Lung, Pleura, and Thymus Cancer
Response of the Trachea and Lung toIrradiation
Thoracic irradiation is an important part of the therapy for many types of cancer, including esophageal cancer, breast cancer, and lung cancer. More than 50% of patients with these types of cancer will receive radiation therapy at some point during the management of the disease. Undiseased parts of the lung inevitably will receive some exposure as part of these treatments, and the lung is the dose-limiting tissue in the treatment of these malignant neoplasms. Optimal treatment planning requires knowledge of the effects of radiation on the normal lung and other normal structures within the treatment field. Although nearly a century has passed since radiation pneumonitis and fibrosis were first described by Evans and Leucutia, we remain unable to circumvent or effectively treat these two side effects of pulmonary irradiation, and they continue to limit the effective treatment of lung cancer.
Radiation Therapy for Lung Carcinoma
Carcinoma of the lung is the most common malignant disease in the United States and in several countries in northern and western Europe. It accounts for one of every six new cancer cases diagnosed in the United States, and it is responsible for one of every four cancer deaths. The striking rise in incidence and the lack of any major improvement in treatment have led to a steep rise in annual mortality during the second half of the 20th century. Since that time, however, the incidence among men in the United States has declined from 102 cases per 100,000 in 1984 to 78.5 cases per 100,000 in 2003, and the incidence among U.S. women is approaching a plateau. Decreases in smoking during this period have been reflected in decreased death rates among men and a near plateau in death rates for women. Nevertheless, lung cancer remains the most common cause of cancer death among U.S. men and has surpassed cancer of the breast as the number one cause of cancer death among U.S. women.
The single most important cause of the lung cancer is the inhalation of tobacco smoke. Many other agents also have been shown to increase the risk of bronchopulmonary cancer, including asbestos, iron ore, radioactive ores, and isopropyl oil.
The mainstay of treatment for patients with small, localized carcinomas of the lung continues to be surgical resection. With current imaging procedures, augmented by cervical mediastinoscopy, anterior mediastinotomy, and transtracheal or transbronchial biopsy, only 20% to 25% of all patients are considered candidates for definitive resection. The remaining patients, except for those with distant metastases, are appropriately treated with radiation alone or, increasingly, with cytotoxic drugs.
The choice of therapy is largely based on the histopathologic type of lung cancer. One classification originally proposed by the World Health Organization and later modified49consists of squamous cell carcinoma, small cell carcinoma, adenocarcinoma, large cell carcinoma, and adenosquamous carcinoma. Squamous cell carcinoma is the single most common histopathologic type, but adenocarcinoma is only slightly less common. Each constitutes somewhat less than one third of all cases of carcinoma of the lung. Included within adenocarcinoma is bronchioalveolar carcinoma, an uncommon lung cancer but one of the few types that is not associated with tobacco inhalation. Squamous cell carcinomas and adenocarcinomas are subject to histologic grading, but most are moderately to poorly differentiated.
Small cell carcinoma includes the lymphocyte-like type also known as oat cell carcinoma. A variant of this, previously thought to represent an intermediate cell type within the small cell grouping, is now recognized as being a mixture of small cell and large cell carcinoma.Large cell carcinoma is quite possibly the most undifferentiated form of adenocarcinoma, and as such large cell carcinoma and adenocarcinoma have been indistinguishable in a variety of clinicopathologic studies. Giant cell carcinoma and clear cell carcinoma are considered variants of large cell carcinoma.
Carcinoid tumors are relatively indolent but unquestionably malignant tumors that tend to occur in younger individuals and are unrelated to the inhalation of tobacco smoke. This type of tumor shows neuroendocrine differentiation, and its relationship to small cell carcinomas is controversial. Carcinoid tumors are parabronchial tumors that often have a small portion extending into the lumen of the bronchus. They occasionally produce vasoactive substances that can cause flushing, diarrhea, and hypotension.
Squamous cell carcinoma is the most likely to remain confined to the thorax, whereas almost every patient with small cell carcinoma will have distant metastasis. Studies of causes of death (Table 19-2) and patterns of failure show that squamous cell carcinoma most often kills by local tumor progression, whereas small cell carcinoma tends to cause death from widespread dissemination. Adenocarcinoma and large cell carcinoma occupy an intermediate place in the spectrum from squamous cell carcinoma to small cell carcinoma; adenocarcinoma and large cell carcinoma are less likely to cause death from intrathoracic tumor progression than is squamous cell carcinoma, but they are more likely to spread beyond the thorax.
The lymphatic drainage of the lungs is shown in Figure 19-11. In surgical series, one fourth to one half of patients who undergo resection have regional lymph node metastasis (Table 19-3). At autopsy, more than 90% of patients are found to have involvement of hilar or mediastinal lymph nodes. However, carcinoma of the lung does not spread in such a predictable manner. Mediastinal lymph nodes and blood vessels are often involved by the time the diagnosis is established. The highly vascular composition of the lung, with its dual circulation of bronchial and pulmonary vessels, provides a ready anatomic explanation for the high frequency of extrathoracic dissemination.
Small cell carcinoma, adenocarcinoma, and large cell carcinoma have a notable propensity to spread to the brain (Table 19-4).50 Even with the relatively high rate of survival among patients with small cell carcinoma (because of effective combinations of chemotherapy), 50% to 80% of patients eventually have metastasis to the brain.Clinical assessments of the frequency of brain metastasis from adenocarcinoma and large cell carcinoma have confirmed the high rate of involvement found in autopsy studies.
Carcinoma of the lung is most often diagnosed from symptoms resulting from the intrathoracic tumor. Cough, dyspnea, chest pain, and hemoptysis are among the most frequent symptoms and signs. However, a large proportion of patients have unexplained weight loss.
Radiographic studies reveal that squamous cell carcinoma and small cell carcinoma tend to occur as central lesions (Table 19-5), whereas adenocarcinoma and large cell carcinoma occur more often as peripheral parenchymal tumors. Small cell carcinoma and large cell carcinoma are often associated with mediastinal abnormalities. Any of the histopathologic types of lung carcinoma may occur in the extreme apex of either lung, with symptoms of shoulder pain, ulnar dysesthesias, Horner’s syndrome, and evidence of chest wall invasion and destruction of the adjacent ribs or vertebrae (i.e., Pancoast syndrome). Obstruction of the superior vena cava can lead to swelling of the face, neck, and arms and evidence of collateral circulation over the anterior chest wall; approximately 4% of all patients with cancer of the lung present with this syndrome.
Paraneoplastic phenomena include clubbing, ectopic hormone production (e.g., adrenocorticotropic hormone, calcitonin, human chorionic gonadotropin, antidiuretic hormone, or parathyroid hormone), and a variety of neuromuscular syndromes. These may disappear with effective treatment of the primary tumor. All but two of the paraneoplastic phenomena are seen more often in patients with small cell carcinoma than in patients with other types of lung cancer—hypercalcemia and clubbing are rare in small cell carcinoma.
Patients who have cancer of the lung should undergo a careful physical examination and selected laboratory and imaging studies. A complete blood count is always appropriate, because anemia or a leukoerythroblastic picture may suggest bone marrow involvement. A biochemical survey, including liver function tests such as alkaline phosphatase and aspartate aminotransferase, can be conducted to help detect hepatic involvement. Carcinoembryonic antigen and lactate dehydrogenase levels may be elevated and may serve as a means of monitoring the effectiveness of therapy.
In addition to plain posteroanterior and lateral chest radiography, CT of the thorax contributes to an appreciation of the extent of the primary tumor and regional lymph node metastasis, and it has an important function in treatment planning if radiation therapy is used. CT of the upper abdomen can be invaluable in the search for occult distant metastasis. Hepatic metastasis can be identified, and the more common adrenal metastasis can be seen. Renal and retroperitoneal lymph node metastases are sometimes identified. CT of the brain is necessary in patients with small cell carcinoma, adenocarcinoma, and large cell carcinoma because as many as 10% of patients without neurologic symptoms or signs may have occult brain metastasis.
Whole-body positron emission tomography (PET) with 18F-fluorodeoxyglucose can improve the rate of detection of regional and distant metastasis in patients with NSCLC. Pieterman and colleagues65 found PET to be more sensitive than CT (91% versus 75%) and more specific than CT (86% versus 66%). In that study, PET identified distant metastases in 11 of 102 patients considered to be free of metastasis by all other pretreatment staging methods. Although PET correctly detected mediastinal lymph node metastasis in 90% of patients with histopathologic evidence of involved lymph nodes, it gave false-positive results for lymph nodes in patients with reactive hyperplasia and silicoanthracosis. PET is complementary to CT for radiation treatment planning. When the complete clinical evaluation is accomplished, more than one half of all patients with lung carcinoma are found to have distant metastasis.
Clinical staging classifications for carcinomas of the lung have been used widely for more than 20 years. The current version of the system advocated by the American Joint Committee on Cancer (AJCC) is shown in Box 19-1. Further illustration of a schema that represents a combination of two previous classification systems for lymph node involvement is given in Figure 19-1267 and in Box 19-2. This combined system was generated to solve problems caused by inconsistent staging; it incorporates anatomic landmarks to identify N1 and N2 nodes.
Indications for Radiation Therapy
There are many indications for radiation therapy for cancer of the lung. Radiation therapy can be used as an adjunct to surgery, in place of surgery for patients with small tumors who cannot undergo surgery, with chemotherapy as a cure for unresectable but nonmetastatic tumors of all cell types, as prophylactic treatment of subclinical metastasis, and as palliative therapy for distressing symptoms. These indications are described further in the following sections.