Chest Radiography

Many lung cancers are detected initially by plain chest radiograph. In certain situations, chest radiography may be sufficient to detect spread to the mediastinum. For example, the presence of bulky lymphadenopathy in the superior or contralateral mediastinal areas may be considered adequate evidence of metastatic disease to preclude further imaging evaluation of the chest. This may be particularly true if the patient is too ill or unwilling to undergo treatment of any kind. Still, most patients should undergo a chest CT scan unless they are so debilitated that no further evaluation or treatment is planned. The chest radiograph is simply too insensitive a measure of mediastinal lymph node involvement with lung cancer and thus further noninvasive or invasive assessment is usually necessary.

Chest Computed Tomography

The vast majority of patients who present with lung cancer will undergo chest CT, which can confirm the suspicion of lung cancer or raise the suspicion of an alternate diagnosis. CT is helpful in defining the size, location, and characteristics of the primary mass (e.g., circumscribed, spiculated, calcified), the presence or absence of lymphadenopathy, and, if performed through the adrenal glands, the presence of abnormalities in the liver and adrenal glands. The bony structures of the thoracic cavity can also be evaluated by chest CT.

Chest CT is the most widely available and commonly used noninvasive modality for evaluation of the mediastinum in lung cancer. Numerous studies of CT have been performed comparing clinical staging by CT with the “gold standards” of mediastinoscopy or surgery. The results demonstrated that, regardless of the lymph node size used as a threshold for defining malignant adenopathy, CT findings in isolation could not be considered as conclusive evidence that lymph nodes were malignant. In other words, in all studies, there are meaningful numbers of false-positive cases detected by CT (see eFigs. 53-1 and 53-2 ). The vast majority of reports evaluating the accuracy of CT for mediastinal lymph node staging have employed the administration of intravenous contrast material. Although contrast is not absolutely necessary in performing chest CT for this indication, it is helpful to distinguish vascular structures from lymph nodes as well as to delineate mediastinal invasion from centrally located tumors. The most widely accepted criterion for an abnormal lymph node on CT is a lymph node with a diameter of 1 cm or greater across the short axis.

The American College of Chest Physicians (ACCP) compiled the studies assessing the performance characteristics of CT for staging the mediastinum in a meta-analytic format. Thirty-five studies were identified, comprising 5111 evaluable patients. The pooled sensitivity of CT for staging the mediastinum was 51% (95% CI, 47% to 54%) and the pooled specificity was 86% (95% CI, 84% to 88%). The corresponding positive and negative likelihood ratios were 3.4 and 0.6, respectively, confirming that CT has a limited ability to either confirm or exclude mediastinal metastasis. However, because CT guides the selection of nodes for biopsy by mediastinoscopy or transbronchial, transthoracic, or transesophageal needle aspiration, it remains an important diagnostic tool in lung cancer. The limitation of CT-based mediastinal lymph node evaluation is evident in that 5% to 15% of patients with clinical T1N0 lesions will be found to have positive lymph node involvement by surgical lymph node sampling ( eFig. 53-3 ). Perhaps the most important message in evaluating the accuracy of CT is that approximately 40% of all nodes deemed malignant by CT criteria are actually benign (see eFigs. 53-1 and 53-2 ), depending on the patient population. Specificity can be affected by clinical factors such as the presence of obstructive pneumonitis. There is no node size that can reliably determine stage and operability. When CT criteria for identification of a metastatic node are met, the clinician must still prove beyond reasonable doubt by biopsy or resection that the node is indeed malignant. Given the limitations of the imperfect sensitivity and specificity of CT, it is usually inappropriate to rely solely on CT to determine mediastinal lymph node status. Nonetheless, CT continues to play an important and necessary role in the evaluation of patients with either a known or suspected lung cancer who are eligible for treatment.

CT can also be helpful in the evaluation of pleural effusion in patients with lung cancer. The CT scan can indicate the presence or absence of fluid, the contour of the pleural space, and whether or not nodules or masses are present on the pleural surface ( eFig. 53-4A and B ). However, the clinician should interpret these findings with caution because pleural disease can predate cancer and the presence of pleural effusion does not guarantee that the cytology will be positive. This is an important staging issue because the finding of malignant pleural effusion in NSCLC is considered evidence of metastatic disease (stage IV). If the pleural fluid has benign cytology (e.g., it represents fluid from obstructive pneumonia), then the patient may still be considered for surgical resection. To resolve this issue, recommendations have been made to perform thoracentesis with cytology on two separate occasions, followed by thoracoscopy to evaluate the pleural surface directly ( eFig. 53-5 ). If the patient remains cytology-negative, then the patient should be considered to be at the lower, nonmetastatic stage and be treated accordingly. Thoracoscopy can be helpful in differentiating the extent of the primary tumor involvement into or through the pleura but, at times, open thoracotomy is needed to sort out this issue. (See Chapters 24 and 82 .)

Positron Emission Tomography

Perhaps the single most notable addition to the staging armamentarium for the evaluation of lung cancer is PET (see Chapter 21 ). Because the image is created by the biologic activity of neoplastic cells, PET is a metabolic imaging technique based on the function of a tissue rather than on its anatomy. Lung cancer cells demonstrate increased cellular uptake of glucose and a higher rate of glycolysis when compared with normal cells. The radiolabeled glucose analogue ¹⁸ F-fluorodeoxyglucose (FDG) undergoes the same cellular uptake as glucose but, after phosphorylation, is not further metabolized and becomes trapped in cells. Accumulation of the isotope can then be identified using a PET detector. Specific criteria for an abnormal PET scan are either a standard uptake value of greater than 2.5 or uptake in the lesion that is greater than the background activity of the mediastinum (see eFig. 53-1B and C , eFig. 53-3B, E , and F , and Fig. 21-1F-J ). It has proved useful in differentiating neoplastic from normal tissues. In two well-performed studies that evaluated the use of PET in the preoperative setting for lung cancer, nearly 20% of patients were staged differently after evaluation by PET (see eFigs. 53-1, 53-2 , and 53-3 , and Fig. 21-3 ), However, the technique is not infallible because certain nonneoplastic processes, including granulomatous ( eFig. 53-6 ) and other inflammatory diseases and infections may also demonstrate positive PET imaging. Furthermore, size limitations are also an issue, with the lower limit of resolution of the study being approximately 7 to 8 mm depending on the intensity of uptake of the isotope in the abnormal cells ( eFig. 53-7A-D ). One should not rely on a negative PET finding for lesions less than 1 cm on CT.

A burgeoning number of studies in the last several years have reported on the utility of PET in the assessment of the mediastinum in patients with lung cancer. Increasing availability of the technology now allows PET to be used widely as a diagnostic tool. PET is primarily a metabolic examination and has limited anatomic resolution. It is possible for PET to identify lymph node stations but not individual lymph nodes. CT provides much more anatomic detail but lacks the functional information provided by PET. The third edition of the ACCP guidelines on lung cancer reviewed the complexity surrounding PET. While PET provides information about the primary tumor, mediastinal lymph nodes, and sites of distant metastasis, the contribution that it makes to the stage evaluation is influenced by a multitude of factors. These include the probability of cancer, likelihood of metastasis, and the extent that the investigation for metastases has been completed by other modalities.

To date, there have been five randomized controlled trials to evaluate the role of PET. The variation in results among the studies was likely due to the significant differences among the patients involved, the prior evaluations, and risk for advanced disease. While two of the studies demonstrated a reduction in the number of noncurative resections from 40% to 20%, another detected no difference in the number of thoracotomies performed or of sites of distant metastasis. This latter study primarily involved stage I patients with extensive preenrollment imaging explaining why there was no difference detected between the PET and conventional staging arms.

Population-based studies using the U.S. National Cancer Data Base and the Surveillance, Epidemiology and End Results registry suggest that the use of PET has had a positive impact on stage migration from stage III to stage IV classification ( eFig. 53-8 ). Conversely, PET adds little to the staging of patients with clinical stage I cancers. PET is also of limited value in those with ground-glass opacities with or without a solid component because these patients are at low risk for nodal and distant metastatic disease.

Compared with conventional staging, staging by PET is, on average, 20% more correct in identifying nodal or distant metastasis in randomized controlled trials. Confirmation of PET findings, however, is imperative because, as is known for CT, PET can be wrong. PET also carries the possibility of incorrectly upstaging a patient. Whereas a negative mediastinal PET may obviate the need for mediastinoscopy before thoracotomy in certain situations, a positive mediastinal PET should not negate further evaluation or the possibility of resection. In the latter case, lymph node sampling should still be pursued because the possibility of a false-positive PET scan cannot be ignored.

Where PET is available, a PET scan should be obtained during the staging evaluation for lung cancer. Newer technology includes CT-PET fusion, a single machine that incorporates CT and PET during the same scan. This allows the clinician to obtain anatomic (CT) and functional (PET) images simultaneously. Studies suggest an improvement in the number of patients correctly staged with this modality over CT or PET alone. The future of PET in lung cancer may also include its use to evaluate response to treatment. Due to potential false positive images, the optimal timing for PET following treatments will require further evaluation, especially when chest radiotherapy is used. For example, it may be more useful later in the post- stereotactic body radiation therapy (SBRT) period (i.e., after the first year) rather than early in the period (i.e., within the first 3 to 6 months).

Magnetic Resonance Imaging

There are very few circumstances in which magnetic resonance imaging (MRI) is a useful tool in staging lung cancer. However, MRI can be useful in evaluating superior sulcus tumors, especially for possible invasion of the brachial plexus, and for evaluating vertebral invasion.

Search for Metastatic Disease

The purpose of extrathoracic scanning in NSCLC is usually to detect metastatic disease at common metastatic sites, such as the adrenal glands, liver, brain, and skeletal system, thereby sparing the patient fruitless surgical intervention. CT of the chest ( eFig. 53-9A ), CT ( eFig. 53-9C ) or MRI with contrast of the brain, and ^99m Tc nuclear imaging of the skeletal system are the conventional staging studies when the clinician needs to evaluate for metastatic disease. The use of whole-body PET and PET-CT (see eFig. 53-8 ) for extrathoracic staging has advanced the field of metastatic disease evaluation. Studies demonstrate that PET and PET-CT outperform conventional staging tests in the evaluation of metastatic disease to key specific distant sites including adrenal glands, liver, and bone (see eFig. 53-8 ). PET reveals unsuspected metastases in 6% to 37% (see eFig. 53-8 and Fig. 21-4 ). This allows for more accurate TNM staging, stage shift, and changes in management including more appropriate consideration of surgical candidacy. Detection of brain metastases is a problem for PET because the high background brain FDG uptake can mask the small size of most brain metastases, which can be either hypermetabolic or hypometabolic. There is some evidence to suggest that integrated PET-CT has an accuracy that nears diagnostic brain CT (see eFig. 53-8B ).

The initial clinical evaluation may reveal abnormalities, such as abnormal symptoms, physical findings, and routine blood tests, that then lead to an expanded clinical evaluation ( Table 53-4 ). If a patient has abnormalities on these clinical evaluations, scans will be abnormal in around 50% of cases. The third iteration of the ACCP guidelines for NSCLC staging recommends PET to evaluate for metastasis (except for metastasis to the brain) for patients with a normal clinical evaluation and no suspicious extrathoracic abnormalities on chest CT being considered for curative-intent treatment. Advanced thoracic lesions and mediastinal lymphadenopathy are important variables because these are associated with more scan abnormalities. This is particularly true for N2 disease, in which asymptomatic metastases have been documented at a higher rate than would have been expected (see eFig. 53-8 ). Although several studies have documented a higher incidence of brain metastases in patients with adenocarcinomas than in those with squamous cell cancers, the largest single series of patients with stage I and II lung cancer found no difference.

Several important caveats must be considered in the search for metastatic disease. First and foremost, there is the problem of false-positive scans. Adrenal adenomas (present in 2% to 9% of the general population), hepatic cysts, degenerative joint disease, old fractures, and a variety of nonmetastatic space-occupying brain lesions are present in the general population. When clinically indicated, additional imaging studies, biopsies, or both are performed to establish the diagnosis; however, complications and costs resulting from such subsequent investigations have received less attention. There is also the problem of false-negative scans, scans that fail to detect actual metastases. For example, in a CT study of the adrenal glands, Pagani found metastatic NSCLC by percutaneous biopsy in 12% of radiologically normal adrenal glands. An additional problem is that the studies in this area often fail to specify exactly which elements make up the prescan clinical evaluation or that the studies use differing clinical indicators. For example, organ-specific findings such as headache and non–organ-specific complaints such as weight loss are both important. In addition, in many studies, abnormal findings on scans have not been pursued with biopsies to prove metastatic disease. Finally, there are few prospective randomized trials and outcome studies to guide appropriate use and interpretation of extrathoracic scanning. It is hoped that careful studies will improve the workup of patients with lung cancer.

Summary

The noninvasive clinical staging of lung cancer relies on the clinical evaluation and a number of readily available staging studies. The clinician must be wary of abnormal scans that may falsely suggest metastatic disease to the mediastinum and distant sites. Tissue confirmation by whatever means necessary is the rule rather than the exception before deciding on correct stage and the most appropriate treatment. If the patient has clinical findings indicative of metastatic disease, further evaluation is necessary because nearly 50% of the time the patient will have metastases. Even if the clinical evaluation is normal and imaging does not demonstrate suspicious extrathoracic abnormalities, PET imaging should be done where available in those being considered for curative-intent treatment.

Sputum Cytology

Sputum cytology is the least invasive method for obtaining a diagnosis of lung cancer. Its accuracy depends on the expertise of the health care team in obtaining the sample (three samples are required), the preservation technique, and the size and location of the lesion. Central lesions are more likely to yield positive cytologic results than are peripheral lesions. Sputum cytology should be obtained in all patients with central lesions who are at risk for more invasive biopsy techniques and considered in those with hemoptysis with or without a mass on chest radiography. Previously published systematic reviews have summarized the performance characteristics for sputum cytology for the diagnosis of suspected lung cancer. The ranges for sensitivity and specificity were 42% to 97% and 68% to 100%, respectively. The accuracy of sputum cytology is highly variable, so, in patients suspected of having lung cancer with negative sputum cytology, further testing should be performed.

Transthoracic Needle Aspiration

Transthoracic needle aspiration (TTNA), usually under ultrasound (see Fig. 19-3 ), CT, or fluoroscopic guidance, is an expedient and relatively safe way to diagnose the primary tumor mass and establish a diagnosis of lung cancer (see Figs. 19-1 and 19-6 ). As a general rule, if a lesion is less than 3 cm in size and lateral to the mid-clavicular line ( eFig. 53-13 ), TTNA should be considered if tissue diagnosis is necessary. One important point about TTNA or other nonsurgical biopsy techniques for peripheral pulmonary lesions is that they afford no preoperative benefit because they do not eliminate the need for surgery in most cases. For a patient presenting with a solitary pulmonary nodule suspicious for malignancy (e.g., noncalcified, upper lobe, spiculated lesion in a long-term smoker), the diagnosis, stage, and therapy can be accomplished simultaneously with a thoracotomy and surgical resection. Thus TTNA may be essential only in certain situations: patients who are poor surgical candidates but who require tissue diagnosis prior to treatment, patients in whom a noncancerous lesion is strongly suspected (see Fig. 19-7 ), patients who request that a diagnosis of cancer be confirmed before considering surgery, and patients with high likelihood of metastatic disease (see Fig. 19-2 ). The sensitivity and specificity of TTNA are 90% and 97%, respectively (see Chapter 19 ).

One drawback of TTNA is the risk of pneumothorax. Several investigations have reported a 15% to 45% risk of pneumothorax for CT-guided TTNA. Although pneumothorax may lead to hemodynamic compromise without therapeutic tube thoracostomy, in most cases of pneumothorax secondary to TTNA, treatment is not required. The primary factors shown to increase the risk or incidence of pneumothorax are the presence of emphysema, a smaller lesion size, and a greater depth of needle penetration from the pleural surface to the edge of the lesion.

Fiberoptic Bronchoscopy

More than 50% of patients with advanced-stage lung cancer will have involvement of the central airways either by bulky endobronchial disease, extension into the airways, or extrinsic compression of the airways by the tumor or by lymphadenopathy. Patients with known or suspected lung cancer may have symptoms due to endobronchial involvement that require airway inspection with broncho­scopy: shortness of breath, unilateral wheezing, hemoptysis, and cough. Endobronchial lesions can be visualized easily and biopsied through a flexible bronchoscope. The yield with three or more biopsies should approach 100% for centrally located lesions. Data from 4507 patients revealed that central endobronchial biopsies provide the highest sensitivity (74%), followed by brushings (61%) and washings (47%). The combination provides a diagnosis in 88% of cases. Endobronchial needle aspiration may be helpful especially when a rim of necrotic debris surrounds an endobronchial malignancy, because deeper tissue penetration may access viable tumor cells. The addition of endobronchial needle aspiration to forceps biopsies and brushings may improve sensitivity to 95% for the diagnosis of endobronchial cancer.

Endoscopic Ultrasound

Endoscopic ultrasound (EUS) is another modality that has significantly impacted lung cancer staging, primarily due to its superior ability to sample the posterior mediastinum through the esophageal wall. Currently, EUS with fine-needle aspiration is performed using real-time ultrasound. In pooled analysis of 2433 patients with lung cancer and mediastinal adenopathy, EUS had a sensitivity and specificity of 89% and 100%, respectively. In patients with lung cancer who have no adenopathy seen on CT, EUS has been shown to sample nodes as small as 3 mm in diameter. This is useful given the high incidence of metastasis found in normal-sized lymph nodes in lung cancer. Based on surgical studies, it may be possible to predict the location of mediastinal lymph node metastases at certain levels based on the location of the tumor. This relationship may influence the use of EUS in certain patients without adenopathy on chest CT. Lymphatic pathways favor spread to aortopulmonary window nodes from left upper lobe tumors and to subcarinal nodes from left and right lower lobe lesions. EUS has been studied in patients with known lung cancer without enlarged mediastinal lymph nodes on CT, and it has detected mediastinal involvement (stage III or IV disease) in up to 42% of cases.

In addition, EUS has the advantage of being able to stage lung cancer from locations outside the mediastinum. The left lobe of the liver, a substantial part of the right lobe of the liver, and the left (but not the right) adrenal gland can be identified and sampled in 97% of patients. In addition, left pleural effusions can be visualized and sampled during an EUS procedure. EUS is increasingly being combined with EBUS for minimally invasive staging of lung cancer.

Endobronchial Ultrasound

Perhaps the greatest addition in the armamentarium for staging lung cancer is endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA). EBUS-TBNA is indicated for the assessment of mediastinal and hilar lymph nodes and diagnosis of lung and mediastinal tumors. It can be used to sample the highest mediastinal (station 1), the upper paratracheal (station 2R, 2L), the lower paratracheal (station 4R, 4L), the subcarinal (station 7), as well as the hilar (station 10) and the interlobar (station 11) lymph nodes ( Fig. 53-1A ). The para-aortic (station 6), aortopulmonary window or subaortic (station 5), paraesophageal (station 8), and pulmonary ligament (station 9) lymph node stations are usually not accessible by this technique (see Fig. 53-1B ). Pooled analysis of 2756 patients shows that EBUS-TBNA has a sensitivity and specificity of 89% and 100%, respectively. If a patient presents with a lung mass and mediastinal lymphadenopathy in accessible lymph node stations, EBUS-TBNA should be considered as the test of first choice because this modality can provide a diagnosis and stage simultaneously. In addition, the role of EBUS in lung cancer has expanded to include preoperative mediastinal staging and tissue acquisition for molecular analysis in addition to immunohistochemical staining.

Mediastinal lymph node maps.

A and B, the 14 stations for lymph nodes used in lung cancer staging are shown in association with anatomic landmarks. The N2 nodes are within the mediastinal pleural envelope (1-9) and the N1 nodes are outside the mediastinal pleural envelope, in the hilar (10) or intrapulmonary (11-14) locations. a, artery; Ao, aorta; A-P, aortic-pulmonary; PA, pulmonary artery; v, vein.

(Redrawn from Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1719, 1997.)

The combination of EUS and EBUS has shown better yield than either technique alone. A pooled analysis from 7 studies and 811 patients showed a sensitivity and specificity of 91% and 100%, respectively. These complementary procedures provide near-complete access to the mediastinum for staging, even in the radiologically normal mediastinum. Among patients with (suspected) NSCLC, a staging strategy combining endosonography and mediastinoscopy compared with mediastinoscopy alone was shown to have greater sensitivity for mediastinal nodal metastases and led to fewer unnecessary thoracotomies.

For further discussion of EBUS, see Chapter 22 .

Mediastinoscopy

Mediastinoscopy is the historical gold standard for invasively staging the mediastinum in patients with known or suspected lung cancer; however, if local expertise is available, ultrasound-guided needle techniques (EBUS-TBNA, EUS, or their combination) are now recommended as the best first tests. If there is mediastinal lymph node enlargement regardless of FDG uptake on PET or if there is FDG uptake in a lymph mediastinal node regardless of its size, a surgical mediastinal procedure should be performed before thoracotomy despite a negative needle technique. Mediastinoscopy is most often used to sample nodes of the paratracheal (station 4), and anterior subcarinal (station 7) region (see Fig. 53-1A ). Because the subcarinal area is more difficult to sample, mediastinoscopy has a lower yield for lymph nodes in this area. An extended cervical mediastinoscopy can be carried out to reach aortopulmonary and para-aortic lymph nodes (stations 5 and 6) by using the same cervical incision as mediastinoscopy but dissecting into a different fascial plane. Alternatively, an anterior mediastinotomy (the so-called Chamberlain procedure) may be needed to sample lymph nodes in these aortopulmonary and para-aortic locations (stations 5 and 6) (see Fig. 53-1B ). Overall, mediastinoscopy has a reported sensitivity of 78%, with a specificity of 100%. Mediastinoscopy may also differentiate between stage IIIA and IIIB mediastinal involvement, which may be important for prognosis and potential therapy. As with any surgical procedure, mediastinoscopy has risks and limitations. It requires general anesthesia, with a morbidity of 2% and a mortality of 0.08%.

Prognostic Factors for Lung Cancer

Based on an analysis of large databases of inoperable lung cancer cases, the strongest predictors of survival are good performance score (Karnofsky scale), lower extent of disease (stage), age, and absence of weight loss. Some reports have shown female gender to be a predictor of better survival, but this varies between studies. Performance score and the presence or absence of symptoms are predictors of outcome even with resectable early-stage disease. For example, in stage I NSCLC patients undergoing curative resection, those who were symptomatic at presentation had worse survival than those who were asymptomatic. Although individual reports have noted superior survival for patients with one cell type of NSCLC versus another, the general consensus in the literature is that histologic subtypes of NSCLC are not a major predictor of survival. Absence of smoking or smoking cessation has been associated with improved survival. The maximal standard uptake value of the primary tumor on PET has been inversely correlated with survival.

In more recent years, there have been numerous reports that various molecular markers are associated with outcome. Some of the best known markers include KRAS, epithelial growth factor receptor (EGFR), EML4-ALK translocation, p53, p16, and BCL2. However, in many instances, the results are conflicting about the prognostic significance of these individual molecular markers, perhaps due to the types of cases under review and to individual laboratory variations in techniques for measuring these molecular markers. In a meta-analysis, KRAS mutations were associated with poorer survival, especially in adenocarcinoma in which the hazard ratio was 1.6 (95% CI, 1.3 to 2). Testing the genetic profile of samples obtained from metastatic lymph nodes or malignant pleural effusions in those patients with stage III and IV disease has become standard practice, because this allows for the selection of targeted drug therapies specific for the mutation as first-line chemotherapy.

Non–Small Cell Lung Cancer Treatment by Stage

This section presents a discussion of the treatment of NSCLC by stage and cell type, followed by a discussion of the treatment of SCLC. Table 53-5 presents an overview of treatment strategies for NSCLC based on stage.

Stage I

In the most recent staging system for NSCLC, stage I NSCLC is broken down into stage IA (tumors ≤ 2 cm [T1a] ( eFig. 53-14A ) and tumors between 2 and 3 cm [T1b]) (see eFig. 53-14B ) and stage IB (tumors between 3 and 5 cm [T2a]) (see eFig. 53-15 ). All stage I tumors are completely surrounded by lung parenchyma greater than 2 cm away from the carina and do not invade the chest wall or parietal pleura ( Fig. 53-2 ). Stage I lung cancer does not include patients who have malignant lymph node disease or patients with metastatic disease. Thus the TNM classification is either T1aN0M0, T1bN0M0 (stage IA), or T2aN0M0 (stage IB). The differences between the two are the size of the primary tumor and the survival after surgical resection. Although stage I disease offers the best chance for long-term survival, the sad fact is that only 15% of all lung cancers present with stage I disease.

Stage I disease.

CT (A) and PET (B) scans of a patient with T1N0M0 tumor ( arrows ) .

The current treatment for stage I lung cancer is surgery alone. The surgical procedure of choice is a lobectomy or pneumonectomy with mediastinal lymph node sampling. It should be recognized that the patient must be a reasonable surgical candidate. The 5-year survival for surgically resected stage IA lung cancer is 73%, whereas the survival for stage IB lung cancer is 58%. Local postoperative radiation for stage I and II lung cancer, after either complete or incomplete resection of the tumor, has not been found to be of any benefit. Postoperative adjuvant chemotherapy has not been shown to improve survival for those with resected stage I disease. A further discussion of postoperative adjuvant therapy is presented later (see “Stage IIIA”).

Some patients are surgically resectable but medically inoperable, usually because the patient does not have the pulmonary reserve to tolerate a lobectomy. These patients, particularly those with T1 tumors, may be able to tolerate a wedge resection or segmentectomy of their tumor as opposed to a lobectomy or pneumonectomy. In such cases, the local recurrence rate is higher than that of a complete resection, but the overall 5-year mortality is no different. However, for patients with smaller peripheral stage I lung cancers, anatomic segmentectomy may offer local control, the opportunity for prolonged disease free survival, and overall survival that is comparable to lobectomy. Still, whenever possible, a complete anatomic resection is preferred over a minimal resection. For discussion of radiofrequency ablation and other nonsurgical treatments, see Chapter 19 .

Patients who are “close calls” for surgery should be thoroughly evaluated by both a pulmonologist and a thoracic surgeon before making a decision on operability. As previously stated, there is a difference between a patient who is resectable and a patient who is operable. Chapter 27 is devoted to the preoperative evaluation of patients with lung disease, but a brief review is warranted here. Patients with a postoperative percent predicted forced expiratory volume in 1 second or diffusion capacity less than 40% will have a higher morbidity and mortality following lung cancer surgery. Patients with borderline values preoperatively should be referred for a differential ventilation-perfusion scan for a better prediction of postoperative function. When there is still a question, a cardiopulmonary exercise test can be obtained. Compared with those with an oxygen consumption greater than 20 mL/kg/min, patients with an oxygen consumption between 11 and 19 mL/kg/min have a higher morbidity but no greater mortality and those with an oxygen consumption less than 10 mL/kg/min have both a higher predicted morbidity and mortality.

For patients who either refuse surgery or are deemed medically unfit for surgery, primary radiotherapy for cure can be considered. This approach was evaluated in a meta-analysis of 1 randomized and 35 nonrandomized trials. The studies were heterogeneous, and the 5-year cancer-specific survival ranged between 13% and 39%. The authors concluded that, even in patients with severe emphysema, radiation therapy can be tolerated if careful planning with three-dimensional conformal techniques is undertaken. Conformal indicates that the radiation is designed in 3 dimensions to match the shape of the tumor allowing maximal targeting to the tumor with minimal injury to adjacent normal tissue.

More recently, stereotactic body radiation therapy has been introduced as a highly precise and accurate delivery method of highly conformal and dose-intensive radiation to small-volume targets. This method is also referred to as stereotactic ablative body radiotherapy and stereotactic radiosurgery. It is a more aggressive dose intensification than could previously be achieved using conventional radiotherapy methods.

In the Radiation Therapy Oncology Group trial (ROTG 0236), patients with biopsy proven stage I NSCLC deemed medically inoperable received stereotactic body radiation therapy with 60 Gy in three fractions. Primary tumor control of 98%, regional control of 87%, and overall survival of 56% at 3 years were achieved. This study and others (ROTG 0618) have demonstrated a dose-response relationship that favors more intensive regimens with biologically equivalent doses of more than 100 Gy consistently resulting in more than 90% primary tumor control for T1 tumors and overall survival greater than 50%. A meta-analysis demonstrated an overall survival improvement with stereotactic body radiation therapy compared with conventionally fractionated radiation therapy.

Stage IIIA

Stage IIIA NSCLC represents a heterogeneous group of patients with N2 disease ( Fig. 53-3 ) and includes T3N1 patients. In addition, within the new staging system, patients with T4N0-1 have been down-staged to IIIA from their previous classification.

Stage IIIA disease.

A, CT depicts a primary tumor mass invading the chest wall, resulting in stage IIIA non–small cell lung cancer (NSCLC; T3N2) ( arrow ). B, CT depicts enlarged aortopulmonary lymph node ( arrow ). C, PET with uptake in primary tumor ( left image, arrow ) and lymph node ( right image, arrow ).

For carefully selected T4N0-1M0 patients, surgery may be indicated with or without neoadjuvant chemotherapy or neoadjuvant chemoradiotherapy (superior sulcus tumors) ( eFigs. 53-17 and 53-18 ). Individuals with T4N0-1 disease due to main carinal involvement have been treated with carinal resection with or without pulmonary resection. Carinal resection carries an operative mortality of 10% to 15% and 5-year survival of approximately 20% in carefully selected series. Patients who are T4N0 solely due to tumor nodules within the ipsilateral nonprimary lobe ( eFig. 53-19 ) have a 5-year survival of around 20% with surgery alone.

There is substantial debate over what constitutes resectable IIIA (N2) disease. However, there is no debate that T3N1 disease is best treated with surgical resection. At surgery, when a complete resection of the lymph nodes and the primary tumor is possible, some patients are found to have occult N2 metastasis. If so, these patients are best served by a resection of all known disease and then by consideration for adjuvant chemotherapy.

It is less certain how best to treat patients when N2 (single or multiple station) metastases are documented before thoracotomy. The new ACCP guidelines used the groupings of infiltrative stage III (N2/N3) tumors and stage III with discrete N2 involvement. In infiltrative stage III with N2/N3 involvement, the mediastinal nodes can no longer be clearly distinguished and measured ( eFig. 53-20 ). These patients have extensive tumor infiltration in the mediastinum, which partially surrounds the major structures. In patients with infiltrative stage III (N2/N3), good performance score, and minimal weight loss (≤10%), the recommended treatment with curative intent is with concurrent chemoradiotherapy.

Two multicenter trials have concluded that concurrent chemoradiotherapy is superior to sequential therapy with chemotherapy followed by thoracic radiotherapy. Concurrent therapy, however, is associated with a higher rate of severe esophagitis than is sequential therapy. The recommended chemotherapy is a platinum doublet and the most common agents are etoposide and cisplatin. Three cooperative group trials of definitive chemoradiotherapy for unresectable stage III had an MST of 19 to 22 months with 2-year survivals of 40% to 45% and a 5-year survival of approximately 20%.

For patients with discrete N2 involvement, the ACCP guidelines recommend that the treatment plan be discussed by a multidisciplinary team. Either definitive chemoradiotherapy or induction therapy followed by surgery is recommended over either surgery or radiation alone. These recommendations were largely influenced by the two cooperative group trials that evaluated the role of surgery in patients with N2 disease. The European trial randomized patients with histologically proven N2 disease to radiotherapy or surgery after initial induction therapy with three cycles of a cisplatin doublet chemotherapy. The MST was 16 months in the surgery arm and 17 months in the radiotherapy arm. The 5-year survival in both arms was 16% and 14%, respectively, and was not significantly different. The North American trial also required pathologic proof of N2 disease and randomized patients to completion radiotherapy or surgery after induction of two cycles of etoposide and cisplatin with concurrent thoracic radiotherapy of 45 Gy in 25 fractions over 5 weeks. The MST was 24 and 22 months in the surgery and radiotherapy arms, respectively, with 5-year survivals of 27% and 20% (hazard ratio 0.87, P =0.24). These survival differences were not statistically significant. However, the PFS favored the surgery arm. A subset analysis in those having only a lobectomy after induction therapy did better than a matched group receiving only chemoradiotherapy. This was an unplanned subset analysis that weakens the strength of this analysis. Accordingly, the role of surgery for stage III with discrete N2 disease has not been definitively answered.

In patients with stage II or IIIA totally resected NSCLC, adjuvant chemotherapy with four cycles of a cisplatin-based doublet chemotherapy is recommended. The Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis evaluated all stages of totally resected disease and observed a 5.4% overall 5-year survival benefit with adjuvant chemotherapy. The benefit was the greatest for patients with stage II and III disease and those with better performance status. The role of postoperative radiation therapy for patients with totally resected stage III (N2) remains controversial. Local recurrence varies in reports from 20% to 60%. Some nonrandomized trials suggest possible benefit from postoperative radiation therapy. Accordingly, this option should be discussed with fit patients. A randomized phase III Adjuvant Radiotherapy (ART) trial is underway to evaluate postoperative radiation therapy in these patients.

Small Cell Lung Cancer

SCLC accounts for approximately 15% of all lung cancers. This cell type has the strongest association with cigarette smoking and is rarely observed in a never-smoker. It is the cell type most commonly associated with paraneoplastic syndromes such as the syndrome of inappropriate (excessive) antidiuretic hormone secretion (SIADH), ectopic corticotropin secretion, Lambert-Eaton myasthenic syndrome (LEMS), and sensory neuropathy.

SCLC usually presents as a centrally located mass in the hilum on chest radiograph ( eFig. 53-21 ) and may be associated with obstructive pneumonia. In 5% or fewer cases, SCLC may present as a solitary pulmonary nodule/mass ( eFig. 53-22 ). SCLC is generally staged according to the Veterans Administration Staging System, and classified as limited disease (LD) or extensive disease (ED). LD is confined to one hemithorax, the mediastinum, and the ipsilateral supraclavicular lymph nodes, and the disease can be encompassed adequately in a safe radiation portal. ED is any disease spread beyond these limits. Malignant pleural effusion or disease extending to the contralateral supraclavicular or hilar lymph nodes is generally considered to be ED. More recently, it has been proposed that the new TNM staging system (7th edition) should also be used for small cell lung cancer. The clinical stage groupings of I to IV were predictive of overall survival and the findings were validated in a cohort from the Surveillance Epidemiology and End Results registry and the California Cancer Registry. The survival rate for patients with LD with pleural effusions was intermediate between those with ED and LD without pleural effusions. The TNM staging is most helpful in potentially resectable patients with T1-2NO disease. Accordingly, it would be advisable to use both the TNM for tumor registries and clinical trials to define patients with minimal disease.

After establishing the histologic diagnosis of SCLC, patients are usually staged with MRI of the brain, CT of the chest (through the adrenal glands), and bone scan or PET. In an evidence-based review of the literature, staging using PET was compared with conventional staging using non-PET imaging. Of 267 patients with LD by conventional imaging, 16% were upstaged by PET. Of 199 patients with ED, PET resulted in 11% being down-staged. In total, staging with PET improves the accuracy of initial staging and radiotherapy planning. If a PET scan is obtained, then a bone scan may be omitted. In the unusual case when SCLC presents as a peripheral nodule, the treatment of choice is surgical resection followed by adjuvant chemotherapy and possibly sequential thoracic radiotherapy. Careful preoperative staging should be performed in these individuals to rule out metastatic disease. Pre-resection mediastinoscopy should also be performed in all patients being considered for resection with curative intent. If there are mediastinal node metastases, then surgery should be abandoned, and the patient treated with concurrent chemoradiotherapy as outlined later. The 5-year survival for peripheral SCLC that is treated with surgery and adjuvant therapy is approximately 40% to 50%. Approximately one third of patients have LD at diagnosis. LD-SCLC has a response rate of 70% to 80% with standard chemotherapy and thoracic radiotherapy ( eFig. 53-23 ), and a complete clinical response of 50% to 60%. In a meta-analysis of trials with chemotherapy alone versus combined chemotherapy and thoracic radiotherapy, survival was significantly better with combined modality therapy. A meta-analysis evaluated the timing of thoracic radiotherapy. Early thoracic radiotherapy (<9 weeks from the start of chemotherapy) resulted in a 5.2% increase in 2-year survival. The interval from start of treatment to the end of radiotherapy was also identified as an important predictor of outcome. Accordingly, data suggest that thoracic radiotherapy should begin early and be completed quickly. Chemotherapy usually consists of a platinum-based regimen. The two most commonly used regimens are etoposide and cisplatin or etoposide and carboplatin. Chemotherapy beyond four to six cycles has not been shown to prolong survival.

The National Comprehensive Cancer Network and the ACCP guidelines recommend treatment with four to six cycles of a platinum-based chemotherapy with either cisplatin or carboplatin plus either etoposide or irinotecan. Multiple trials have evaluated a number of the novel molecularly targeted agents but to date none have shown improved outcomes when added to standard treatment of small cell lung cancer. A number of trials evaluating insulin-like growth factor receptor inhibitors, antiangiogenesis, and immunomodulatory drugs are under evaluation.

If a patient with SCLC achieves a complete remission, then there is a 50% chance of development of cranial metastasis within the next 2 years. A meta-analysis of seven randomized trials of prophylactic cranial irradiation (PCI) versus no PCI for patients in complete remission reported an observed beneficial effect after PCI, with a 5.4% increase in absolute survival (20.7% vs. 15.3%) at 3 years. The major questions raised by the meta-analysis concern the optimal dose of PCI and the neuropsychological sequelae. PCI is recommended in patients who achieve a complete remission with initial therapy. PCI has also been shown to result in a survival advantage in patients with ED-SCLC who achieve a complete or partial response to initial therapy. PCI at 25 Gy in 10 fractions is the standard dose fractionation used in SCLC.

When patients relapse after initial therapy, the median survival is 3 to 4 months. There are no cures with second-line therapy. If a patient has been off treatment for 6 months or longer, then it is reasonable to use the same agents that he or she received initially. If initial therapy did not include a platinum agent, then second-line therapy should be with a platinum-containing doublet. Currently, the only drug approved for second-line treatment of SCLC by the FDA is single-agent topotecan. Other single agents such as oral etoposide, paclitaxel, docetaxel, irinotecan, gemcitabine, and amrubicin are active but are not yet approved by the FDA for second-line treatment of SCLC. Amrubicin is commercially available and approved for second-line treatment in Japan but is not available in the United States. No molecularly targeted therapy has been approved for SCLC in either the first-line or second-line setting.