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Suggested Citation:"6 Lung Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"6 Lung Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"6 Lung Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Suggested Citation:"6 Lung Cancer." National Academies of Sciences, Engineering, and Medicine. 2021. Diagnosing and Treating Adult Cancers and Associated Impairments. Washington, DC: The National Academies Press. doi: 10.17226/25956.
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Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

6 Lung Cancer Lung cancer is the most common cause of cancer mortality in the United States, despite reductions in smoking over the past 50 years that have led to a decrease in smoking-related lung cancer incidence and mortality. Lung cancers are broadly classified as non-small-cell lung cancer (NSCLC) or small-cell lung cancer (SCLC). NSCLC accounts for the majority (80–85%) of all lung cancer cases in the United States, while SCLC, which has a much poorer prognosis, represents approximately 10–15% of lung cancers (ACS, 2019). For more about the epidemiology of lung of cancer, see Chapter 3. Recent advances in lung cancer care (i.e., prevention, screening, diag- nosis, and treatment) have contributed to improved outcomes for patients, including longer survival and less mortality for patients with NSCLC. Nonetheless, the morbidity and mortality associated with lung cancer re- mains high. The impairments and subsequent functional limitations expe- rienced by lung cancer survivors are a consequence of the adverse effects of the cancer itself; of the adverse effects of its treatment; and of the high risk of recurrence, metastases, or development of new primary cancers, as well as the presence of major comorbid conditions often associated with smok- ing and aging. To help manage these impairments and functional limitations as well as the adverse effects from both the cancer and its treatment, pal- liative and supportive care may be recommended for patients at the time of their diagnosis or during the course of treatment. Two of the most common comorbidities in lung cancer survivors are chronic obstructive pulmonary disease (COPD) and cardiovascular disease. Metastases of the primary lung cancer and new primary cancers are also highly likely to occur in this population. Adults with either NSCLC or SCLC, who are often current or 155 PREPUBLICATION COPY—Uncorrected Proofs

156 DIAGNOSING AND TREATING ADULT CANCERS former smokers, have a particularly high risk of developing other tobacco- associated malignancies, including another lung cancer (NSCLC, SCLC) or other cancers of the head and neck, bladder, esophagus, or pancreas. Ongoing monitoring for new primary cancers, disease progression, and cancer recurrence requires frequent physical examination and imaging and is standard of care for the lung cancer (see Figure 4-1). This chapter describes the screening, diagnosis, treatment, and survi- vorship of lung cancer in adults beginning with risk factors and survival rates. This is followed by information about the diagnosis and staging of lung cancer, and the treatment of NSCLC and SCLC. The final sec- tion describes the range of lung cancer-related impairments that survivors may experience and identifies the potential adverse effects on survivor functioning. RISK FACTORS Cigarette smoking, along with cigar and pipe smoking, is by far the leading risk factor for lung cancer. In smokers, the risk of developing lung cancer increases with age and with both the quantity and the duration of smoking. The second-leading cause of lung cancer in the United States is exposure to radon gas, which is released from soil and can accumulate in indoor air (NCI, 2011). Other risk factors include exposure to second-hand smoke, asbestos, certain metals (e.g., chromium, cadmium, arsenic), some organic chemicals, radiation, air pollution, and diesel exhaust. Increased risk is also associated with specific occupational exposures (i.e., rubber manufacturing, paving, roofing, painting, and chimney sweeping) (Field and Withers, 2012). A personal or family history of lung cancer is another risk factor for lung cancer (Cannon-Albright et al., 2019). There are cer- tain genes and chromosomes (e.g., TP53 germline sequence variations and a marker on chromosome 15) that are linked to an increased risk of lung cancer (Zappa and Mousa, 2016). LUNG CANCER SCREENING Lung cancer typically presents in an advanced stage (stages are defined below), so the development of a screening test for high-risk individuals is an important advancement in lung cancer care (de Koning et al., 2020; National Lung Screening Trial Research Team et al., 2011). In 2013 the U.S. Preventive Services Task Force (USPSTF) recommended annual screen- ing for lung cancer with low-dose computed tomography (LDCT) in adults ages 55 through 80 years who have at least a 30-pack-a-year smoking his- tory and currently smoke or have quit within the past 15 years (USPSTF, 2013). At the time of this report’s publication, USPSTF was in the process PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 157 of updating its 2013 lung cancer screening recommendations (USPSTF, 2020). On July 7, 2020, USPSTF released a draft decision analysis about lung cancer screening for public comment. The proposed screening guide- line broadens the target population by expanding the age range to include ages 50 to 80 years and by reducing the number of pack-years of smok- ing exposure to 20 years (see Table 4-1). USPSTF states that such changes would potentially increase the eligible population beyond that defined by the current criteria and may reduce disparities in eligibility by sex and race/ ethnicity (CISNET, 2020). Despite guideline recommendations and insurance coverage for those at high risk of lung cancer (under the Patient Protection and Affordable Care Act, Medicare Part B, and some state Medicaid programs), lung cancer screening is not widely performed. Overall, only 5.7% of high-risk individ- uals were screened in 2019 (ALA, 2020). Moreover, in 2020 only 38 states covered screening of high-risk Medicaid enrollees (ALA, 2020). Barriers to the implementation of lung cancer screening are the subject of research investigations; for example, some studies are examining clinician-related factors affecting screening practices (Ersek et al., 2016; Lewis et al., 2015). Lung cancer may be suspected on the basis of screening, incidentally detected lung nodules when imaging is performed for other purposes, or patient-reported symptoms. When it is suspected, protocols for diagnosis and cancer staging, which often occur simultaneously, are the foundations for clinical decisions about appropriate lung cancer treatment. DIAGNOSIS AND STAGING OF LUNG CANCER Diagnosing lung cancer, classifying the type, and determining the extent of the disease (cancer stage) are critically important to treatment manage- ment. Current approaches to the diagnosis of lung cancer include not only the conventional histology (the microscopic examination of body tissues) but also immunohistochemistry and molecular and immune panels. The most common presenting symptoms of lung cancer include cough, hemoptysis, dyspnea (shortness of breath), anorexia, fatigue, weight loss and neurologic symptoms caused by paraneoplastic symptoms. In most cases the choice of diagnostic test is driven by the patients’ presenting symp- toms, which may raise suggest an advanced stage spread (bone pain, head- ache, or weight loss) or point to a more local stage (cough, pneumonia). Tests and procedures determine the presence of lung cancer and identify the lung cancer stage. Generally, lung cancer patients receive a computed tomography (CT) scan and a positron emission tomography (PET) scan; a brain magnetic resonance imaging (MRI) scan is recommended in stage II and higher, is optional for patients with stage IB disease and is not recommended for PREPUBLICATION COPY—Uncorrected Proofs

158 DIAGNOSING AND TREATING ADULT CANCERS patients with stage IA disease (NCCN, 2020b). These procedures are used to detect the possible presence of sub-clinical or asymptomatic distant me- tastases. Patients with lung cancer stages II–III may undergo bronchoscopy, endobronchial ultrasound, or percutaneous lung needle biopsy to radiologi- cally or pathologically confirm indeterminate findings of PET or CT scans. Other diagnostic tools may include image-guided transthoracic needle core biopsy, thoracentesis, and mediastinoscopy (NCCN, 2020b). Because both NSCLC and SCLC frequently spread to the liver, adrenal glands, bone and brain, staging has traditionally been with a CT scan of the chest and abdo- men with intravenous contrast along with brain imaging with an MRI scan. When an MRI scan is contraindicated, a contrast enhanced CT scan of the brain is acceptable. If cancer appears localized after a CT scan, a fluorode- oxyglucose positron emission tomography (FDG-PET) scan is performed because it images the whole body including bones and is the most sensitive test for cancer outside of the brain. A diagnosis of lung cancer is confirmed by a pathologist primarily based on light microscopy of tumor tissue, obtained by a needle biopsy or surgical resection. This type of histologic work-up is usually adequate to distinguish SCLC from NSCLC and to differentiate among the subtypes of NSCLC. Specifically, NSCLC is further classified as either squamous (25%) or non-squamous lung cancer; the majority of non-squamous lung cancer is adenocarcinoma (40% of lung cancers), and there are other types (large cell, poorly differentiated NSCLC-not otherwise specified, other rare) that account for small percentages of all lung cancers (PDQ® Adult Treatment Editorial Board, 2020). Further testing with immunohis- tochemistry (CK7, CD20, TTF-1, P63, and/or napsin) may be needed to confirm lung cancer subtypes or to distinguish metastatic cancers that may mimic primary lung cancer. In addition, there are molecular and immu- nologic techniques for more complete pathological profiling for NSCLC that not only aid lung cancer diagnosis but that are essential for treatment decisions and prognosis. In the current molecular era, more complete pathological profiling for NSCLC requires a large tissue sample, which can be challenging to obtain in advanced disease. When the cancer is localized (early stage), the tumor is resected, which usually produces enough tissue for pathologic diagnosis. In the case of a late-stage cancer that cannot be resected due to excessive risk or metastases, a needle biopsy is performed instead, which yields a small volume of tissue that may not support the diagnostic assessment necessary for selecting appropriate treatment in advanced disease. In such instances the emerging practice is to obtain multiple tissue cores at the time of core needle biopsy, or to perform the analysis on tumor genetic material in the blood, which is referred to as a “liquid biopsy.” PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 159 Lung Cancer Stages As discussed in Chapter 4, the American Joint Committee on Can- cer’s (AJCC’s) Eighth Edition AJCC Cancer Staging Manual (AJCC, 2017; Goldstraw et al., 2016; Kay et al., 2017) is the staging model used for most cancers, including lung cancer, to characterize the malignancy. In the AJCC staging system, TNM stands for tumor (T), node (N), and distant metas- tases (M) (see Table 6-1). In lung cancer staging, the T stage characterizes the size of the tumor and the degree of local extension to other structures within the lung. The N stage characterizes the location of lymph node in- volvement within the chest as follows: N0 indicates no nodal spread; N1 indicates cancer involved nodes limited within the lung proper that could TABLE 6-1 Anatomic Staging of Lung Cancer Stage Detailed Stage TMN Stage 0 Stage 0 • Tis, N0, M0 1 Stage 1A • T1mi, N0, M0 • T1, N0, M0 Stage 1B • T2, N0, M0 2 Stage 2A • T2, N0, M0 Stage 2B • T1, N1, M0 • T2, N1, M0 • T3, N0, M0 3 Stage 3A • T1, N2, M0 • T2, N2, M0 • T3, N1, M0 • T4, N0, M0 • T4, N1, M0 Stage 3B • T1, N3, M0 • T2, N3, M0 • T3, N2, M0 • T4, N2, M0 Stage 3C • T3, N3, M0 • T4, N3, M0 4 Stage 4A • Any T, any N, M1 Stage 4B • Any T, any N, M1 NOTE: M = presence or absence of distant metastasis; N = extent of regional lymph node spread; T = size or extent of the primary tumor; Tis = carcinoma in situ; T1mi = minimally invasive adenocarcinoma. SOURCES: Used with the permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual, Eighth Edition (2017) published by Springer International Publishing: the American College of Surgeons. Amin, M.B., Edge, S.B., Greene, F.L., et al. (Eds.). AJCC Cancer Staging Manual, 8th Ed. Springer New York, 2017, with permission. PREPUBLICATION COPY—Uncorrected Proofs

160 DIAGNOSING AND TREATING ADULT CANCERS be removed with the primary tumor; and N2 and N3 indicate regionally involved nodes limited to the mediastinum (area between the lungs in the middle of the chest) that could be potentially resected separately from the tumor, or distant nodal spread that is metastatic (outside of the thorax). The M stage distinguishes intrathoracic metastases (M1a) from extratho- racic ones, with the latter split into single-site metastasis (M1b) or multiple- site metastases (M1c) (Kay et al., 2017). TNM classifications for lung cancer are translated to Stages I, II, III and IV. Stage I and stage II are limited to the lung itself with no lymph node involvement or else involvement of only the hilar lymph nodes (N1 region). Stage III is defined by larger cancers and those that have spread to the me- diastinum or low neck lymph node regions outside of the lung (N2 or N3 regions). A stage IV cancer is widespread with systemic metastatic disease. A significant proportion of NSCLC cases (40%) are stage IV at the time of diagnosis (PDQ® Adult Treatment Editorial Board, 2020). As with other solid tumors, the TNM staging can be used to diagnosis SCLC. However, the predominant basis for SCLC treatment decisions is the Veterans Administration Lung Group 2-stage system, which defines limited- stage (LS) and extensive-stage (ES) SCLC (Kalemkerian, 2012). LS-SCLC, which occurs in approximately one-third of SCLC patients, is defined as disease that is confined to the hemithorax (one side of the chest) of origin, the mediastinum, or the supraclavicular nodes (nodes located above the col- larbone) and that can be encompassed within a tolerable radiation field. ES- SCLC, which occurs in approximately two-thirds of SCLC patients, is defined as disease that has spread beyond the supraclavicular areas and lung and is too widespread to be included within a tolerable radiation field. Patients with dis- tant metastases by definition have extensive-stage disease (Wang et al., 2019). Survival Rates Lung cancer is one of the most lethal cancers: more than half of people with lung cancer die within 1 year of being diagnosed (SEER, 2020, n.d.- c). The all-stage 5-year survival rate for NSCLC is 24.9% and only 6.5% for SCLC (SEER, n.d.-a,-b). Table 6-2 shows the 5-year survival rates for NSCLC and SCLC by stage at the time of diagnosis. Although lung cancer stages I-III are potentially curable, the reason for this high mortality rate is two-fold: First, most patients are diagnosed in advanced stages of the disease, when the cancer has metastasized to distant organs, and is incurable (stage IV). Second, the recurrence rate for those diagnosed with earlier stages (stages I–III) approaches 50% for NSCLC and 80% for SCLC. If lung cancer is diagnosed at an early (localized) stage, the overall 5-year survival improves dramatically to 59%; however, only 17% of lung cancers are diagnosed at this stage (SEER, n.d.-d). PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 161 TABLE 6-2 5-Year Survival Rates Since Diagnosis (diagnosed between 2010 and 2016) Stage Percent Surviving NSCLC Percent Surviving SCLC Stage I or II (localized) 63.1 27.2 Stage III (regional spread) 35.4 16.4 Stage IV (metastatic) 6.9 2.9 All stages combined 24.9 6.5 SOURCE: Howlader et al., 2020. SCLC typically grows quickly, is highly metastatic, and is usually rap- idly fatal. In 2012 the U.S. Congress classified SCLC as a recalcitrant can- cer—that is, a cancer with a 5-year relative survival rate of less than 20% and estimated to cause the death of at least 30,000 individuals per year in the United States—and it authorized the National Cancer Institute to specifically dedicate resources to combat this disease.1 LUNG CANCER TREATMENT In general, treatment options for lung cancer are determined by the histology, stage, and molecular characteristics of the tumor and by the patient’s general health and comorbidities. This section presents an over- view of the current treatments for NSCLC and for SCLC. It reflects the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology®, which are the leading evidence-based, consensus driven rec- ommendations for the management of cancer in the United States (NCCN, 2020a,b). The NCCN guidelines state that clinical trials provide the best management option for patients, but the committee recognizes that such trials are not always available or accessible for an individual patient diag- nosed with lung cancer. Lung cancer treatments are generally categorized as local/regional ther- apies (surgery, radiation therapy, ablation) or systemic therapies (chemo- therapy, immunotherapy, targeted therapy), and the various types are often used in combination. Improved survival of patients with lung cancer have followed from recent advances in genetics and biomarker testing, particu- larly for NSCLC, which have led to personalized medicine approaches with targeted treatments (Riely et al., 2009). As described in Chapter 4, targeted therapies are based on the identification of specific features of a patient’s tumor (e.g., an abnormal ALK gene) that may respond to the therapy. Chemotherapy, the foundation of medical oncology, is no longer the most 1  Recalcitrant Cancer Act of 2012, HR 733, 112th Congress. PREPUBLICATION COPY—Uncorrected Proofs

162 DIAGNOSING AND TREATING ADULT CANCERS effective systemic treatment for either NSCLC or SCLC lung cancer (Mok et al., 2016; Reck et al., 2016; Solomon et al., 2014; Zhou et al., 2011). Treatment of Non-Small-Cell Lung Cancer This section describes the standard therapies that are used to treat NSCLC and is organized into treatments for cancer stages I–II, stage III, and stage IV. Stages I–II NSCLC Surgery is the standard-of-care approach for patients with stage I or stage II NSCLC who are deemed medically fit for surgery (NCCN, 2020b). Patients need to undergo an extensive preoperative evaluation of heart and lung function to determine if they are medically fit for surgery, which is typically done by a thoracic surgeon. While surgical resection is the treat- ment of choice for stages I–II NSCLC, many patients are not candidates for surgery either because of medical comorbidities, or deficits in functional status or in pulmonary function, or because of refusal to undergo surgery. For these patients, radiation therapy, ablation, and chemotherapy are al- ternatives to surgery. Surgery The surgical resection of a NSCLC stages I–II tumor involves the removal of the primary cancer within the lung, usually done by removing a single lobe of the lung (lobectomy), plus the removal of several lymph nodes within the mediastinum. Traditionally, the removal of a lobe of a lung required a thoracotomy, which involves a large incision and resulting scar extending from the patient’s back to the side. More recently, less invasive techniques have emerged and a growing number of patients may undergo video-assisted thorascopic surgery (VATS), which requires only small inci- sions to insert a camera and surgical instruments to remove the specimen. A recent analysis of the Society of Thoracic Surgeons General Thoracic Surgery Database of patients aged 65 or older who had undergone lobec- tomy for stage I lung cancer showed that 42% underwent a thoracotomy and 58% received a VATS procedure (Boffa et al., 2018). VATS procedures are also being done with robotic assistance. VATS lobectomy has equivalent or slightly improved safety and efficacy, as well as better patient outcomes, compared with traditional open lobectomy (Aoki et al., 2007; Yan et al., 2009). The removal of the entire lung (pneumonectomy) may be required in patients with tumors that are located near critical structures in the cen- ter of the chest such as the major airways, or that cross a lung fissure to involve more than one lobe. (James and Faber, 1999). Pneumonectomy is associated with a number of potential complications that involve not only PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 163 the respiratory system, but also the cardiovascular system and the pleural space, and that may result in a significant risk of perioperative mortality and long-term morbidity (Kopec et al., 1998). For these reasons the rate of pneumonectomy is declining. Sublobular resection, either segmentectomy or wedge resection, may be an option for some patients, particularly those with poor pulmonary reserve and with small peripheral nodules (<2 cm) (NCCN, 2020b). Mediastinal staging, removal, and evaluation of lymph nodes between the lungs, is a key element of lung cancer surgery mainly for prognosis and treatment planning. The optimal extent of lymph node surgery remains uncertain. A meta-analysis demonstrated that the dissection of the most at-risk lymph nodes results in a small improvement in survival compared with no lymph node sampling (Manser et al., 2005). A greater number of lymph nodes removed at the time of surgery improves the accuracy of staging (Gajra et al., 2003). Those found to have incidental tumor involve- ment of mediastinal lymph nodes (N2 or N3) are, by definition, upstaged to stage III. Radiation therapy When surgical resection of a NSCLC stage I or node- negative stage II tumor is not feasible, radiation as a single treatment mo- dality is often used. Over the past 20 years, radiation therapy has improved considerably, and the current state-of-the-art technique is called stereotactic body radiation therapy (SBRT) (also referred to as stereotactic ablative radiotherapy; see Chapter 4). For patients with stages I–II NSCLC who are not surgical candidates, SBRT is the treatment of choice (Schneider et al., 2018). SBRT delivers a dose of 10–34 Gy as one fraction for small, periph- eral tumors, and up to 60–70 Gy total dose in 8–10 fractions for central tumors (NCCN, 2020b). SBRT is suitable for localized tumors because features of the technology (such as the ability to adjust patient position) ensure that high doses of radiation are delivered to a precise location. SBRT has resulted in excellent local tumor control for stages I–II NSCLC in pro- spective studies with long-term primary tumor control rates of greater than 90% (Hobbs et al., 2018; Senthi et al., 2012). Nevertheless, patients still need close monitoring for recurrences elsewhere in the same lobe or lung, in the lymph node regions, and especially in distant organs (e.g., liver, bones, adrenal glands, brain, opposite lung). Clinical trials are under way comparing surgical resection to SBRT. Should SBRT demonstrate better outcomes than surgery, it is possible that the standard of care for patients with stages I–II NSCLC would change (Chang et al., 2015; University of Texas Southwestern Medical Center, 2015; VA ORD, 2016). The acute effects of SBRT are minimal and generally do not peak until 1 week or longer after treatment. Fatigue is the most commonly reported PREPUBLICATION COPY—Uncorrected Proofs

164 DIAGNOSING AND TREATING ADULT CANCERS acute effect and skin irritation (radiation dermatitis) is typically not seen or is quite mild. Some patients may experience cough from transient in- flammation in the lung or airways. Additional sequelae of SBRT, such as scarring of the lung (lung fibrosis), are discussed in the section on life after cancer diagnosis. Percutaneous image-guided ablation approaches Although radiation ther- apy is the preferred treatment approach for patients with stages I–II NSCLC when surgery is not an option, in some cases (e.g., small tumors in stage I NSCLC), interventional radiologists can remove the tumors, with CT guid- ance, using techniques such as radiofrequency ablation, microwave abla- tion, or cryoablation (see Chapter 4 for more detail on ablation techniques). To induce tumor necrosis, these local ablative techniques rely on thermal energy: radiofrequency ablation (Ambrogi et al., 2011) and microwave ablation apply heat to the tumor while cryoablation applies intense cold (Gage and Baust, 1998). Patients who require treatment of multiple synchronous or meta- chronous primary tumors are often good candidates for percutaneous ab- lation techniques. The best outcomes with percutaneous ablation have been reported for tumors less than 3 centimeters. With larger tumors, there are added complexities to the procedure, thus increasing the risk of complications. Pneumothorax, pleural effusion, and hemothorax are the most com- mon complications of ablation (Kashima et al., 2011). In different studies the rate of pneumothorax ranges from 1.3% to 60%, and requires thora- costomy tube placement in roughly 15% of patients (Kashima et al., 2011; Zheng et al., 2014). Other complications are less common, but include aseptic pleuritis (2.3%), pneumonia (<2.0%), and bleeding requiring blood transfusion (1.6%). In one study, deaths following ablation were 0.4% (Dupuy et al., 2006). Complication rates are influenced by longer ablation times, the use of multiple probes, the size and location of the lesion, and underlying lung disease. Chemotherapy for high-probability of recurrence Some patients with stage I–II NSCLC have a substantial probability of recurrence even after surgi- cal resection, SBRT, or local ablation techniques. The probability that subclinical cancer has been left behind at the time of surgery is propor- tional to the stage, tumor size, nodal spread, and degree of invasion. For example, Brandt et al. (2018) found a distance recurrence rate of 20–50% with increasing T tumor stage in node-negative disease even after complete resection. A systematic review by the Cochrane Collaborative supports the use adjuvant chemotherapy with a platinum-based agent following lung resection in early-stage lung cancer (Burdett et al., 2015). Adjuvant PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 165 chemotherapy following surgery was found to result in an absolute increase in survival of 4% (from 60% to 64%) at 5 years; a similar improvement was seen when adjuvant chemotherapy was given after surgery and post- operative radiation (from 29% to 33%) (Burdett et al., 2015). The NCCN guidelines recommend adjuvant chemotherapy with cisplatin plus a second chemotherapy agent (e.g., pemetrexed, gemcitabine, or docetaxel) given every 3 weeks for four cycles (NCCN, 2020b). Recurrence-free survival improved by 15%, time to locoregional recurrence improved by 21%, and time to distant recurrence improved by 25% as a result of adjuvant chemo- therapy (Burdett et al., 2015). In some cases, the administration of neoadjuvant therapy can also result in a reduction of tumor mass and thereby make some surgeries more likely to achieve a complete resection of the tumor. Neoadjuvant chemotherapy may also remove micro-metastases and improve patient treatment completion (Subramanian and Puri, 2020). One study found that neoadjuvant chemotherapy increased 5-year recurrence-free survival by 6% (from 30% to 36%) and yielded a 10% absolute benefit for distant recur- rence (NSCLC Meta-analysis Collaborative Group, 2014). Although there are fewer studies on the use of neoadjuvant chemotherapy for early-stage NSCLC compared with adjuvant chemotherapy, Brandt et al. (2020) found that among patients with cT2-4N0-1M0 NSCLC, there is no significant dif- ference in 5-year disease-free survival or overall survival between patients receiving adjuvant or neoadjuvant platinum-based chemotherapy, however, those receiving neoadjuvant chemotherapy were more likely to complete their therapy and had fewer severe toxicities from it. Several studies are evaluating immunotherapy alone or in combination with chemotherapy as neoadjuvant or adjuvant therapy for early-stage NSCLC. It is likely that these agents may be introduced into the manage- ment of resectable NSCLC in the near future (Cascone et al., 2019; Forde et al., 2018; Kwiatkowski et al., 2019). Stage III NSCLC Stage III NSCLC represents a heterogeneous group of diseases divided into three major categories (see Table 6-1). Stage IIIA NSCLC can range from very large tumors with or without small nodes in the ipsilateral hilum (T3 N1 or T4 ± N1) to very small tumors with ipsilateral mediastinal nodes (T1–T2, N2). Stage IIIB NSCLC ranges from large tumors with ipsilateral mediastinal nodes (T3–T4, N2) to small tumors with contralateral or supra- clavicular nodes (T1–T2, N3). Stage IIIC NSCLC consists of large tumors with contralateral or supraclavicular nodes (T3–T4, N3) (AJCC, 2017). Due to the high probability of relapse, stage III NSCLC is treated with multiple treatment modalities in order to address the various malignant PREPUBLICATION COPY—Uncorrected Proofs

166 DIAGNOSING AND TREATING ADULT CANCERS behaviors of the cancer. Presently this includes combinations of local/re- gional treatments such as surgery and radiation with systemic treatments such as chemotherapy and/or immunotherapy. In short, stage III NSCLC lung cancer is quite diverse and so is its treatment. Surgery For stage III NCSLC, surgery is sometimes used in conjunction with chemotherapy and radiation therapy (trimodal therapy). Patients with larger or more involved nodes may not be candidates for surgery. Patients with one or more small (<3 cm in size) involved lymph nodes may be candi- dates for surgical resection (NCCN, 2020b). Patients with a greater number of metastatic nodes are not candidates for surgery. A randomized clinical trial demonstrated that patients in stage IIIA (pN2) disease, who received neoadjuvant chemotherapy (cisplatin plus etoposide) with radiation therapy followed by resection did not have improved survival, but those who were treated with a lobectomy rather than a pneumonectomy had longer median and 5-year progression-free survival (12.8 months and 22.4%, respectively) compared with patients who received chemotherapy and radiation therapy but did not undergo surgery (10.5 months and 11.1%, respectively); 5-year overall survival was also significantly improved in those receiving lobec- tomy after chemotherapy and radiation compared with those who did not (27.2% versus 20.3%) (Albain et al., 2009). N0 status at thoracotomy was predictive of overall survival. A majority of patients have extensive lymph node involvement of the mediastinum or do not have the physiologic re- serve to tolerate such surgery. The use of surgery remains controversial in stage III NSCLC. Ultimately, a multidisciplinary approach is recommended for patients with stage III lung cancer that is resectable. Concurrent chemotherapy and radiation therapy Chemotherapy given at the same time as radiation therapy (concurrent chemoradiation) is the stan- dard of care treatment for unresectable stage III NSCLC and may also be administered prior to, or following, surgical resection in patients for whom surgery may be curative. More than 40 years ago patients with unresectable stage III NSCLC were treated with radiation therapy alone (60 Gy in 30 treatments) (Cali- kusu and Altinok, 2018) and had a poor chance of survival. Subsequent re- search provided evidence supporting the use of both radiation therapy and chemotherapy (Kubota et al., 1994). More recently, several randomized tri- als have demonstrated that concurrent chemoradiation resulted in superior survival rates compared with chemotherapy followed by radiation therapy (sequential chemoradiation) (Auperin et al., 2010; O’Rourke et al., 2010). The radiation dose used with concurrent chemotherapy remains 60 Gy in 30 fractions. This dose of radiation results in better survival rates PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 167 than does a higher dose of radiation (74 Gy in 37 fractions) (Bradley et al., 2015, 2020). Several chemotherapy regimens may be used for concurrent chemo- radiation. A common strategy uses the histology of the lung cancer to choose the most appropriate regimen. For patients with non-squamous cell histologies, the preferred regimen is carboplatin or cisplatin plus peme- trexed. For patients with squamous cell histology, the preferred regimens are carboplatin plus paclitaxel or cisplatin plus etoposide (NCCN, 2020b). Each regimen has a standardized administration protocol, with a specified number of days and cycles. Consolidation therapy Despite the gradual improvements in survival rates that have been seen in patients with unresectable stage III NSCLC, over the past few decades, it is still the case that more than 50% of these patients will ultimately develop distant metastases (Bradley et al., 2015). Consolidation therapy involves giving additional therapies upon completion of concurrent chemotherapy and radiation therapy to try to reduce the risk of distant metastases, and ultimately improve survival rates. Numerous studies have investigated consolidation chemotherapy (Bradley et al., 2015, 2020; Kelly et al., 2008; Tsujino et al., 2013). A landmark randomized study in 2017 demonstrated that stage III NSCLC patients treated with concurrent che- motherapy and radiation followed by 1 year of immunotherapy with dur- valumab achieved a significant reduction in the risk of disease progression or death compared with those who did not receive durvalumab (Antonia et al., 2017). In addition, the overall survival improved with consolidation durvalumab, with two-thirds of the patients alive at 2 years and a median overall survival time that has not yet been reached (Gray et al., 2020). Acute toxicities of chemoradiation For most patients with stage III NSCLC, a common side effect of concurrent chemoradiation, in addition to fatigue and skin irritation, is radiation esophagitis resulting from radiation target- ing lymph nodes located in close proximity to the esophagus. This irritation of the esophagus can manifest itself as heartburn, difficulty swallowing, or pain with swallowing. Radiation esophagitis is managed with oral medica- tions and rinses, but if it is severe enough it can lead to severe dehydration and weight loss that may necessitate hospital admission possibly the place- ment of a feeding tube. The risk of developing radiation esophagitis and its severity are directly related to radiation dose-volume parameters including the mean dose to the esophagus, and factors such as the volume of the esophagus that receives 60 Gy or higher (Verma et al., 2017). In addition to esophagitis, patients who receive chemoradiation are also at risk of decreased blood counts (white blood cells, red blood cells, and PREPUBLICATION COPY—Uncorrected Proofs

168 DIAGNOSING AND TREATING ADULT CANCERS platelets). Depending on the severity of the decrease in these blood counts, the chemotherapy may need to be dose-reduced or withheld at some point during treatment. Radiation therapy generally continues even in the setting of decreased blood counts unless the patient is hospitalized with fevers and low blood counts or the platelets or red blood cells get to dangerously low levels that require transfusions. Radiation dose-volume parameters to the vertebral bodies (spine bones) may be associated with the risk of developing decreased blood counts, and this is an area of active investigation with the goal of reduc- ing the risk of patients developing hematologic toxicities (Verma et al., 2017). Cough and shortness of breath are additional possible acute effects of chemoradiation. If these symptoms develop during treatment, they are usually indicative of an acute inflammatory reaction in the lung or airways and are managed conservatively with cough medications, mucolytics, and sometimes short acting inhalers. Radiation pneumonitis refers to a severe inflammatory reaction in the lungs that can develop anywhere from 1 to 6 months after radiation. Radiation pneumonitis is considered a subacute reaction because it generally does not develop in the acute setting (during chemoradiation therapy) and it does not develop in the late setting (>6 months from the end of radiation). The incidence of radiation pneumonitis is strongly dependent on radiation dose-volume parameters. Symptomatic radiation pneumonitis is managed with high doses of corticosteroids with a prolonged taper. Some patients may need to be hospitalized for supple- mental oxygen. Radiation pneumonitis is usually not fatal if it is detected early and treated appropriately (Verma et al., 2017). Stage IV NSCLC Until recently, all patients with metastatic stage IV NSCLC were treated with similar courses of systemic chemotherapy, but treatment has evolved to a more personalized or precision approach (see Chapter 4). In these ap- proaches, tumor features that drive the malignant behavior of the cancer are targeted, when possible, so that each cancer is treated with the most effective drug for that tumor. The identification of the molecular and im- munologic features of the cancer has become the most important element for treatment of late-stage NSCLC. Targeted therapy The molecular assay for NSCLC typically consists of a broad next-generation sequencing gene panel that evaluates genetic aberra- tions (e.g., DNA mutations and translocations) known to be drivers of lung cancer. Drugs that inhibit the abnormal protein products of these driver genes are used to treat the specific cancer with the driver gene. FDA has approved a number of therapies that target molecular ab- normalities in NSCLC. Most of these agents are oral, and most of the mutations where effective agents exist occur in patients with no smoking PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 169 history. These therapies have very different side effects than conventional chemotherapy. Currently, FDA-approved inhibitors for EGFR, ALK, ROS, BRAF, MET and RET are included in national guidelines and are standard of care for NSCLC (ACS, 2020; Bironzo and Di Maio, 2018; PDQ® Adult Treatment Editorial Board, 2020). EFGR, the most commonly identified actionable mutation in patients with metastatic NSCLC, occurs in approxi- mately 13% of such patients (Eberhard et al., 2005). EGFR is more com- mon in lung cancers in nonsmokers than in smokers (51% versus 10%), East Asians, women, and NSCLC adenocarcinomas (Shigematsu et al., 2005). ALK is the second most common actionable mutation occurring at a frequency of 5% with ROS, BRAF, MET and RET occurring at frequencies of less than 5% (Griffin and Ramirez, 2017). Many additional inhibitors of genetic driver of cancer are under development. Osimertinib is an EGFR inhibitor approved for EGFR-driven lung cancer. In a randomized clinical trial of EGFR-mutated NSCLC, compar- ing osimertinib with erlotinib (a EFGR-tyrosine kinase inhibitor [TKI]), the median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months versus 10.2 months) (Soria et al., 2017). In addition, adverse events were less frequent with osimertinib than with standard EGFR-TKIs (34% versus 45%) and there were few neurologic events for osimertinib. Osimertinib has also been tested against conventional chemotherapy and has been shown to be superior (Mok et al., 2016; Soria et al., 2017). Molecular studies of resistance to EGFR inhibi- tors continue to be evaluated. Immunotherapies The concept of an immune panel is evolving. Presently, there are only two immune biomarkers approved for the treatment of NSCLC: programmed death (PD) ligand 1 (PD-L1) (PDQ® Adult Treat- ment Editorial Board, 2020) and the tumor mutational burden (FDA, 2020). The programed death pathway is a protective pathway of normal tissue for immune regulation that is commonly hijacked by tumor tissue. NSCLC and other tumors over-expressing PD-L1 are insensitive to T-cell killing, but that sensitivity can be restored by anti-PD therapy (see Chapter 8 for more information on immunotherapy). The tumor mutational burden measures the number of mutations per megabyte of DNA and is a measure of how susceptible a tumor is to recognition by the immune system. When the protein PD-L1 is present on greater than 50% of lung cancer cells, immunotherapy with the programmed cell death 1 (PD-1) inhibitor pembrolizumab has been shown to be superior to combination chemother- apy with a cisplatin-based regimen (Reck et al., 2016). Follow-up data at 3 years post-treatment showed the overall survival rate was 43.7% among patients in the pembrolizumab arm versus 24.9% in the chemotherapy arm (ASCO Post Staff, 2019). It is estimated that 25% of patients who were treated with pembrolizumab may be alive at 5 years (Garon et al., 2019). PREPUBLICATION COPY—Uncorrected Proofs

170 DIAGNOSING AND TREATING ADULT CANCERS In addition, in patients with NSCLC whose cancer had progressed after chemotherapy, the PD-1 inhibitors, nivolumab and pembrolizumab, as well as the PD-L1 inhibitor, atezolizumab, all demonstrated improved survival compared with conventional chemotherapy. Approximately 15% were alive at 5 years (Garon et al., 2019; Gettinger et al., 2018). In the absence of a targetable DNA biomarker or elevated PD-L1, randomized clinical studies have shown positive results from concurrent chemoimmunotherapy versus sequential chemotherapy followed by stan- dard-of-care immunotherapy (Gandhi et al., 2018). Survival data (Gadgeel et al., 2020) showed an improvement in overall survival across all PD-L1 categories that were evaluated. Median progression-free survival was 9 months in the pembrolizumab-combination group and 4.9 months in the placebo-combination group. Acute toxicities related to PD-1- and PD-L1-based immunotherapies for lung cancer are less frequent than and different from those associated with conventional chemotherapy (e.g., nausea, hair loss, infections, neuropathy). PD-1 inhibitors inhibit an inhibitor of the immune system and, as such, pro- vide a general, non-specific activation of the immune system. The goal is to stimulate immune activation against the cancer only, but this activation can also stimulate autoimmunity against normal organs. The organs most com- monly affected by excessive immune stimulation are the skin (dermatitis), bowel (colitis), endocrine organs (hypophysitis, thyroiditis, diabetes), and lung (pneumonitis), among others. Such nonspecific immune stimulation is treated with immune suppression, most commonly with steroids. While the side effects may be life-threatening, they are generally reversible and easily managed in most cases. Endocrine organ dysfunction may be remedied by replacing the associated hormone deficiency (NCCN, 2020a). Oligometastatic NSCLC Oligometastatic lung cancer is a unique subtype of NSCLC in which the metastases are limited in number and organ sites. While there are no universally accepted-criteria for defining the oligometa- static state, a European Consensus definition indicates that it includes up to five metastases from three organ sites (Dingemans et al., 2019). Oligo- metastatic disease is an important category of metastatic lung cancer as it represents a clinical scenario in which metastasis-directed local therapies (radiation or surgery), in addition to systemic therapy, may play a role in potentially curing patients with otherwise incurable stage IV disease. The question of whether oligometastatic disease is potentially curable is particularly important in NSCLC because the incidence of oligometastases may range from 26% to 55% (Parikh et al., 2014; Torok et al., 2017; Yano et al., 2013). Data from prospective randomized clinical trials of oligometa- static NSCLC support aggressive local regional therapy and ablation of me- tastases (Gomez et al., 2016, 2019; Iyengar et al., 2018; Palma et al., 2019). PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 171 Based on these studies, integrating local therapy with systemic therapies should be strongly considered for patients with oligometastatic NSCLC, with a multidisciplinary discussion to help guide the appropriate timing of local therapy (before or after first-line systemic therapy) and choice of local therapy (radiation, thermal ablation, or surgery) for each case. Treatment of Small Cell Lung Cancer Unlike other common solid tumors, SCLC is very sensitive to chemo- therapy and radiation therapy when it is initially diagnosed. However, resistance to the chemotherapy develops rapidly in more than 90% of patients, leading to disease recurrence. Second-line chemotherapies are relatively ineffective, so the mortality rate for this disease is high (Farago and Keane, 2018). The prognosis of SCLC is poor, with survival measured in months (Poirier et al., 2020); the median overall survival of patients with limited-stage SCLC (LS-SCLC) is 15–20 months and 8–13 months for those diagnosed with extensive-stage SCLC (ES-SCLC) (Zhong et al., 2020). Because SCLC is considered a systemic disease, chemotherapy is a cornerstone of its treatment even in cases where the disease is limited to a single lesion in the lungs. In addition, surgery is typically not used in SCLC. While surgical resection followed by adjuvant chemotherapy is a reasonable option for early-stage disease (Zhong et al., 2020), most surgical cases of SCLC occur because of an initial misdiagnosis as NSCLC. Treatment of LS-SCLC, which has not changed over the last four de- cades, consists of a standard first-line chemotherapy regimen with concur- rent radiation. The chemotherapy typically consists of a platinum-based agent and etoposide (NCCN, 2020b). The treatment of ES-SCLC uses the same systemic chemotherapy without concurrent radiation; again, the chemotherapy would include a platinum agent and etoposide or irinotecan (NCCN, 2020a). For the first time in over a decade, the survival of patients with ES-SCLC recently showed improvement, with survival increasing by a median of 2 months when standard chemotherapy was combined with the PD-L1 inhibitors atezolizumab (Horn et al., 2018) or durvalumab (Paz-Ares et al., 2019). Approximately 20% of SCLC patients are diagnosed with brain me- tastases at the initial diagnosis (Goncalves et al., 2016). Importantly, many of these patients have no neurologic symptoms indicative of brain metas- tases (Hochstenbag et al., 2000). The rate of brain metastases increases significantly among patients who survive for more than 1 year after treat- ment (Schouten et al., 2002). To counteract this predilection of SCLC to metastasize to the brain, prophylactic cranial irradiation in the absence of detectable brain metastases, is a component of therapy for LS-SCLC patients who achieve a complete or near-complete response to systemic PREPUBLICATION COPY—Uncorrected Proofs

172 DIAGNOSING AND TREATING ADULT CANCERS chemotherapy and thoracic radiation. This treatment reduces the risk of brain metastases and improves survival (Rudin et al., 2015). However, this approach is currently being questioned because of late cognitive effects of prophylactic cranial irradiation and because of the option of effective MRI surveillance and stereotactic radiation therapy, which can effectively man- age brain metastases after they are diagnosed (Lukas et al., 2017). When SCLC recurs, treatment is relatively ineffective. A recurrence of ES-SCLC after first-line chemotherapy is categorized as refractory (i.e., occurs within a 60–90 days after first-line chemotherapy ends) or sensitive (i.e., occurs after at least 60–90 days after end of first-line chemotherapy). Topotecan, a topoisomerase 1 inhibitor and the only FDA-approved agent for recurrent SCLC, is associated with a 1-year overall survival of 9% for refractory recurrent SCLC and 27% for sensitive recurrent SCLC (Horita et al., 2015). Topotecan resulted in a mean survival rate of 33–35 weeks and a 1-year survival rate of 29–33% in patients with either ES- or LS-SCLC, although the type of recurrence was not specified (Eckardt et al., 2007). Tumor shrinkage following third-line chemotherapy in metastatic SCLC is uncommon; however, two PD-1 inhibitors, nivolumab and pembrolizumab, have been approved for this indication (Chung et al., 2020; Ready et al., 2020). Acute treatment-related impairments are those associated with che- motherapy and radiation (see Acute Toxicities of Chemoradiation above) because most patients with LS-SCLC receive concurrent chemoradiation and some patients with ES-SCLC receive consolidative chest radiation after the completion of chemotherapy (Slotman et al., 2015). Similarly, late-onset and long-term impairments are associated with chemotherapy (peripheral and sensory neuropathy) and radiation therapy (pulmonary and cardiac complications) as well as with cognitive impairment stemming from pro- phylactic cranial radiation. These impairments are discussed in the section on Life after Cancer Diagnosis. SUMMARY OF LUNG CANCER DIAGNOSTIC EVALUATION AND TREATMENT Table 6-3 summarizes the information presented in the preceding sec- tions on the diagnosis and treatment of stage I–II, stage III, and stage IV NSCLC and LS- and ES-SCLC. LIFE AFTER LUNG CANCER DIAGNOSIS A lung cancer survivor’s health status and quality of life (QOL) are often degraded not only by the cancer and its treatment, but also by vari- ous comorbid medical conditions, including COPD and emphysema as well PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 173 TABLE 6-3 Summary of Lung Cancer Diagnosis and Treatment Stage Diagnostic Evaluation Treatment Non-small-cell lung cancer Stage I or II CT scan; PET scan; MRI Resectable tumors: (localized) scan; endobronchial • Surgery: open, video or robot-assisted ultrasound; mediastinoscopy; lobectomy; or pneumonectomy percutaneous lung biopsy • Adjuvant chemotherapy, if risk of relapse is >25% Unresectable tumors due to limited organ function: • Stereotactic radiotherapy • Radiofrequency ablation Stage III CT scan; PET scan; MRI Resectable tumors: (regional spread) scan; endobronchial • Surgery ± radiation ± neoadjuvant ultrasound; mediastinoscopy; chemotherapy percutaneous lung biopsy Unresectable tumors: • Chemotherapy + radiation + immunotherapy Stage IV CT scan; PET scan; MRI • Chemotherapy ± immunotherapy ± (metastatic) scan; needle biopsy; targeted therapy molecular and DNA • Radiation for palliation biomarkers Small-cell lung cancer Limited stage CT scan, MRI scan, bone • Chemotherapy with radiation ± scintigraphy, FDG-PET scan prophylactic cranial irradiation Extensive stage CT scan, MRI scan, bone • Chemotherapy ± immunotherapy ± scintigraphy, FDG-PET scan radiation NOTES: The symbol ± in the treatment column means “with or without.” The exact treat- ment regimen is determined on a case-by-case basis. CT = computed tomography; DNA = deoxyribonucleic acid; FDG-PET = fluorodeoxyglucose positron emission tomography; MRI = magnetic resonance imaging; PET = positron emission tomography. as recurrent or new cancers. Therefore, in addition to an accurate diagno- sis and appropriate treatment regimen, supporting the optimal health and functioning of lung cancer survivors involves care for the adverse sequelae of the primary lung cancer and its treatment along with health promotion and disease-prevention activities, such as smoking cessation, and monitoring for evidence of recurrence and new cancers (Vijayvergia et al., 2015). For example, the American Society of Clinical Oncology currently recommends that patients with stage I–III NSCLC and SCLC who have been curatively treated and who have no symptoms of recurrent disease should undergo imaging for recurrence every 6 months for 2 years and then once per year PREPUBLICATION COPY—Uncorrected Proofs

174 DIAGNOSING AND TREATING ADULT CANCERS in order to detect any new primary lung cancers (Schneider et al., 2020). See Chapter 10 for more information about cancer survivorship care. Often persistent and overlapping, cancer-related sequelae impair a lung cancer survivor’s ability to maintain good health and function. Some of these sequelae may resolve within 6 months (acute effects), others may be- come chronic (long-term effects), and still others may develop in the months to years after treatment ends (late-onset effects) (Vijayvergia et al., 2015). The sections below described the range of late-onset and long-term physi- cal, psychological, and psychosocial impairments that adversely affect a lung cancer survivor’s overall QOL and that increase the risk for functional limitations. See Chapter 9 for more on functional limitations. Physical Effects In general, the physical effects caused by lung cancer and its treatments include respiratory problems, fatigue, pain, reduced appetite, neuropathy, and ototoxicity (e.g., inner ear problems from drug toxicity resulting in hearing loss or tinnitus) (Ha et al., 2020; Hung et al., 2011; Yang et al., 2012). These physical impairments tend to become chronic. For example, a 7-year longitudinal study of 477 lung cancer survivors (mostly of NSCLC) showed persistent physical symptoms that did not lessen over time and that diminished the survivors’ QOL (Yang et al., 2012). Among survivors reporting declines in QOL (n = 155), significant symptoms were fatigue (69%), pain (59%), dyspnea (58%), depressed appetite (49%), and cough- ing (42%). Fatigue is the most commonly reported symptom among survivors of lung cancer, affecting up to 90% of them and it may persist for months to years after treatment (Hung et al., 2011). There is an association between moderate to severe fatigue and impairment in daily functioning. Among NSCLC survivors with moderate to severe fatigue, one in four (23.7%) was functionally impaired, that is, their ability to work or to independently care for their personal needs outside the home was limited (Hung et al., 2011). Contributing factors to fatigue include comorbid health conditions, pain, depression, anxiety, sleep disturbances, and changes in breathing capacity (Hung et al., 2011; Sugimura and Yang, 2006). Studies suggest that fatigue can resolve in 3 to 6 months in some cases, such as after lung cancer sur- gery (Brunelli et al., 2007; Win et al., 2005), or it can persist for months to years after treatment completion (Kenny et al., 2008; Sarna et al., 2008). Between 80% and 100% of all cancer survivors experience pain (Rausch et al., 2012), and pain significantly diminishes their QOL (Sugimura and Yang, 2006). Chronic pain was reported by 25% of long-term NSCLC sur- vivors followed at a survivorship clinic (Huang et al., 2014). Many NSCLC survivors who undergo surgery may experience post-thoracotomy pain—a PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 175 pain syndrome involving burning, dysesthesia, and aching along the thora- cotomy incision—that can persist for a prolonged period (>2 months) after surgery (Rogers and Duffy, 2000). Thirty percent of patients report con- tinued pain up to 5 years after surgery (Dajczman et al., 1991). Pain may also be due to chemotherapy-induced peripheral neuropathy, as described below (and in Chapter 9). In one study, nearly two-thirds of lung cancer patients experience dys- pnea, cough, wheezing, phlegm, pain, and decreased functionality (Sarna et al., 2004). Physical, cognitive, and emotional functions may be adversely affected by dyspnea (Sugimura and Yang, 2006). Persistent cough can interfere with speech, eating, and sleeping and thus significantly affect psy- chological, social, and physical QOL (Harle et al., 2012). Psychological and Psychosocial Effects Lung cancer and its treatment put survivors at risk for various effects that affect their psychosocial well-being, including psychological health (e.g., anxiety, depression, fear of recurrence), interpersonal connections (e.g., relationships, role in family), financial security (e.g., loss of employ- ment or insurance, cost of cancer care), and behavioral health (e.g., capacity for a healthy lifestyle). At least 40% of NSCLC survivors report psychological distress, which is significantly higher than the rates seen in survivors of other cancers (Chapple et al., 2004; Zabora et al., 2001). Even mild symptoms of emo- tional and psychological distress can affect daily functioning and QOL and are associated with a decline in both cognitive and social functioning (Fox and Lyon, 2006; Shi et al., 2011). Psychological distress in long-term cancer survivors has been associ- ated with non-adherence to cancer surveillance screening recommenda- tions (Katz et al., 2009) and a lack of engagement in healthful behaviors, such as exercise (Courneya et al., 2008) and smoking cessation (Schnoll et al., 2010). Patients with lung cancer who continue to smoke in the perioperative period have higher postoperative pulmonary morbidity and mortality (Vaporciyan et al., 2002). In long-term NSCLC survivors, greater motivational readiness for physical activity was associated with improved QOL (Clark et al., 2008), although nearly 66% of survivors did not meet national physical activity guidelines during the post-treatment period (Car- mack et al., 2011; Coups et al., 2009). Lung cancer significantly increases the risk of departure from the work- force compared with other cancers such as colon cancer (odds ratio 2.8 for stage II disease and 6.1 for stage III disease) (Earle et al., 2010). One study of 5-year cancer survivors showed that lung cancer survivors had the greatest decline in employment rates of all cancer survivors (Torp et PREPUBLICATION COPY—Uncorrected Proofs

176 DIAGNOSING AND TREATING ADULT CANCERS al., 2013). Loss of employment after a lung cancer diagnosis can eliminate health insurance benefits, leading to the survivor missing follow-up care and recommended treatments. One study found that among patients with lung cancer, 40% had limited financial reserves (<2 months) and that there was a strong association between greater financial strain and poor physical and mental well-being (Lathan et al., 2016). Effects by Treatment Modality This section summarizes specific long-term and late-onset effects related to lung cancer and its treatment with surgery, chemotherapy, or radiation therapy or a combination of them. The long-term effects of immunotherapy are not known despite the fact that it has become a mainstay of lung cancer treatment (Vijayvergia et al., 2015). Surgery Lung cancer patients undergoing lobectomy show improved QOL scores (except for pain) within 3 months postoperatively, indicating good recovery. After pneumonectomy, physical functioning, pain, shoulder func- tion, and dyspnea have not returned to baseline even 12 months after surgery (Balduyck et al., 2007). After surgical resection of NSCLC, QOL indicators for physical functioning, pain, and dyspnea are significantly im- paired even at 24 months. QOL—as determined by physical function, social function, role function, global health, and pain—was better after lobectomy than after pneumonectomy (Bezjak et al., 2008; Schulte et al., 2009). QOL may improve sooner in lung cancer patients who undergo VATS procedures than in those who undergo open thoracotomy (Aoki et al., 2007). Evalua- tion of pain and musculoskeletal function after surgery, with referral to and treatment from appropriate rehabilitation specialists, can improve function. Chemotherapy The long-term toxicities of adjuvant cisplatin-based chemotherapy in- clude sensory neuropathy and hearing loss, which have been estimated to occur in approximately 48% and 21% of patients, respectively (Winton et al., 2005). These toxicities may persist for up to 30 months post-treatment (Bezjak et al., 2008) and can affect overall QOL during this time (Aziz, 2002). Adjuvant therapy increases the chance of survival but leads to a decline in overall QOL, although QOL tends to improve once the treatment is completed. For example, a retrospective study of NSCLC patients who underwent surgery found that that adjuvant therapy improved long-term QOL at a median follow-up of 4.8 years (Ilonen et al., 2013). Chapter 9 PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 177 provides additional information about chemotherapy-related toxicities and management. Radiation Therapy Scarring in the lung (lung fibrosis) can develop in an area that received radiation years after the treatment is complete. The treatment for radiation- induced lung fibrosis is often supportive, with supplemental oxygen and pulmonary medications. In lung cancer survivors who receive adjuvant radiation, advanced age and higher radiotherapy doses predict an increased risk of death from intercurrent diseases (i.e., a disease occurring at the same time as another unrelated disease) (Machtay et al., 2001). Additional long- term or late-onset toxicities of chemoradiation therapy include esopha- geal strictures, pulmonary toxicity, and cardiac toxicity. Recent studies on cardiotoxicity from chemoradiation for patients with stage III NSCLC suggest that major cardiac events are occurring within 1–2 years of treat- ment and that increased radiation doses to the heart are associated with a significantly increased risk of mortality (Atkins et al., 2019; Ming et al., 2016). More research on the cardiotoxicity of chemoradiation for stage III NSCLC is needed. Other acute effects of chemoradiation, such as radiation pneumonitis were discussed earlier in the chapter. These effects are further described in Chapter 9. SBRT can also damage normal body tissues, and the risk of damage depends on whether the tumor is located in the periphery of the lung (near the ribs or chest wall) or in the central portion of the lung (near the major airways, heart, or esophagus). SBRT to peripheral tumors can cause chest wall pain resulting from rib fractures or from inflammation of the chest wall muscles; the incidence of pain is about 8% (Coroller et al., 2014). This pain is managed conservatively with oral medications and generally resolves over time. SBRT for the treatment of central tumors is potentially life- threating and has the risk of long-term complications that can significantly impair physical functioning, including lung collapse and resulting pneumo- nias; damage to blood vessels; tracheo-esophageal fistulas; fatal radiation pneumonitis; and narrowing or perforation of the esophagus. Overall, the incidence of fatal adverse effects attributable to SBRT for central tumors has been reported to be 3.7% (Haseltine et al., 2016). In the case of SCLC, treatment may include radiation to the patient’s whole brain to prevent metastases from lung cancer. This treatment, pro- phylactic cranial irradiation, is associated with cognitive impairment; an oral medication, memantine, has been shown to modestly improve neu- rocognitive function in patients receiving whole-brain radiation therapy (Brown et al., 2013). Early studies show that avoiding the hippocampus when using whole brain radiation therapy plus memantine results in modest PREPUBLICATION COPY—Uncorrected Proofs

178 DIAGNOSING AND TREATING ADULT CANCERS improvements in neurocognitive function compared to standard whole brain radiation therapy plus memantine (Brown et al., 2020). Currently, there is an ongoing randomized clinical trial of hippocampal avoidance prophylactic cranial irradiation versus standard prophylactic cranial ir- radiation for patients with SCLC (The Netherlands Cancer Institute and Dutch Cancer Society, 2013). Cranial radiation may also affect the neuro- endocrine system in the brain, and if long-term survival is achieved, there is a risk of visual, hearing, or dental complications and new benign or malignant tumors (Chowdhary et al., 2012; Rahman et al., 2020). FINDINGS AND CONCLUSIONS Findings 1. Lung cancer is broadly classified into NSCLC and SCLC. NSCLC is more prevalent, but SCLC has a poorer prognosis. 2. Smoking and age are major risk factors for lung cancer. Other risk factors include exposure to radon gas, second-hand exposure to smoking, asbestos, radiation, air pollution, and some metals. 3. Lung cancer death rates have declined due to reductions in smok- ing and, particularly for NSCLC, from recent advances in genetics and biomarkers testing. 4. Standard diagnostic procedures for lung cancer include CT scans MRIs, PET scans, and endobronchial ultrasound. In certain cases, additional diagnostic profiling may be necessary using a FDG-PET scan, mediastinoscopy, percutaneous lung biopsy, immunohisto- chemistry, or gene profiling. 5. Most lung cancers are diagnosed at an advanced stage (stage IV NSCLC or extensive-stage SCLC), with metastatic spread to other organ systems in the body. 6. Treatment strategies are determined on the basis of tumor histol- ogy, tumor location/size, stage, molecular characteristics, as well as the patient’s general health and comorbidities. 7. Surgical resection (lobectomy) is the standard of care for patients diagnosed with NSCLC stage I and II who are medically fit for surgery. In certain cases of stage I or stage II NSCLC, the addition of neoadjuvant chemotherapy has survival benefits. The potential for long-term benefits with the addition of neoadjuvant immuno- therapy is still being investigated for this group of patients. 8. Stage III NSCLC is treated with multiple modalities depending on tumor characteristics (e.g., the possibility of surgical resection) and patient factors (e.g., other medical conditions). Possible treatments PREPUBLICATION COPY—Uncorrected Proofs

LUNG CANCER 179 include chemotherapy, radiation, immunotherapy, and targeted therapy. 9. Stage IV NSCLC requires systemic therapies, with local therapies (radiation, surgery) generally used to improve symptoms; however, when metastases are limited in number and organ (oligometa- static), local therapies may play a role in improving outcomes. 10. Treatment of SCLC includes the use of chemotherapy, radiation, and prophylactic cranial radiation. SCLC develops resistance to chemotherapy in the vast majority of patients, leading to recur- rence, which is usually fatal. 11. The diagnosis and treatment of lung cancer results in numerous acute as well as late-onset and long-term effects. The pulmonary and cardiovascular systems are most often affected. 12. Adverse effect profiles coincide with treatment regimens and their known adverse effects (e.g., cisplatin—neuropathy, ototoxicity). These adverse effects may have long-lasting impacts on the survi- vors’ physical, psychological, psychosocial, and behavioral well- being; reduce their quality of life; and affect their ability to work. 13. Common impairments reported by lung cancer survivors that can interfere with their quality of life include respiratory problems, fatigue, pain, and neuropathy. Pain is the most common cause of disability and often is associated with depression, anxiety, and sleep disturbances. 14. Psychosocial effects of lung cancer can result in decrements to psychological health (anxiety, depression, fear of recurrence), in- terpersonal relationships (connectedness), financial security (job insecurity, disability), and behavioral health (capacity for a healthy life style). These effects may have a significant impact on work abil- ity, return to work, and productivity. Conclusions 1. Reductions in smoking and improvements in screening, diagnosis, and treatment options have contributed to lower lung cancer death rates; however, survivors experience numerous adverse effects and impairments that can result in functional limitations. 2. As a result of recent advances in immunotherapy and targeted therapy, chemotherapy is no longer the most effective systemic treatment for many cases of lung cancer. 3. Changes in the treatment of NSCLC in recent years have produced improvements in survival. Some patients with metastatic NSCLC are now achieving 5-year survival; however, this longevity is still extremely rare for SCLC. PREPUBLICATION COPY—Uncorrected Proofs

180 DIAGNOSING AND TREATING ADULT CANCERS 4. Survivors of lung cancer may have cancer-related impairments as a consequence of their cancer and its treatment. The high risk of lung cancer recurrence, metastases, or the development of new primary cancers, and the major comorbid conditions often associated with smoking and aging, such as chronic obstructive pulmonary disease, can increase the number and severity of any impairments. REFERENCES ACS (American Cancer Society). 2019. What is lung cancer? https://www.cancer.org/cancer/ lung-cancer/about/what-is.html (accessed November 13, 2020). ACS. 2020. Targeted drug therapy for non-small cell lung cancer. https://www.cancer.org/ cancer/lung-cancer/treating-non-small-cell/targeted-therapies.html (accessed November 12, 2020). AJCC (American Joint Committee on Cancer). 2017. AJCC cancer staging manual, eighth edition. New York: Springer International Publishing. ALA (American Lung Association). 2020. State of lung cancer 2020: Lung cancer key find- ings. https://www.lung.org/research/state-of-lung-cancer/key-findings (accessed October 12, 2020). Albain, K.S., R.S. Swann, V.W. Rusch, A.T. Turrisi, 3rd, F.A. Shepherd, C. Smith, Y. Chen, R.B. Livingston, R.H. Feins, D.R. Gandara, W.A. Fry, G. Darling, D.H. Johnson, M.R. Green, R.C. Miller, J. Ley, W.T. Sause, and J.D. Cox. 2009. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: A phase III randomised controlled trial. The Lancet 374(9687):379–386. Ambrogi, M.C., O. Fanucchi, R. Cioni, P. Dini, A. De Liperi, C. Cappelli, F. Davini, C. Bar- tolozzi, and A. Mussi. 2011. Long-term results of radiofrequency ablation treatment of stage I non-small cell lung cancer: A prospective intention-to-treat study. Journal of Thoracic Oncology 6(12):2044–2051. Amin, M. B., F.L. Greene, S.B. Edge, C.C. Compton, J.E. Gershenwald, R.K. Brookland, L. Meyer, D.M. Gress, D.R. Byrd, and D.P. Winchester. 2017. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA: A Cancer Journal for Clinicians 67(2):93–99. Antonia, S.J., A. Villegas, D. Daniel, D. Vicente, S. Murakami, R. Hui, T. Yokoi, A. Chiap- pori, K.H. Lee, M. de Wit, B.C. Cho, M. Bourhaba, X. Quantin, T. Tokito, T. Mekhail, D. Planchard, Y.C. Kim, C.S. Karapetis, S. Hiret, G. Ostoros, K. Kubota, J.E. Gray, L. Paz-Ares, J. de Castro Carpeno, C. Wadsworth, G. Melillo, H. Jiang, Y. Huang, P.A. Dennis, M. Ozguroglu, for the PACIFIC Investigators. 2017. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. New England Journal of Medicine 377(20):1919–1929. Aoki, T., M. Tsuchida, T. Hashimoto, M. Saito, T. Koike, and J.-I. Hayashi. 2007. Quality of life after lung cancer surgery: Video-assisted thoracic surgery versus thoracotomy. Heart, Lung and Circulation 16(4):285–289. The ASCO Post staff. 2019. WCLC 2019: Keynote-024 survival update shows benefit with pembrolizumab vs chemotherapy in advanced NSCLS. https://ascopost.com/news/ september-2019/keynote-024-survival-update (accessed November 11, 2020). Atkins, K.M., B. Rawal, T.L. Chaunzwa, N. Lamba, D.S. Bitterman, C.L. Williams, D.E. Kozono, E.H. Baldini, A.B. Chen, P.L. Nguyen, A.V. D’Amico, A. Nohria, U. Hoffmann, H.J.W.L. Aerts, and R.H. Mak. 2019. Cardiac radiation dose, cardiac disease, and mortality in patients with lung cancer. Journal of the American College of Cardiology 73(23):2976–2987. PREPUBLICATION COPY—Uncorrected Proofs

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Diagnosing and Treating Adult Cancers and Associated Impairments Get This Book
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Cancer is the second leading cause of death among adults in the United States after heart disease. However, improvements in cancer treatment and earlier detection are leading to growing numbers of cancer survivors. As the number of cancer survivors grows, there is increased interest in how cancer and its treatments may affect a person's ability to work, whether the person has maintained employment throughout the treatment or is returning to work at a previous, current, or new place of employment. Cancer-related impairments and resulting functional limitations may or may not lead to disability as defined by the U.S. Social Security Administration (SSA), however, adults surviving cancer who are unable to work because of cancer-related impairments and functional limitations may apply for disability benefits from SSA.

At the request of SSA, Diagnosing and Treating Adult Cancers and Associated Impairments provides background information on breast cancer, lung cancer, and selected other cancers to assist SSA in its review of the listing of impairments for disability assessments. This report addresses several specific topics, including determining the latest standards of care as well as new technologies for understanding disease processes, treatment modalities, and the effect of cancer on a person's health and functioning, in order to inform SSA's evaluation of disability claims for adults with cancer.

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