followed by standard radiation therapy with platinum-based chemotherapy administered concurrently with standard radiation therapy or hyperfractionated radiation therapy.⁶ In this study, elderly patients (70 years or older) had a higher incidence of esophagitis than did younger patients. This difference was noticed regardless of whether radiation therapy was administered once daily (42% vs 33%) or twice daily (60% vs 42%).

The symptoms of acute radiation-induced esophagitis usually begin in the second or third week of radiation therapy, when patients have received around 18-30 Gy. The symptoms often begin with difficulty in swallowing solids and sometimes progress to worsening dysphagia for liquids and painful swallowing (odynophagia) and persistent pain requiring narcotics or intravenous hydration. The severity of esophagitis reaches its peak at around 1 month in about one-fourth of patients and at around 2 months in one-third of patients.⁴ Although the severity of esophagitis is often well documented in prospective studies, the data on the duration of symptomatic esophagitis affecting quality of life are sparse. A few patients with acute severe esophagitis may develop esophageal stricture requiring dilatation several months after the completion of radiation therapy.

Treatment of acute esophagitis is entirely symptomatic. A bland diet that would not irritate the already inflamed esophagus is recommended. An oral suspension mixture consisting of a local anesthetic (lidocaine), surface-coating agent (diphenhydramine), and nystatin mixture taken before meals may offer some transient symptomatic relief for patients with mild to moderately severe esophagitis. At this phase, it is critical to provide dietary counseling to maintain adequate caloric and fluid intake. Patients with severe esophagitis may require intravenous fluids and placement of a gastrostomy/jejunostomy tube for enteral feeding. Parenteral nutrition should be avoided, if possible, in view of the associated risks (chiefly infection-related complications). Endoscopic evaluation may be necessary in some patients suspected of superadded fungal or viral infections.

Amifostine (Ethyol), an organic thiophosphate that is converted to its active metabolite by cellular alkaline phosphatase, has been evaluated as a possible treatment alternative for patients with radiation-induced esophagitis. The data on the ability of amifostine to prevent or ameliorate radiation-induced esophagitis are somewhat conflicting. Greek investigators reported  a significant decrease (41%) in the incidence of esophagitis with the use of amifostine along with concurrent chemoradiation therapy compared with chemoradiation therapy alone.^7,8  Similar results have been reported in small studies  from the United States and Singapore.^9,10 However, a larger US cooperative group phase III study (RTOG 9801) involving 243 patients treated with chemoradiation therapy reported no reduction in the development of severe esophagitis (as defined by the NCI-CTC and physician assessment) with the addition of amifostine.¹¹ At this time, amifostine is not used regularly in the United States for the prevention of esophagitis in patients receiving concurrent chemoradiation therapy for locally advanced NSCLC.

Fatigue

Fatigue is a common problem in patients with cancer. In one study, fatigue was reported to be present in more than 75% of patients undergoing radiation therapy for lung cancer.¹² Fatigue is related to the disease process itself; radiation therapy; chemotherapy; and other factors, including anemia and coexistent infections. Psychological stress and cytokine production have also been suggested as possible additional causes of fatigue in these patients. In the absence of extensive disease, radiation-related fatigue lasts a few weeks to months. Identifying and correcting reversible factors such as anemia and infection may ameliorate some of the symptoms. Unfortunately, there are no specific treatments for cancer-related fatigue. More awareness of cancer-related fatigue is absolutely necessary.

Skin Reactions

Skin reactions are common after radiation therapy. They range from erythema, dry desquamation to moist desquamation and frank ulcer to acute mild irritation to frank ulceration. Typical changes occur with higher doses of radiation (around 2,000 cGy).¹³ The Cancer Care Ontario’s supportive care group (SCCG) systematically reviewed the data from well over two dozen trials to find optimal strategies for prevention and treatment of skin reactions. In this review, washing with mild soap was the only method shown to be effective in preventing skin reactions. In the opinion of the SCCG experts, plain, unscented, lanolin-free hydrophobic ointment was thought to be helpful in preventing severe skin reactions.  Topical moisturizing creams, along with topical steroids, may relieve symptoms in patients with established skin reactions.

Cough

Cough, a common symptom in patients with lung cancer, is often a result of multiple factors, including the disease process, superimposed infections, and possibly inflammation of the tracheobronchial tree from radiation. Radiation pneumonitis (discussed later) develops much later in the course of treatment. Cough is managed symptomatically with either over-the-counter cough suppressants or prescription narcotics (hydromorphone, morphine).

Lhermitte's Sign

Lhermitte's sign, an infrequent sequela of radiation to the cervical spinal cord, presents as transient tingling along the spine upon neck flexion. Although this complication has been reported more commonly in patients with Hodgkin's lymphoma receiving mantle field radiation or in those receiving neck radiation, occasionally patients treated for locally advanced NSCLC report similar symptoms. After radiotherapy, some patients may complain of tingling and numbness in the back, shooting down the spine upon neck flexion. In an analysis of 40 patients who developed Lhermitte’s sign¹⁴ compared with those who did not, two factors emerged as strong predictors of eventual development of Lhermitte’s sign: the use of larger fractions (200 cGy) and total radiation exceeding 5,000 Gy to the cervical spinal cord.

Delayed Complications

Delayed complications from chemoradiation therapy typically occur a month to sometimes several years after definitive treatment. The most common delayed complication is radiation pneumonitis. Others include esophageal stricture; cardiac complications manifesting as pericardial effusion, constrictive pericarditis, or cardiomyopathy; and myelopathy.

Radiation Pneumonitis

Radiation pneumonitis (and its sequela of radiation fibrosis) is one of the devastating complications of thoracic radiation therapy. Widespread use of conformal radiation therapy has not completely eliminated the problem of radiation pneumonitis. It is critical for clinicians to understand the risk factors, clinical presentation, treatment, and prevention of radiation pneumonitis. Acute radiation pneumonitis refers to lung inflammation within 3 months of the initiation of radiation therapy. Radiation fibrosis typically occurs 6 months after radiation treatment.

The grading of severity of radiation pneumonitis differs from one cooperative group to another, with most differences noted in defining grades 2 and 3 (Table 2). The incidence of radiation pneumonitis (grade 2 or higher) varies from 15% with two-dimensional radiotherapy to anywhere between 2% and 31% with more modern conformal radiation treatment.¹⁵ The incidence of radiation pneumonitis varies depending on several components, including those related to radiation, the presence or absence of concurrent chemotherapy, and perhaps individualized factors related to cytokine production.

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The most important predictor of radiation pneumonitis is the volume of lung radiated. The greater the volume of lung receiving more than 20 Gy, the higher the risk for developing radiation pneumonitis. The area of lung radiated may matter as well. Radiation to the lower lung field is associated with a greater risk of radiation pneumonitis.^16,17 In an analysis conducted at our institution, the risk of radiation pneumonitis was higher when the inferior portion of the lung was radiated (44%) than when superior (16%) or middle regions (30%) of the lung were radiated.¹⁶

Several circulating factors have been studied to predict the eventual development of radiation pneumonitis, with the most extensively studied being transforming growth factor-beta (TGF-β). High levels of TGF-β in the blood have been correlated with higher rates of radiation pneumonitis.¹⁵ Other factors studied include interleukin-1 (IL-1), IL-6, surfactant, and platelet-derived growth factor (PDGF). However, none of these biomarkers is used in the clinic to predict the development of radiation pneumonitis. Moreover, these characteristics have a good one-to-one correlation in single-variable models; the sensitivity, specificity, and positive predictive values are usually low. A combination of dosimetric and clinical characteristics or dosimetric and biologic factors such as TGF-β1 levels has been shown¹⁵ to predict the development of radiation pneumonitis in retrospective studies. Prospective validation of these models is necessary to confirm these provocative findings.

The treatment of acute radiation pneumonitis includes appropriate use of bronchodilators and corticosteroids. Patients with significant and progressive hypoxia will require mechanical ventilation. There is no role for antibiotics in the treatment of radiation pneumonitis, unless there is a concern for superadded infection. Corticosteroids should be tapered gradually.

Lung fibrosis is a sequela of radiation pneumonitis. Not surprisingly, the same risk factors that predispose patients to radiation pneumonitis are associated with the development of radiation-induced lung fibrosis.

Esophageal Stricture

Radiation-induced esophageal stricture is an uncommon but devastating complication of radiation therapy for locally advanced NSCLC. In a recent study from Duke University, among 254 patients with unresectable NSCLC treated with combined-modality therapy, 10 developed symptomatic esophageal stricture.¹⁸ In this study, the location (defined endoscopically and radiologically) and the extent of the esophageal stricture corresponded to the 60 Gy isodose line. The authors suggested that limiting the length of the esophagus receiving > 60 Gy of radiation may decrease the severity of radiation-induced esophageal strictures.  It is likely that high-dose/accelerated thoracic radiation, use of brachytherapy in addition to external-beam radiation therapy, and the use of concurrent chemotherapy along with radiation therapy may increase the risk of esophageal stricture. The addition of bevacizumab (Avastin), an inhibitor of vascular endothelial growth factor (VEGF), in combination with chemotherapy and radiation therapy in patients with limited SCLC has resulted in tracheoesophageal fistula in two patients and suspected tracheoesophageal fistula in another patient.¹⁹ Symptomatic esophageal stricture requires repeated dilatation, stents, or placement of a gastrostomy tube.

Cardiac Complications

Radiation-induced cardiac damage could result in radiation pericarditis, radiation cardiomyopathy, and premature or accelerated coronary artery disease.^20,21  In addition, the heart can be affected indirectly by lung fibrosis and thoracic duct fibrosis, leading to chylothorax. Most data on long-term cardiac complications following chest radiation therapy have been obtained from patients treated successfully for breast cancer or Hodgkin’s lymphoma.

Pericarditis is the most common cardiac complication secondary to thoracic radiation therapy. Early-onset acute pericarditis, an uncommon complication, occurs occasionally during radiation therapy for a large tumor contiguous to the heart. The more common delayed pericarditis typically occurs 4 months to several years after radiotherapy. This form of pericardial inflammation presents as acute pericarditis or as chronic pericardial effusion with some degree of tamponade; it is estimated that approximately 20% of cases may result in chronic or constrictive pericarditis.²¹ Radiation-induced symptomatic cardiomyopathy is an uncommon problem, particularly when anthracyclines are not used in the treatment of cancer. Conduction abnormalities and valvular fibrosis are rare complications of chest radiation therapy.

Myelopathy

Occurring 6 weeks to 6 months after radiation therapy, early to delayed myelopathy is a transient complication that involves the cervical or thoracic spinal cord. This complication has been reported to occur in 3% of patients receiving at least 30 Gy of radiation (for the treatment of Hodgkin’s lymphoma involving the mantle field) and in up to 8% of patients receiving at least 50 Gy of radiation.²² Transient demyelination resulting from radiation injury to oligodendrocytes is thought to be the main pathogenetic mechanism. Patients often present with Lhermitte’s sign, as previously discussed. Imaging studies are usually unremarkable. Progressive myelopathy is an uncommon complication, seen in less than 1% of patients when exposure of the spinal cord to radiation is kept within the “safe” range (less than 45 Gy in 22 to 25 fractions).²²

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