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 cancer, see Chapter 3.

Recent advances in lung cancer care (i.e., prevention, screening, diagnosis, 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 remain high. The impairments and subsequent functional limitations experienced 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 smoking and aging. To help manage these impairments and functional limitations as well as the adverse effects from both the cancer and its treatment, palliative 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

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 the standard of care for lung cancer (see Figure 4-1).

This chapter describes the screening, diagnosis, treatment, and survivorship 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 section 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 certain 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 screening 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 history 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

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 guideline 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 smoking 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 individuals 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 management. Current approaches to the diagnosis of lung cancer include not only conventional histology (the microscopic examination of body tissues), but also immunohistochemistry¹ 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 symptoms, which may suggest an advanced stage (bone pain, headache, 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

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¹ Immunohistochemistry is a laboratory method that uses antibodies to check for certain antigens (biomarkers) in a sample of tissue.

resonance imaging (MRI) scan is recommended in stage II and higher, is optional for patients with stage IB disease, and is not recommended for patients with stage IA disease (NCCN, 2020b). These procedures are used to detect the possible presence of sub-clinical or asymptomatic distant metastases. Patients with lung cancer stages II–III may undergo bronchoscopy, endobronchial ultrasound, or percutaneous lung needle biopsy to radiologically 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 with intravenous contrast of the chest and abdomen along with brain imaging using an MRI scan. When an MRI scan is contraindicated, a contrast enhanced CT scan of the brain is acceptable. If cancer appears localized with a CT scan, a fluorodeoxyglucose 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 immunohistochemistry (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 immunologic techniques for more complete pathological profiling of 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.”

Lung Cancer Stages

As discussed in Chapter 4, the American Joint Committee on Cancer’s (AJCC’s) AJCC Cancer Staging Manual, Eighth Edition (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 metastases (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 involvement 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

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.

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 extrathoracic 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 mediastinum 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 collarbone) 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 distant 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).

TABLE 6-2 5-Year Survival Rates Since Diagnosis (diagnosed between 2010 and 2016)

SOURCE: Howlader et al., 2020.

SCLC typically grows quickly, is highly metastatic, and is usually rapidly fatal. In 2012 the U.S. Congress classified SCLC as a recalcitrant cancer—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.²

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 overview 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 recommendations 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 diagnosed with lung cancer.

Lung cancer treatments are generally categorized as local/regional therapies (surgery, radiation therapy, ablation) or systemic therapies (chemotherapy, 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, particularly 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

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² Recalcitrant Cancer Act of 2012, HR 733, 112th Congress.

effective systemic treatment for either NSCLC or SCLC (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 eligible 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 treatment 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 alternatives to surgery.

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 involvement of mediastinal lymph nodes (N2 or N3) are, by definition, upstaged to stage III.

acute effect and skin irritation (radiation dermatitis) is typically not seen or is quite mild. Some patients may experience cough from transient inflammation 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 Lung Cancer Diagnosis.

in survival of 4% (from 60% to 64%) at 5 years; a similar improvement was seen when adjuvant chemotherapy was given after surgery and postoperative 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 chemotherapy (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, 2019). 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 recurrence (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. (2019) found that among patients with cT2-4N0-1M0 NSCLC, there is no significant difference 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 management 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 supraclavicular 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

behaviors of the cancer. Presently this includes combinations of local/regional 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.

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 chemoradiation. 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 pemetrexed. 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.

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 reducing 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 after 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 supplemental 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 approaches, 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 immunologic features of the cancer has become the most important element for treatment of late-stage NSCLC.

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 approximately 13% of such patients (Eberhard et al., 2005). EGFR is more common 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 drivers 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, comparing 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 fewer 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 inhibitors continue to be evaluated.

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 standard-of-care immunotherapy (Gandhi et al., 2018). Survival data 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 (Gadgeel et al., 2020).

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, provide 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 commonly 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).

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 chemotherapy 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 LS-SCLC is 15–20 months and 8–13 months for those diagnosed with 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 past four decades, consists of a standard first-line chemotherapy regimen with concurrent 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 metastases at the initial diagnosis (Goncalves et al., 2016). Importantly, many of these patients have no neurologic symptoms indicative of brain metastases (Hochstenbag et al., 2000). The rate of brain metastases increases significantly among patients who survive for more than 1 year after treatment (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

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 manage 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 60–90 days after first-line chemotherapy ends) or sensitive (i.e., occurs 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 chemotherapy 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 prophylactic cranial radiation. These impairments are discussed in the section on Life After Lung Cancer Diagnosis.

SUMMARY OF LUNG CANCER DIAGNOSTIC EVALUATION AND TREATMENT

Table 6-3 summarizes the information presented in the preceding sections 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 various comorbid medical conditions, including COPD and emphysema as well

TABLE 6-3 Summary of Lung Cancer Diagnosis and Treatment

NOTES: The symbol ± in the treatment column means “with or without.” The exact treatment 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 diagnosis 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 primary 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 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 become 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 physical, psychological, and psychosocial impairments that may adversely affect a lung cancer survivor’s overall QOL and 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 coughing (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 surgery (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 survivors followed at a survivorship clinic (Huang et al., 2014). Many NSCLC survivors who undergo surgery may experience post-thoracotomy pain—a pain syndrome involving burning, dysesthesia, and aching along the

thoracotomy incision—that can persist for a prolonged period (>2 months) after surgery (Rogers and Duffy, 2000). Thirty percent of patients report continued 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 experienced dyspnea, 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 psychological, 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 employment 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 emotional 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 associated with non-adherence to cancer surveillance screening recommendations (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 (Carmack et al., 2011; Coups et al., 2009).

Lung cancer significantly increases the risk of departure from the workforce 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 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 function, and dyspnea had 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 impaired 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). Evaluation 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 include 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 adjuvant therapy improved long-term QOL at a median follow-up of 4.8 years (Ilonen et al., 2013). Chapter 9

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 esophageal 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 treatment 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-threatening and has the risk of long-term complications that can significantly impair physical functioning, including lung collapse and resulting pneumonias; 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 prophylactic cranial irradiation is associated with cognitive impairment; an oral medication, memantine, has been shown to modestly improve neurocognitive 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 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 irradiation 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 smoking 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, immunohistochemistry, 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 histology, 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 immunotherapy 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

8. 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 (oligometastatic), 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 recurrence, 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 survivors’ 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), interpersonal 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 ability, 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.

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.

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