An Overview of the Epidemiology, Types of Lung Cancer, Staging, and Rehabilitation Continuum of Care

Epidemiology

Lung cancer incidence and prevalence trends have evolved due to changes in screening and primary prevention, while early detection and improved treatments increase survivorship. Data from 2012 report that providers are annually diagnosing approximately 1.8 million new cases of lung cancer with 1.6 million related deaths. In developed countries, the age standardized risk (ASR) of incidence and mortality was 1.4–1.5-fold higher and 1.5–1.8 fold higher, respectively, than in less developed countries. ASR is used for comparing rates between populations in diseases for which age contributes significantly to risk.

Within the United States, most cases of lung cancer are attributable to exposures like tobacco smoke, asbestos, and radon. Although incidence declined in the United States from 2007 to 2016, there are still approximately 150,000 annual lung cancer deaths. The rate of incidence decline varies based on age, sex, and geographic status. For individuals 55 years and older, rates were highest in men from nonmetropolitan counties. In individuals 35–54 years old, there were no sex differences in incidence, but the same nonmetropolitan geographic predominance persisted. This difference appears to be growing as rates decline in both men and women from metropolitan areas faster than nonmetropolitan areas.

Racial/Ethnic Differences

When not adjusting for smoking status, African American and Native Hawaiian men had the highest incidence of lung cancer of 252.1 per 100,000 individuals. For women, incidence was similar among African Americans, Native Hawaiians, and whites, with 146.8, 167.4, and 135.1 individuals per 100,000, respectively. For all lung cancer types, Japanese American and Latino individuals had significantly lower risk than African Americans, with relative risks ranging from 0.36 (95% CI = 0.33 to 0.45) for Latino women to 0.59 (95% CI = 0.52 to 0.65) for Japanese-American men. Native Hawaiians had a much higher rate of developing small cell lung cancer (SCLC) than any other group, and African Americans had the highest incidence of nonsmall cell lung cancer (NSCLC).

Smoking dramatically increases excess relative risk (ERR) relative to nonsmokers in a dose-dependent relationship when stratified by 25 pack-years versus 50 pack-years. ERR for all types of lung cancer in the 25 pack-years subgroup increases to 21.9 (Native Hawaiian), 19.1 (African American), 11.9 (White), 10.1 (Japanese American), and 8 (Latino) with the highest proportion being SCLC and squamous cell carcinomas (SCCs). In the 50 pack-years group, ERR for all lung cancer subtypes increased to 35.3 (Native Hawaiian), 31.7 (AA), 24.0 (White), 21.4 (Japanese American), and 20.0 (Latino). Similarly, the greatest increases in risk were for developing SCLC and squamous cell.

Screening

Researchers have attempted to identify the best method and frequency of lung cancer screening. The National Lung Screening Trial (NLST) aimed to determine if low-dose helical computed tomography (LDCT) could screen for lung cancer and reduce mortality. Patients with substantial (30+ pack-years) and recent/current smoking histories were included; former smokers must have quit within the previous 15 years. Study participants underwent three screenings using either radiography or LDCT (T0, T1, and T2) at 1-year intervals, with the first screening (T0) soon after the time of randomization. All-cause mortality in the LDCT group was reduced by 6.7% (95% CI, 1.2 to 13.6; P = .02) relative to the radiography group; however, 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positives.

After a median of 6.5 years of follow-up, the LDCT participants sustained a significant reduction in lung cancer mortality, replicating and demonstrating the durability of the initial NLST findings. Therefore, the 3.3% absolute risk reduction (ARR) did not suggest a length time bias of distant cases caught earlier but instead suggested screening with LDCT likely prevented additional deaths.

Subtypes of Lung Cancer

“Lung cancer” comprises malignancies in the trachea, bronchus, and lung. Certain subtypes have greater associations with smoking than others, and evolving trends in subtype incidence may be the result of changes in tobacco consumption amount or delivery. Classification designations have changed over time, as previously, lung cancer was mainly divided into two major histologic groups based on World Health Organization (WHO) guidelines. Cancers were designated either SCLC or NSCLC, which includes SCC, large cell carcinoma, and adenocarcinoma.

In 2015, the WHO modified these classifications. Improvement in genetic testing of tumor cells provided a strong foundation for reclassification of SCC, adenocarcinoma, and large cell carcinoma, and targeted medicines make these classifications more clinically relevant. New concepts in adenocarcinoma classification including lepidic versus invasive pattern designations impact the approach to tumor size measurement for Tumor, Node, Metastasis (TNM) staging of small tumors ≤3 cm, which determines the surgical management of patients. Now, pathology includes histologic pattern descriptions such as lepidic, acinar, papillary, micropapillary, and solid.

With SCC, descriptions include morphologic details such as unequivocal keratinization and well-formed classical bridges. For both adenocarcinoma and SCC, when pathologists cannot clearly differentiate by simple microscopy, at least one immunohistochemical stain is used to classify the tumor and, for adenocarcinoma, rule out the potential for it being a metastasis from different site. Tumors that do not resemble squamous cell or adenocarcinoma under microscopy or staining are designated non-small cell carcinoma (NSCC) since metastasis cannot be ruled out. If the tumor expresses pneumocyte markers, the designation is “NSCC favor adenocarcinoma,” and should be specified as “NSCC favor squamous cell carcinoma” when expressing SCC markers. Additionally, other IHC stains such as hormonal staining could add specificity beyond NSCC not otherwise specified (NOS).

Beyond the IHC descriptions, adenocarcinoma is designated in situ versus minimally invasive if:

The updated recommendations discontinued the use of the “small cell” subtype of SCC due to the confusion with SCLC. “Clear cell” is now recognized as a cytologic feature that may occur in other subtypes. The remaining recognized subtypes include keratinizing, nonkeratinizing, and basaloid.

In neuroendocrine tumors, many unique features of carcinoid (nonlarge cell neuroendocrine) tumors differentiate them from higher-grade small cell carcinoma and large cell neuroendocrine carcinomas. These typically carry better prognoses, are less associated with smoking, occur in younger populations, and, unlike SCLC and LCNEC, have fewer genetic abnormalities. The most important criterion for differentiating carcinoid subtypes from high-grade SCLC or LCNEC is the mitotic rate, and the presence of necrosis is important to consider as SCLC/LCNEC has higher mitotic rates with greater necrosis.

Neurologic Syndromes

The variety of paraneoplastic neurologic syndromes (PNSs) is too extensive to cover thoroughly considering that fewer than 1% of patients with cancer will develop any of the potential manifestations, although rates are higher in SCLC at approximately 3%–5%. Typically, PNSs are progressive and debilitating within weeks to months. The higher incidence in SCLC is due to tumors' expression of various antigens and patients' development of targeted antibodies. For example, approximately 20% of patients with SCLC have detectable levels of circulating antibodies targeting the Hu protein, which is also a normal component of neurons. Some cases suggest a favorable prognosis with anti-Hu antibody-related PNS, as the targeted immune response has even resulted in spontaneous regression of the tumor. Often, treating the underlying malignancy improves symptoms of PNS. Immunosuppressives may also temporarily improve symptoms, but without lasting effect.

These unique paraneoplastic syndromes and local structural impacts are relevant to rehabilitation specialists as they may result in impairments that therapies should target or restrictions around which therapies must be designed. Moreover, understanding the etiology of progressive weakness, worsening pain, or a new-onset movement disorder may provide an accurate diagnosis when imaging may be negative. This would allow for targeted workup instead of wasting resources and delaying rehabilitation.

Encephalomyelitis is a classical PNS which includes subacute cerebellar degeneration (SCD), myelitis, brainstem encephalitis, and limbic encephalitis. ^, Cases of SCD have been documented in SCC and SCLC, and the same antibodies associated with Lambert–Eaton Myasthenic Syndrome (antibodies to voltage gated calcium channels) are present in a significant percentage of SCD cases. Lambert–Eaton Myasthenic Syndrome, almost always associated with SCLC and rarely with NSCLC, ^, is a neuromuscular junction disorder in which antibodies impair calcium release in the presynaptic neuron with hallmark proximal muscle weakness that improves with activity and autonomic changes such as dry mouth or constipation. ^,

Opsoclonus-myoclonus, like LEMS, is predominantly associated with SCLC but has been reported in patients with NSCLC. This disorder is characterized by rapid, randomly directed conjugate eye movements (opsoclonus) with myoclonus occurring in muscles of the head/neck, trunk, and limbs. Subacute sensory neuropathy is often characterized by subacute/asymmetric numbness and/or a stocking-glove distribution of pain , , . Chronic gastrointestinal pseudoobstruction is autonomic dysfunction with symptoms of nausea/vomiting, gastroparesis, and constipation without mechanical obstruction often seen in SCLC but has been documented in NSCLC. ^,

In cases of polymyositis and dermatomyositis associated with lung cancer, SCLC (29%) and SCC (21%) were the most common types ; both are myopathic disorders, and dermatomyositis also features distinct cutaneous findings. Some patients that have recovered from cancer and dermatomyositis may have reactivation of the dermatomyositis without cancer recurrence. “Stiff-man syndrome” (SMS) (with many variants) is characterized by skeletal muscle stiffness and spasms seen in patients with SCLC. SMS is associated with antiglutamic acid decarboxylase antibodies in cerebrospinal fluid or serum, symptoms of continuous muscle activity in trunk, and proximal limb muscles, and heightened reflexes. Patients with lung cancer (often SCLC ) may develop movement disorders such as classic symmetric choreoathetosis involving the muscles of the neck, trunk, and limbs, although some patients may have unilateral presentation of chorea, dystonia, or orobuccal dyskinesia.

Additional PNSs include the following:

• Acute necrotizing myopathy

• Syndromes of the peripheral nervous system

• Syndromes of the neuromuscular junction and muscle (including myasthenia gravis)

• Guillain–Barre syndrome

• Acute pandysautonomia

• Acquired neuromyotonia

• Acute sensorimotor neuropathy

• Brachial neuritis

• Subacute/chronic sensorimotor neuropathies

• Neuropathy and paraproteinaemia

• Neuropathy with vasculitis

• Autonomic neuropathies

• Optic neuritis

• Cancer-associated retinopathy

• Melanoma-associated retinopathy

• Necrotizing myelopathy

• Motor neuron diseases

Rheumatologic Conditions

Hypertrophic pulmonary osteoarthropathy (HPO) is a constellation of symptoms including symmetric polyarthritis, periostitis of long tubular bones, and clubbing of fingers that is associated with pulmonary disorders—not exclusively lung cancer ). At least 70% of HPO cases are associated with lung cancer, typically NSCLC ; alternatively, cases of HPO are rare in lung cancer. The hallmark symptom of HPO is periostitis, often the tibia or fibula, but may include any tubular bone. Possibly related to the noninflammatory etiology, NSAIDs have only modest effect on pain. Like other paraneoplastic syndromes, one of the most effective treatments for HPO is to treat the underlying malignancy, ^, and other treatments include bisphosphonates, octreotide, ^, and gefitinib.

Determining Prognosis

Although the oncologist will likely be primary in providing prognostic information to the patient, rehabilitation practitioners benefit in being able to determine general prognosis to aid in goal setting and discharge planning. The first consideration of establishing prognosis is designating the patient's malignancy SCLC or NSCLC.

In NSCLC, prognostic information is predominantly based off initial staging using the TNM classification. TNM staging categorizes tumors based on primary tumor characteristics (T), regional lymph node involvement (N), and metastases (M). Presently, molecular features of lung cancer tumors are not included in the TNM system. The ultimate stage (I through IV) is determined by the combination of T, N, and M descriptors. Metastatic sites such as skin, liver, and four or more sites carry particularly worse prognostic weight. Previous racial associations between worse outcomes with NSCLC and African descent have been discounted after rigorous multivariate analysis demonstrated the association was the result of socioeconomic and performance status. Important survival factors include performance status (baseline functional status), which is the greatest nonstaging factor, ^, smoking status, and anorexia/weight loss. Presently, studies attempting to add prognostic value from specific types of NSCLC have shown inconsistent results.

With SCLC, initial prognostication had traditionally used a two-stage system between designations of limited versus extensive disease (ED). “Limited” disease is restricted to the ipsilateral hemithorax/regional lymph nodes and can be encompassed in a safe radiotherapy field. This is significant, because SCLC is highly responsive to radiation due to its rapid growth. However, the designation now differentiates timing of treatment modalities as treatment for extensive stage SCLC also includes radiotherapy. Recent data have shown benefits of using the full TNM staging system to qualify SCLC stage, and overall, prognostic factors for SCLC and NSCLC are similar : extent of disease, ECOG performance status, and presence of weight loss. Other considerations include presence of anemia, leukocytosis, and elevations in serum erythrocyte sedimentation rate, lactate dehydrogenase (LDH), and neuron-specific enolase (NSE). Data suggest prognostic value of these in univariate analysis in both limited and ED although the difference in median survival within subgroups was less substantial for these factors in ED.

Importance of Prehabilitation in Patients With Lung Cancer

Comprehensive cancer rehabilitation begins with prehabilitation. Surgeons are integrating prehabilitation into preoperative planning, given that this represents an investment in functional and physiological capacity with hopes of improving their tolerance to stressful interventions that benefit recovery. In one study of cardiothoracic surgeons, an overwhelming majority of respondents were willing to delay surgical resection beyond the current average 20-day waiting period to allow patients to participate in prehabilitation.

The Enhanced Recovery after Surgery (ERAS) gradually refers to patient-centered, evidence-based, multidisciplinary pathways to reduce patients' stress response to surgery, facilitate recovery, and optimize physiologic function. This team updates recommendations on best practices for different surgical procedures. In a recent update for lung surgical procedures, ERAS and the European Society of Thoracic Surgeons (ESTS) included key recommendations of prehabilitation for high-risk patients as well as other components of a multimodal program such as nutritional screening and smoking cessation.