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Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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3

Cancer

Cancer is the term used to refer to a group of diseases in which some of the body’s cells divide without stopping and spread into surrounding tissue, forming growths called tumors (NCI, 2015a). Cancerous tumors are malignant, meaning that they can both invade nearby tissues and form new tumors far from the original tumor (NCI, 2015a). Cancer can start almost anywhere in the body, and it is broadly classified by the type of tissue that the growths originate from (e.g., carcinoma begins in the epithelial tissue, and leukemia is from the white blood cells in bone marrow) and the location in the body where the cancer first develops (e.g., breast cancer or colon cancer) (NIH, 2019). In this way, a patient with breast cancer can be more specifically said to have a breast carcinoma.

Cancer-related functional impairment can be caused by the cancer itself (e.g., a direct invasion of the lungs causing compromised breathing, or of the bone marrow causing anemia) or caused by cancer treatments such as surgery, radiation therapy (RT), and systemic therapy (e.g., fatigue or lymphedema). Cancer treatment–related functional impairments can be those that develop during treatment but are transient (e.g., post-surgical pain), long-term side effects that develop during treatment but are chronic (e.g., neuropathic pain from chemotherapy), late effects that develop after the completion of treatment (e.g., radiation fibrosis syndrome), or secondary effects that result from acute and long-term side effects. Comorbidities frequently occur with cancer (as noted in Chapter 2). Impairments related to cancer have their own trajectories, diagnostic methodologies, treatments, and outcomes. Given the importance of cancer-related impairments to

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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disability, the committee will address the items in the Statement of Task for common cancer-related impairments in addition to the cancers themselves.

This chapter responds to the items in the Statement of Task related to cancers and disabling conditions related to cancers. The Statement of Task asks the committee to identify specific, long-lasting (12-month duration or longer) medical conditions in adults that are temporarily disabling and that improve with treatment after a period of time to a point that the condition is no longer disabling. Based on those criteria, the committee chose cancers with the potential to cause cancer- or treatment-related morbidity but that have also seen promising advances in their treatment and in the management of the impairments they cause. The committee selected the following cancers, acknowledging that others might also fit the criteria: breast cancer (excluding ductal carcinoma in situ [DCIS]), melanoma, renal cancer, head and neck cancers, advanced epithelial ovary cancer, non-small-cell lung cancer (NSCLC), and diffuse large B-cell lymphoma. The committee excluded cancers less likely to be disabling, including two of the examples given in the Statement of Task—non-melanoma skin cancer and thyroid cancer. The committee also excluded cancers less likely to improve with treatment, such as most advanced-stage cancers. In addition, the committee has selected the following disabling cancer-related impairments as those that might improve or be managed with treatment: pain, cancer-related fatigue (CRF), cardiotoxicity, chemotherapy induced peripheral neuropathy, lymphedema, pulmonary dysfunction, and cognitive dysfunction (CD).

The chapter first presents general U.S. cancer statistics and discusses diagnostic criteria, treatments, treatment settings, and other items delineated in the committee’s Statement of Task that are common among all of the selected cancers, including a framework for considering the length of time from treatment to functional improvement that accounts for the fact that cancer does not fit neatly into the concept of a disease whose symptoms typically improve with safe treatment. Then, for each cancer and cancer-related impairment chosen the committee reviews the specific professionally accepted diagnostic criteria, treatments, the length of time of treatment, and standard measures of outcomes for those conditions. Each cancer-specific discussion includes a table of diagnostic criteria, treatments, outcomes, and monitoring by cancer stage. Information on advanced-stage cancers are included in the tables for reference and comparison, though it should be noted that advanced-stage cancers are unlikely to improve with treatment. Finally, the chapter discusses new and developing cancer treatments that might improve survivorship or functional status, discusses variation in treatment response, and reviews papers related to cancer and return to work. The committee acknowledges the importance of access to treatment in the improvement of cancer status, functional improvement, and return to work. However, as noted in Chapter 1, information on issues related to

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
×

access to treatment are not addressed in this report at the request of the study sponsor.

EPIDEMIOLOGY OF CANCER IN THE UNITED STATES

Mortality and survival are the most commonly reported cancer outcomes. They are tracked by federal and state statistical agencies to assess whether preventive efforts and treatments are improving for specific cancers (NCI, 2019a). Data are collected from medical records and death certificates. This section reviews statistics for cancers in the U.S. population, which will help the reader understand the comparative burden and epidemiologic trends of the various cancers in the United States.

Incidence

In 2019, 1,762,450 new cancer cases were projected to occur in the United States (Siegel et al., 2019). Overall, cancer incidence is higher among men than women, except in the 30–55 age range (see Figure 3-1). Between 2010 and 2020 the number of new cancer cases in the United States is expected to increase by about 24 percent in men and 21 percent in women to more than 1 million cases per year in men, and 900,000 cases per year in women (CDC, 2018).

Figure 3-2 depicts the most common sites of new cancer estimated for 2019 by sex according to the American Cancer Society (ACS). In 2019 an estimated 268,600 women were diagnosed with breast cancer, making it the most common cancer diagnosis. Lung and bronchus cancers were the second most common cancer diagnoses, with an estimated 116,440 new cases among men and 111,710 new cases among women. Prostate cancer was the leading cancer diagnosis among men and the third most common diagnosis overall, with 174,650 expected cases (see Figure 3-2). The 12 most common cancer sites estimated for 2019 account for more than three-quarters of all new cancer cases (ACS, 2019).

The incidence rates of lung cancer have seen a steady decline among both men and women across all age groups since 1985, in part reflecting the effectiveness of public health and regulatory tobacco control programs and policies (Farrelly, 2008; Siegel et al., 2019). Meanwhile, the rates of new liver cancers are rising faster than for any other cancer. People infected with hepatitis C virus are at greater risk for liver cancer. From 2013 through 2016 nearly 2.4 million Americans, or 1 percent of adults, were living with hepatitis C, and the incidence of hepatitis C infection has been increasing since 2010 (Hofmeister et al., 2019). Other risk factors for liver cancer include obesity, alcohol consumption, and smoking (ACS, 2019a; Calle and Kaaks, 2004). Data published by Sung and colleagues (2019) also suggest

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Image
FIGURE 3-1 Average annual cancer incidence rates and case distribution by age, United States, 2011–2015.
SOURCE: ACS (2019a) analysis of 18 SEER registries (2000–2015). Reproduced with permission.
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Image
FIGURE 3-2 Ten leading sites of new cancer cases—2019 estimates.
SOURCE: Siegel et al., 2019. Reproduced with permission.

that the risk of obesity-related cancers seems to be increasing in a stepwise manner in successively younger birth cohorts in the United States. The rates of new cases rose for melanoma skin cancer, thyroid cancer, endometrial cancer, and pancreatic cancer (ACS, 2019a).

While incidence rates remain markedly higher among older adults, several troubling trends in increasing incidence are occurring among younger, working-age adults. Increasing colorectal cancer incidence is of particular concern among young adults. Siegel and colleagues (2017) examined Surveillance, Epidemiology, and End Results (SEER) data and found that among adults ages 20–39, colon cancer incidence rates have increased by 1.0–2.4 percent annually since the mid-1980s, and rectal cancer incidence rates have increased even more drastically by 3.2 percent annually from 1974 to 2013 in adults ages 20–29. In contrast, for adults age 55 and older, incidence rates have generally declined since the mid-1980s for colon cancer and since 1974 for rectal cancer. Although the incidence rates have declined, the risks of colon and rectal cancers remain greater than previous decades. Compared with adults born in 1950, those born in 1990 have double the risk of colon cancer and quadruple the risk of rectal cancer (Siegel et al., 2017).

Survivorship

During the 1970s about one in every two people diagnosed with cancer survived at least 5 years. Now, more than two out of every three survive that long (ACS, 2014). As a result, the number of cancer survivors is steadily increasing—from 14 million in 2014 to almost 18 million expected by 2022 (Fuentes et al., 2017). Much of the increase can be traced to earlier detection and improvements in cancer therapies for many cancers (ACS, 2014; Fuentes et al., 2017).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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The Social Security Administration (SSA) asked the committee to examine cancers that are “long-lasting,” meaning 12 months in duration or longer. One might assume that the “duration” could be measured using survival statistics. However, survival statistics are usually expressed as 5-year survival rates (Mayo Clinic, 2018a) and are often not indicative of survival for patients diagnosed in more recent time periods. This is because computations are often based on patients who were diagnosed many years ago, as they require many years of data that are not typically available of recent patients.

Additionally, survival statistics are usually presented without consideration of the stage or treatment of the cancer. Survival rates can be expressed in terms of overall survival or relative survival. Overall survival rates include all people who have been diagnosed with the cancer and do not distinguish those diagnosed with early-stage, localized tumors from those diagnosed with late-stage, metastatic cancer. In many cases they aggregate different cell types diagnosed in the same organ system, which may have different prognoses. Overall survival rates do not specify whether cancer survivors are still undergoing treatment at 5 years or if they have achieved remission, meaning they have become cancer free. The following cancers have overall 5-year survival rates of 80 percent or higher: uterine, Hodgkin lymphoma, breast, melanoma, testis, thyroid, and prostate (NCI, 2019a). Survival depends on many factors, including the aggressiveness of the disease, the stage at diagnosis, available treatments, and the age and health of the patient. Additionally, black patients have lower survival rates than white patients for every cancer type except for kidney and pancreatic cancers. Disparities are greatest for melanoma (absolute difference of 26 percent) and uterine cancer (absolute difference of 21 percent), in part due to later stage diagnoses in black patients (Siegel et al., 2019).

Relative survival refers to the proportion of people who are alive for a designated time (usually 5 years) after a cancer diagnosis divided by the proportion of people of similar age, race, and other recorded characteristics that are expected to be alive in the absence of cancer, based on normal life expectancy. As with overall survival rates, relative survival rates do not distinguish among patients who no longer have evidence of cancer and those who have relapsed or are still in treatment; nor does it represent the proportion of people who are cured, because cancer death can occur beyond 5 years after diagnosis (ACS, 2019b). Although relative survival rates provide some indication about the average experience of cancer patients, they should be interpreted with caution for several reasons. First, 5-year survival rates do not reflect the most recent advances in detection and treatment because they are based on patients who were diagnosed at least 5 years in the past. Second, they do not account for many factors that influence individual survival, such as access to treatment, comorbid conditions, and

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
×

biologic or behavioral differences among patients. Third, improvements in survival rates over time do not always indicate progress against cancer. For example, increases in average survival rates may occur when screening results in the detection of cancers that may never have caused harm if left undetected (ACS, 2019b).

Table 3-1 shows 5-year relative survival rates by stage at diagnosis, illustrating that while survival is high for most cancers that are confined to the organ of origin, it is low for malignant cancers with distant metastases. For example, breast cancer, melanoma, and prostate cancer all have 5-year relative survival rates of nearly 100 percent for local tumors, but the survival rates for distant metastases are between 20 percent and 30 percent (see Table 3-1). Many cancers are often not diagnosed until they have spread to other organs, and some cancers spread more quickly than others, so survival is affected both by the stage at diagnosis and also by the natural progression of the cell type. For example, only one-third of people diagnosed with local pancreatic cancer survive for 5 years, compared with 90 percent of people diagnosed with local colon cancer.

Table 3-2 presents trends in 5-year survival by cancer site and year of diagnosis from 1981 through 2015. The table shows small increases in survival rates for selected cancers.

TABLE 3-1 5-Year Relative Survival Rates (%) by Stage at Diagnosis, United States, 2008–2014

All Stages Local Regional Distant
Breast (female) 90 99 85 27
Colon 64 90 71 14
Colon and rectum 65 90 71 14
Esophagus 19 45 24 5
Kidney 75 93 69 12
Larynx 61 78 46 34
Liver 18 31 11 2
Lung and bronchus 19 56 30 5
Melanoma of the skin 92 98 64 23
Oral cavity and pharynx 65 84 65 39
Ovary 47 92 75 29
Pancreas 9 34 12 3
Prostate 98 >99 >99 30
Rectum 67 89 70 15
Stomach 31 68 31 5
Testis 95 99 96 74
Thyroid 98 >99 98 56
Urinary bladder 77 69 35 5
Uterine cervix 66 92 56 17
Uterine corpus 81 95 69 16

SOURCE: NCI, 2019a.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-2 Trends in Cancer 5-Year Survival Rates (Percent by Year of Diagnosis)

All Cancers Breast Thyroid Melanoma Non-Small-Cell Lung and Bronchus (Invasive) Ovarian (Invasive) Leukemia Hodgkin Lymphoma Myeloma Oral Cavity and Pharynx Renal
1981–1983 50.2 76.1 93.6 82.8 17.1 38.9 37.3 74.3 27.5 51.7 50
1984–1986 52.4 79 93.2 86.6 16.6 38.4 40.5 78.4 27.3 54.1 54.5
1987–1989 55.3 84 94.4 88.1 16.9 38.2 42.9 79.2 27.2 53.6 56.7
1990–1992 59.9 85.2 94.3 89.3 17.7 40.6 45.2 81.8 29.3 55.4 60.2
1993–1995 61.3 86.4 95.4 89.7 18.7 41.6 47.6 81.7 31.7 57.7 61.5
1996–1998 63.3 88.2 95.6 91 19.4 43.9 48.4 85.1 32.5 57.8 62.5
1999–2001 66 89.7 96.5 92.2 20 43.9 51 85.1 34.6 60.3 64.9
2002–2004 67.1 90 97.3 93.2 19.6 43.8 58.3 86.2 42.6 63.9 69.2
2005–2008 68.7 90.8 98 93.3 21.8 45.3 62.3 89 47.5 65.5 74.5
2009–2015 69.3 91.3 98.5 94.2 25.1 48.4 65.8 88.5 53.7 68.4 75.5

SOURCE: NCI, 2019a.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Mortality

Cancer is the second leading cause of death in the United States (Siegel et al., 2019). Cancer death rates (mortality rates) are a good measure of progress against the disease because they represent a final outcome, whereas survival rates are only finite time periods and do not signify whether the patient will survive for any period beyond what is measured (e.g., 5 years). The overall age-adjusted cancer death rate rose during most of the 20th century, peaking in 1991 at 215 cancer deaths per 100,000 people, mainly because of the tobacco epidemic. Data from U.S. death certificates show that from 1999 to 2017 cancer death rates for adults ages 45–64 declined by 19 percent (Curtin, 2019). Additionally, from 2007 to 2016, the cancer death rate declined annually by 1.4 percent in women and 1.8 percent in men (Siegel et al., 2019). Declines in cancer mortality over the past two decades are primarily the result of steady reductions in smoking and advances in early detection and treatment, which are reflected in the rapid declines for the four major cancers—lung, breast, prostate, and colorectal (ACS, 2018). Specifically, the death rate for lung cancer dropped by 45 percent from 1990 to 2015 among males and by 19 percent from 2002 to 2015 among females; the death rate for breast cancer dropped by 39 percent from 1989 to 2015; for prostate cancer, the death rate dropped by 52 percent from 1993 to 2015; and for colorectal cancer the death rate dropped by 52 percent from 1970 to 2015 (ACS, 2018). Death rates rose from 2012 through 2016 for cancers of the liver, pancreas, and uterine corpus as well as for cancers of the brain and nervous system, soft tissue, and sites within the oral cavity and pharynx associated with the human papillomavirus (Siegel et al., 2019).

The Charlson Comorbidity Index, NCI Comorbidity Index, and Elixhauser scores use physician-reported data on comorbid conditions to predict mortality risk in cancer patients based on a combined comorbidity score (Austin et al., 2015; NCI, 2019b). These summary comorbidity measures are considered to be valid prognostic tools in cancer research (Austin et al., 2016; Elixhauser et al., 1998; Frenkel et al., 2014).

Median Age of Onset for Selected Cancers

Table 3-3 presents the median age at diagnosis by gender for the selected cancers from 2011 to 2015. The age of onset for most of the cancers that the committee chose to discuss is 62 years or older.

Gender Distribution for Selected Cancers

Figure 3-3 shows gender distribution for the selected cancers based on U.S. prevalence on January 1, 2016. Renal cancer, cancers of the oral cavity

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-3 Median Age of Cancer Patients at Diagnosis, 2011–2015

Site Total Males Females
Breast 62 68 62
Kidney and renal pelvis 64 64 65
Lung and bronchus 70 70 71
Melanoma of the skin 64 66 60
Non-Hodgkin lymphoma 67 66 68
Oral cavity and pharynx 63 62 65
Other non-epithelial skin 71 72 70
Ovary 63 63
Thyroid 51 55 50

SOURCE: NCI, 2019a.

Image
FIGURE 3-3 Gender distribution (%) of selected cancers, based on U.S. prevalence on January 1, 2016.
SOURCE: NCI, 2019a.
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
×

and pharynx, myeloma, Hodgkin lymphoma, leukemia, and melanoma are more common among men, while non-small-cell lung and bronchus cancers and thyroid cancer are more common among women. Women make up nearly all of the population living with breast cancer, although about 0.5 percent of those living with breast cancer were men.

Cancer Statistics as Measures of Outcomes Improvement

The committee was asked to identify standard measures of outcomes improvement for medical conditions, with mortality given as an example. The committee notes that although the population statistics reviewed in this section, including mortality, are the most commonly reported cancer outcomes, they do not reflect individual cancer patients’ functional impairments such as pain or CD. To address those important outcome measures, patients are assessed primarily through the use of patient-rated scales (e.g., the Patient-Reported Outcomes Measurement Information System [PROMIS] scale), with results recorded on medical records and used to assess changes in patient function. Various stages of remission for cancer, and symptoms and impairments associated with cancer treatments such as lymphedema, discussed later in the chapter, are also recorded on medical records and are considered professionally accepted standard measures of outcomes improvement for cancer.

CROSS-CUTTING ISSUES FOR SELECTED CANCERS

Many of the selected cancers share the same diagnostic criteria, treatments, treatment settings, and other items delineated in the committee’s Statement of Task. In an effort to avoid redundancy, those items that are common to the selected cancers are described in this section. This section covers the following topics broadly as they relate across all of the selected cancers: diagnostic criteria, medical professionals involved in cancer care, cancer treatments, treatment settings, a framework for understanding length of time from treatment to functional improvement, standard measures of outcomes for the selected cancers, and pain. Whether and how these characteristics differ for each of the selected cancers and any additional specifics relevant to the Statement of Task are described in the sections that follow devoted to each of the selected cancers.

Professionally Accepted Diagnostic Criteria for Selected Cancers

Tissue biopsy with an accurate pathology review is the standard for diagnosing cancer. A complete evaluation also requires other elements, including a thorough history and physical examination, laboratory tests

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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(including tests for tumor markers), and imaging, to determine the stage and characteristics of the cancer and to guide treatment (NCI, 2019b). Testing is also used to monitor progression and to gauge the effectiveness of the treatment. In some cases, it is necessary to repeat testing when a person’s condition has changed. Following initial cancer diagnosis, it is important to monitor for improvement, treatment response, and recurrence (Graham et al., 2014).

Diagnostic criteria specific to each of the selected cancers are discussed in the cancer-specific sections and summarized in Tables 3-5 through 3-13. The tables, summarized from the National Comprehensive Cancer Network (NCCN)1 guidelines, are meant to guide readers in identifying diagnostic tests that are particular to each cancer and are not meant to serve as clinical guidance. Tissue biopsy is common to all cancers as the standard diagnostic criteria, and it is not repeated in the tables.

Biopsy

During a biopsy, a sample of cells is collected for testing. In most cases, a biopsy is the only way to definitively diagnose cancer (Mayo Clinic, 2019). Methods by which a sample may be collected include

  1. Needle biopsy of tissue or cytologic exam of body fluid. This method is used for bone marrow aspirations, lumbar puncture (spinal tap), and organ biopsies (breast, lung, liver, prostate).
  2. Endoscopy, in which an endoscope is inserted into natural body openings, such as the mouth or anus, to visualize internal areas of the body. If abnormal tissue is observed, it will be removed along with some of the surrounding normal tissue through the endoscope. Examples include colonoscopy (for colon and rectum), bronchoscopy (for trachea, bronchii, and lungs), and upper endoscopy (esophagus and stomach).
  3. Surgery during which an area of abnormal cells is removed during an operation either as excisional (removing the entire area of abnormal cells) or incisional (just part of the abnormal area is removed). Tissue samples are subsequently analyzed in the pathology laboratory for analysis (NCI, 2015b).

If the biopsy and other tests indicate the presence of cancer, additional tests may be ordered to help in making decisions about the treatment plan.

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1 The National Comprehensive Cancer Network is the organization that develops the NCCN Clinical Practice Guidelines in Oncology to help health care professionals diagnose, treat, and manage cancer patient care.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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The tumor may also be tested further for other tumor or genetic markers. Staging studies are then required once a tissue diagnosis of cancer has been confirmed (Mayo Clinic, 2019).

History and Physical Examination

During the physical examination, the physician may palpate areas of the body for lumps that may indicate a tumor. In addition, he or she may look for abnormalities, such as changes in skin color or an enlargement of an organ, which may indicate the presence of cancer (NCI, 2019b).

Laboratory Tests

High or low levels of specific substances in the body may be a sign of cancer. Laboratory assays of blood, urine, other body fluids, or tissues that are used to evaluate these substances can help diagnose cancer. However, abnormal lab results are not a sure sign of cancer. Blood chemistry tests may examine metabolites, electrolytes, fats, proteins, and enzymes and usually include tests for blood urea nitrogen and creatinine (NCI, 2013). Most laboratory tests used in cancer diagnosis and assessment include a complete blood count, which measures the amount of various types of blood cells in the body and indicates whether abnormal cells are found (Mayo Clinic, 2019).

Testing for cancer gene mutations (in somatic cells) may also be used to detect the presence or absence of specific inherited mutations in genes known to play a role in cancer development. Examples include the epidermal growth factor receptor (EGFR) receptor mutation or the anaplastic lymphoma kinase (ALK) mutation, which may be a target for treatment. Genetic testing (in germline) is often used to assess cancer risk, such as testing for the breast cancer type 1 (BRCA1) and breast cancer type 2 (BRCA2) gene mutations, which play a role in breast, ovary, and other cancers (NCI, 2013). Cytogenetic analysis measures changes in the number or structure of chromosomes in a patient’s white blood cells or bone marrow cells and may be used for diagnosis and help in treatment decisions. Immunophenotyping, used to identify cells based on the types of antigens present on the cell surface, is also used for the diagnosis, staging, and monitoring of cancers of the blood system and other hematologic disorders, such as leukemias and lymphomas. It is most often done on blood or bone marrow samples, but it may also be done on other bodily fluids or biopsy tissue samples. Sputum cytology is used to look for the presence of lung cancer. Tumor marker tests are used to identify a broad range of specific proteins or genes in tissue, blood, or other bodily fluids that may be signs of cancer or certain benign

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
×

conditions. In addition to aiding diagnosis, the results of these tests may be used to guide treatment (NCI, 2013).

Imaging

Imaging tests allow the examination of bones and internal organs in a non-invasive way. Imaging tests used in diagnosing cancer may include a computerized tomography (CT) scan with or without contrasting material, a bone scan, magnetic resonance imaging (MRI) with or without a contrasting agent, a positron emission tomography (PET) scan, ultrasound, and X-rays, among others (Bashir et al., 2015). Bone scans, which are a type of nuclear scan that check for abnormal areas or damage in the bones, may be used to diagnose bone cancer or cancer that has spread to the bones (also called metastatic bone tumors). There are several types of PET scans. An FDG-PET (glucose) scan, also a type of nuclear scan, is able to produce detailed three-dimensional images of areas where glucose is taken up, which can be valuable because cancer cells often take up more glucose than healthy cells. An ultrasound exam, or sonogram, uses high-energy sound waves, while X-ray scans use low doses of radiation to create images of structures within the body (Bashir et al., 2015).

Medical Professionals Involved in the Care of Selected Cancers

A cancer diagnosis is usually traumatic and introduces the patient to a confusing system of physician generalists and specialists, diagnostic tests, and treatments, which are not always seamlessly coordinated. Cancer patients may see, over the course of their treatment, surgeons, medical oncologists, radiation oncologists, interventional radiologists, internal medical subspecialties such as endocrinology and dermatology, advanced practice providers such as nurse practitioners and physician assistants, nurses, social workers, clinical trials coordinators, patient navigators, and genetics counselors. During and after treatment the patients may see registered dietitians; physical, speech, and occupational therapists; and rehabilitation physicians (Fennell et al., 2010; IOM, 2013; Ko and Chaudhry, 2002; Litton et al., 2010). Their primary care doctors may treat non-cancer-related conditions that may affect their treatment or health. High-quality cancer care depends on the effective management of a great number of factors. Optimum outcomes require careful coordination between multiple treatments and treatment providers, the exchange of technical information, and regular communication between all of the providers and physician disciplines involved in the treatment (IOM, 2013).

The composition of cancer care teams varies with the type and stage of cancer (Taplin et al., 2015), and members of the cancer care teams involved

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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with specific cancer tumor sites are listed in the below sections devoted to the particular cancers. Multimodal care is the current standard and requires the collaboration of multiple disciplines (Bayat Mokhtari et al., 2017). Care can be classified as being directed toward the cancer, toward the medical complications, or toward symptoms and impairments. Cancer-directed care is delivered to patients with disease deemed appropriate for cancer therapy. The goal of treatment is cure, temporization (i.e., delaying the progression of the disease), or palliation (i.e., easing the symptoms without curing the disease). A majority of patients with curable disease receive care delivered by surgical, radiation, and medical oncology teams. Other team members include interventional radiologists and various surgical subspecialties, depending on the tumor location. A similar array of clinicians may deliver temporizing and palliative treatments (IOM, 2013). However, because cancer is often metastatic at the point when temporizing and palliative treatments are used, systemic treatments administered by medical oncologists are the mainstay. Radiation and surgical oncologists may palliate late-stage disease, but this is highly variable, depending on the location of metastatic spread and the severity of the symptoms and impairments caused by metastatic foci (Lutz et al., 2014).

Medical complication–directed care is frequently delivered by oncologic specialists when complications are temporally associated with treatment. However, as this linkage becomes less obvious, the care teams that manage complications become more disparate. Depending on the nature of the complications, various medical specialties, including cardiology, endocrinology, pulmonology, and gastroenterology, may assume primary management responsibilities (NASEM, 2013).

Symptom/impairment–directed care is principally delivered by supportive care disciplines (Stark and Lewis, 2013). The participation of oncologic specialties in managing symptoms and impairments has been robustly shown to be sporadic, with under-treatment being common. Supportive care disciplines include palliative care, physical medicine and rehabilitation, psychiatry/psychology, and pain medicine (Kumar et al., 2012). Depending on the phase of the disease and the goals of care, supportive care teams may also include physical, occupational, or speech therapists; social workers; and vocational counselors (Kumar et al., 2012).

Cancer Treatments for Selected Cancers

There are many types of treatments used in cancer therapy. Systemic therapies involve the use of drugs that spread throughout the body and include chemotherapy, hormonal therapy, targeted drug therapy, and immunotherapy. Other treatments such as radiation and surgical treatments target a particular site. The type of treatment an individual undergoes depends

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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on the results of diagnostic testing and the site and stage of the cancer as well as individual factors and, to some degree, patient preference. Although some people with cancer undergo only one treatment, most cancers are treated with a combination (Bayat Mokhtari et al., 2017; NCI, 2019b).

Table 3-4 shows the cancers that the committee chose and their common curative treatments. Treatments that are specific to each cancer site are discussed in the cancer-specific sections and summarized in Tables 3-5 through 3-11. It should be noted that the NCCN encourages patients to choose to undergo clinical trial therapy rather than the standard of care outlined in their guidelines when the clinical trial therapy is available and appropriate for the patient (NCCN, 2019a,b,c,d,e,f,g). Additionally, Tables 3-5 through 3-11 summarize the NCCN guidelines current as of this publication; readers should understand that, given the rapidly developing field of cancer treatments, the guidelines change frequently. Toxic effects of cancer therapy cause much of the disability that occurs in patients with cancer. Those effects will be discussed in the section on common cancer impairments.

Chemotherapy

Chemotherapy is a drug treatment that uses chemicals to kill fast-growing cells. Many different chemotherapy drugs are available, and they

TABLE 3-4 Selected Cancers and Commonly Used Treatments

Cancers
Therapy Invasive Breast Cutaneous Melanoma Renal Head and Neck Advanced Epithelial Ovary Non-Small-Cell Lung Diffuse Large B-Cell Lymphoma
Chemotherapy
Hormone therapy
Immune
modulators
Radiation therapy
Surgery
Targeted therapy

SOURCES: NCCN, 2019a,b,c,d,e,f,g.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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are used alone or in combination to treat a wide variety of cancers. One example of how chemotherapy is used in combination with other treatments is a process called neoadjuvant chemotherapy, or chemotherapy that is used prior to surgery or RT to reduce tumor size (NCI, 2015c). In a variation called adjuvant therapy, chemotherapy is used to destroy cancer cells that might remain after treatment with surgery or RT (NCI, 2015c). Although chemotherapy can effectively eliminate cancer cells, it also harms normal tissues, resulting in treatment toxicities. While some chemotherapy toxicities are mild and treatable, others cause serious disablement (Mayo Clinic, 2017). Chemotherapy is used in the treatment of all of the selected cancers with the exception of renal cancers.

Hormone Therapy

Hormone therapy, also called endocrine therapy, is a cancer treatment that slows or stops the growth of cancers that use hormones to grow, such as breast, thyroid, and ovarian cancers. Hormone therapy is most often used in combination with other cancer treatments. As with chemotherapy, hormone therapy can be used as a neoadjuvant or adjuvant therapy (NCI, 2015d). Hormone therapy falls into two broad groups: those that block the ability to produce hormones and those that interfere with how hormones behave. Because of these mechanisms of action, toxicities from hormone therapy include those related to the inability to produce the hormones that are being treated (NCI, 2015d).

Immune Modulators

Immune modulators treat advanced cancer by enhancing the body’s immune response against cancer. Immune-modulating agents include cytokines and immunomodulatory drugs. Cytokines are proteins made by white blood cells, and they include interferons and interleukins, which activate natural killer cells and killer T cells. Other cytokines are erythropoietin, IL-11, GM-CSF, and G-CSF, which promote the growth of red and white blood cells damaged by chemotherapy. Immunomodulatory drugs stimulate the immune system by causing cells to release cytokines (NCI, 2019d). A review of the immune modulator drugs concludes that based on preliminary studies of CTLA-4, PD-1, and programmed death-ligand 1 (PD-L1)-blocking antibodies, immune modulation is a viable treatment across malignancy types (Naidoo et al., 2014). A relatively new type of therapy, immune modulator drugs have now become a standard of care and are used in the treatment of a subset of all of the selected cancers (NCCN, 2020).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Targeted Therapy

Much of the current cancer drug development focuses on targeted agent therapies (NCI, 2018). Unlike chemotherapies, which act on all rapidly dividing normal and cancerous cells, targeted agent therapies block the growth of cancer by interfering with specific molecules that are involved in the growth, progression, and spread of cancer. Targeted therapies generally act by blocking tumor cell proliferation, rather than killing tumor cells, which is the case with standard chemotherapies (NCI, 2018). Targeted therapies have become standard practice for treating patients with NSCLC (Sgambato et al., 2018; Shea et al., 2016; Stinchcomb, 2016). Phase III trials showed that targeted therapies have greater efficacy than chemotherapy in treating NSCLC patients with an activating EGFR mutation and in patients with ALK rearrangements (Stinchcomb, 2016). Targeted therapies are now used in the treatment of all of the selected cancers (NCCN, 2019a,b,c,d,e,f,g).

Radiation Therapy

RT is a type of cancer therapy that uses X-rays and other types of high-energy particles or waves to destroy or damage cancer cells. Radiation works by damaging the DNA in cancer cells, keeping them from growing and dividing. Unlike chemotherapy, RT is a local treatment, carried out with the goal of destroying as few normal cells as possible. Nearby normal cells that are affected generally recover (ACS, 2018). RT can be used alone or in combination with other therapies. It can be used as neoadjuvant therapy or adjuvant therapy in early-stage cancers, and it can be used to treat symptoms in advanced cancers. It can be administered externally using a machine that directs high-energy rays from outside the body into the tumor, internally by inserting a radioactive source into the body in a process called brachytherapy, and systemically using oral or intravenous drugs (ACS, 2018). More than half of people with cancer undergo RT (ACS, 2018). RT is used in the treatment of all of the selected cancers (NCCN, 2019a,b,c,d,e,f,g).

Surgery

Surgery is often used to treat solid tumors that are locally contained. The surgical treatment of cancer involves the removal of cancer from a patient’s body through an open or minimally invasive procedure; the specific details of the procedure depend on the purpose of the surgery, the site and amount of tissue that needs removal, and, in some cases, the patient’s preference (NCI, 2015b). Surgery is used in the treatment of all of the

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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selected cancers except for diffuse large B-cell lymphoma, a liquid cancer (NCCN, 2019a,b,c,d,e,f,g).

Cancer Treatment Settings

Cancer care is most often provided in outpatient settings (NASEM, 2019). The initial patient encounter with a cancer care system often occurs in an office or clinic, where cancer-related procedures such as history and physical examinations, blood samples, and endoscopies take place. Cancer therapies are typically delivered in specialized facilities in hospital outpatient units and community-based medical offices or clinics (Gospodarowicz et al., 2015). Cancer patients in the last phases of an incurable disease might live out the remainder of their lives in hospice care. Cancer treatment settings specific to each cancer site are noted in the sections devoted to the selected cancers.

Length of Time from Treatment to Functional Improvement

The length of time from start of cancer treatment until a person’s functioning improves to the point that the condition is no longer disabling involves two timeframes: (1) the time to remission of the cancer, and (2) the time to recovery from toxicities, symptoms, and functional impairments.

In each of the sections devoted to the selected cancers, the committee provides suggested timeframes for reviewing whether the cancer has achieved remission. These timeframes indicate the average time it takes to complete therapy for the selected cancers and are not an estimate of the time to remission of cancer, which the committee was not able to determine. The committee calculated the timeframes based on the 2019 NCCN guideline indications of time to recovery from surgery (typically 6 weeks), radiation (typically 7 weeks), chemotherapy cycles, and other therapies that are generally prescribed in the treatment of the selected cancers.

Cancer treatments will cause functional decline, which is expected and anticipated. If the cancer is cured, then the functional status can be treated for and might improve. The committee notes that it is the cancer patient’s disease status (i.e., whether the cancer is in complete, partial, or no remission) more than the cancer site and stage that is an appropriate indicator of whether the patient’s functional status might improve. It is clearly the case that fewer functional impairments exist for early-stage malignancies, but disease status is a global indicator of functional status improvement across all stages. If a patient’s cancer achieves complete remission, functional status improvement is probable, and it is reasonable to evaluate the patient’s functional status 12 months after complete remission; if the cancer achieves stable partial remission, then functional status improvement is possible, and

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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it is also reasonable to evaluate the patient’s functional status 12 months after achieving stable partial remission; if the patient has no response to treatment or experiences progression of disease, then functional improvement is unlikely.

The data on the time interval to review impairments for progression and relapse depend on the average survival time and on the treatments available for each impairment. The committee reviewed the literature on the time from treatment to functional improvement for each of the selected cancer-related impairments. The data that the committee found, if any, are noted in each of the sections devoted to the selected impairments. The times given assume that the cancer is in complete remission, with the expectation that functional declines will improve over time. As will be described in subsequent sections, there are many instances where treatment-related functional declines are permanent or progressive.

Standard Measures of Outcomes for the Selected Cancers

Outcomes to monitor for patients with cancer include the various lengths of remission and progression, depending on the cancer site and stage. The ideal outcome of cancer treatment is complete remission, meaning that the treatment has resulted in the disappearance of all measurable signs of cancer. Partial remission means the cancerous tumors are reduced by at least 50 percent. When cancers grow, spread, and worsen, it is called cancer progression. If the cancer has not changed, it is called a stable disease (ACS, 2019c). It is important to understand that these outcomes are episodic, meaning a person can be in remission for 1 month or more, and then the cancer recurs. There is no way to predict how long a remission will last, and remission does not equate to cure. Some cancers, such as ovarian cancer, follow a natural cycle of recurrence and remission and can be managed as chronic diseases (ACS, 2019c). Even while a patient’s cancer is in complete remission, he or she might experience a number of functional impairments, which are discussed in the next section.

Pain

Disabling pain is common across all types and stages of cancer. Pain prevalence rates reported in a recent review and meta-analysis were 39.3 percent after curative treatment; 55.0 percent during anticancer treatment; and 66.4 percent in metastatic disease (Van den Beuken-van Everdingen et al., 2016). Across all stages, 38.0 percent of patients in this study reported experiencing moderate to severe pain (operationalized as a numerical rating scale score ≥5 out of 10). The diversity of cancer types, treatments, and potential pain generators renders a comprehensive characterization of

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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cancer pain unfeasible. This section, therefore, focuses on common pain syndromes, principally among disease-free cancer survivors, as these individuals are most likely to improve with treatment.

A majority of the large-scale epidemiologic efforts that have used patient-reported outcomes to characterize pain among survivors have not distinguished the locations or sources of the pain; furthermore, few of the reports have compared cancer survivors to the general population. As a consequence, the literature is limited in ascribing pain to cancer alone. While pain is clearly common among cancer survivors, with nearly 50 percent of patients in some cohorts reporting pain (Gartner et al., 2009; Green et al., 2011; Jiang et al., 2019), it is difficult to demonstrate whether the pain is a direct result of cancer because co-existent pain generators are common and tend to reinforce each other. The aggregate effects of these various sources of pain ultimately determine whether a cancer survivor becomes disabled. Few high-quality data from long-term follow-up are available to inform expectations of the persistence and treatment responsiveness of specific cancer pain syndromes. Additionally, limited research has been devoted to accurately distinguishing the etiologic contributors to different pain syndromes that might inform their treatment.

All cancer treatments, including surgery, radiation, and systemic therapies, have the potential to produce chronic pain among disease-free survivors. Because multimodal cancer treatment is the current standard, it is not uncommon for survivors to have multiple different treatment-associated pain generators. Combined nociceptive and neuropathic pain is common (Leysen et al., 2019), and recently a group of clinicians proposed a set of guidelines for classifying the pain experienced by cancer survivors as predominant neuropathic, nociceptive, or central sensitization pain (Nijs et al., 2016). Awareness of a survivor’s prior treatment exposures as well as the time course, distribution, and quality of the pain can help to clarify the probable duration, likelihood of spontaneous resolution, and treatment responsiveness.

Treatment-related pain tends to conform to specific patterns. Post-surgical pain, for example, is generally localized and restricted to the treated area. However, nerves are often sacrificed or injured during surgical procedures for cancer, which leads to pain that may be referred far from the operative site. Common syndromes include post-thoracotomy and post-mastectomy pain (Hetmann et al., 2017; Tait et al., 2018; Wang et al., 2018). The latter is a misnomer, since any surgical manipulation used to treat breast cancer—biopsy, lumpectomy, or axillary dissection—has the potential to cause lasting pain, although the more extensive and aggressive surgeries have a higher likelihood. Post-mastectomy pain is also representative in that other components of multimodal treatment plans (e.g., radiation and chemotherapy) have the potential to exacerbate the localized pain that

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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is initially triggered by surgery. Psycho-emotional distress is associated with pain severity and persistence (Katz et al., 2005; Schreiber et al., 2014). This “multi-hit” phenomenon may contribute to pain after amputation or limb salvage surgeries as well as to chronic abdominal pain, particularly in the presence of recurrent cancer (Mercadante et al., 2014).

Pain syndromes engendered by systemic therapies are fewer and less diverse, although they are no less harmful. Multiple chemotherapy subtypes cause persistent neuropathy, which may produce burning pain or dysesthesias. Taxane chemotherapy may be complicated by arthralgias or myalgias that persist after acute treatment in as many as 50 percent of survivors (Chiu et al., 2018). Aromatase inhibitors may also produce severe multifocal arthralgias (Beckwee et al., 2017). This syndrome may improve modestly with pharmacologic treatment (Henry et al., 2018). The functional impact of both taxane and aromatase inhibitor-induced arthralgias can be devastating because movement and activity may aggravate the pain. However, the long-term functional impacts of both syndromes have been only poorly characterized (Chiu et al., 2017). The potential for targeted biological treatments, such as the immune checkpoint inhibitors (ICIs), to produce persistent pain is a topic of active scrutiny and discovery. Reports indicate that the ICIs have the potential to cause arthralgias (Cappelli et al., 2017) and to engender new rheumatoid arthritis and polymyalgia rheumatic (Belkhir et al., 2017). The ICIs may also cause neuropathies, though these have yet to be robustly characterized with respect to incidence, associated pain, and chronicity (Hottinger, 2016).

The long-term severity and persistence of cancer-related pain among disease-free survivors remains under-researched. A landmark population-based study on Danish women reported a 47 percent prevalence of pain among disease-free breast cancer survivors 2–3 years following the completion of therapy (Gartner et al., 2009). A higher prevalence—60 percent—was found in a 3-year study of a more limited cohort of breast cancer survivors (Rietman et al., 2004). Additionally, some evidence suggests that the proportion of breast cancer survivors who report severe pain may increase over time. For example, in the long-term follow-up of 1,183 survivors, 27.8 percent reported severe pain at 40 months, which increased to 32.3 percent at 10 years (Forsythe et al., 2013). Similar estimates from non–breast cancer cohorts are generally lacking, but the few reports that have been published suggest that pain remains similarly an issue. For example, among a cohort of 175 head and neck cancer survivors at a median of 6.6 years after diagnosis, 45.1 percent reported pain, and 11.5 percent reported severe pain (Cramer et al., 2018).

Cancer pain is most prevalent among patients with metastatic disease. Bone metastases are the most common pain generator (Falk et al., 2014; Milgrom et al., 2017). Among patients with advanced cancer, it is estimated

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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that 60 percent to 84 percent experience bone pain (Mercadante, 1997). Patients with metastatic disease are subject to the aforementioned treatment-related pain syndromes, which are frequently more cumulative and severe in later stages. Additional pain syndromes common to this population include liver capsule distension, brain-tumor-related headache, neural compression, and extrinsic visceral compression, which may affect the gastrointestinal tract or ureter (Cherny et al., 2015). While most pain syndromes in late-stage disease can be ameliorated, many patients experience residual pain and remain prone to the development of new pain generators. Therefore, although the pain is inadequately characterized, it is reasonable to assume that few patients with advanced-stage cancer and disabling pain will improve sufficiently to resume gainful employment.

BREAST CANCER

It is estimated that in 2019 there will be 268,600 new cases of invasive breast cancer diagnosed in women and 2,670 new cases diagnosed in men (ACS, 2019a). The female breast cancer death rate peaked at 33 per 100,000 in 1989, then declined by 40 percent—to 20 per 100,000—in 2016. This progress reflects improvements in both early detection (through screening as well as increased awareness of symptoms) and treatment and translates to an estimated 348,800 fewer breast cancer deaths than would have been expected if the death rate had remained at its peak. From 2007 to 2016 the breast cancer death rate declined by 1.8 percent per year (ACS, 2019a). The 5- and 10-year relative survival rates for women with invasive breast cancer are 90 percent and 83 percent, respectively. Sixty-two percent of cases are diagnosed at a localized stage (no spread to lymph nodes, nearby structures, or other locations outside the breast), for which the 5-year survival is 99 percent.

Most breast cancers (80 percent) are invasive, meaning that the cancer has spread beyond the tissue of origin and into surrounding healthy tissue (ACS, 2017). DCIS, a non-invasive presence of abnormal cells inside a milk duct in the breast, is considered a precursor to invasive cancer and is also associated with an increased risk for developing a new invasive breast cancer (Mayo Clinic, 2018a). This section focuses on invasive breast cancer. Table 3-5 describes the diagnostics, therapy, outcome, and monitoring for invasive breast cancer, excluding DCIS.

Professionally Accepted Diagnostic Criteria for Breast Cancer

Breast cancer is typically detected during either a screening mammographic or an MRI examination, either before symptoms have developed or after a woman has noticed a lump. When cancer is suspected, a

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-5 Diagnostics, Treatments, Outcomes, and Monitoring for Breast Cancer (Excludes DCIS)

Early Stage Locally Advanced Advanced Stage
Diagnostics*
  • Diagnostic bilateral mammogram/ultrasound, breast MRI
  • Tumor biopsy with ER/PR/HER2 tissue testing
  • Axillary ultrasound/imaging plus percutaneous biopsy if suspicious node
  • Genetic counseling and testing as indicated, tumor multigene assay (if ER/PR positive and HER2 negative)
  • CT, FDG PET/CT, MRI, bone scan as clinically indicated
Same as early stage
  • Chest CT, abdominal/pelvic CT or MRI, bone scan, FDG PET/CT
  • Biopsy with ER/PR/HER2 tissue testing, tumor PIK3CA mutation testing if ER/PR positive and HER2 negative; germline BRCA 1/2 testing if HER2 negative; PDL-1 biomarker testing for triple negative (HR and HER2 negative), genetic counseling
  • Brain/spine MRI, symptomatic and long and weight bearing bone X-rays if clinically indicated
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Treatment
  • Lumpectomy/surgical axillary staging/RT
  • Total mastectomy/surgical axillary staging/reconstruction ± RT
  • Adjuvant endocrine therapy (premenopausal ovarian suppression/ablation), chemotherapy, HER2 targeted agents
  • Option of neoadjuvant chemotherapy (pre-surgery)
  • Neoadjuvant chemotherapy, HER2 targeted therapy
  • Total mastectomy/surgical axillary staging/reconstruction + RT
  • Lumpectomy/surgical axillary staging/RT
  • Adjuvant hormonal therapy, HER2 directed therapy, occasional oral chemotherapy (capecitabine)
  • Hormonal therapy (plus premenopausal ovarian suppression/ablation), targeted agents (HER2, CDK, PICK3A, m-TOR, PARP), chemotherapy, immunotherapy, palliative RT
  • Orthopedic bone stabilization, skeletal directed agents if bone metastases
Disease outcomes of treatment
  • Complete remission
  • Recurrence
Same as early stage
  • Complete remission (rare)
  • Partial remission
  • Stable disease
  • Progressive disease
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Early Stage Locally Advanced Advanced Stage
Post-treatment monitoring
  • History and physical, 1–4 times annually through 5 years and then annually
  • Annual mammogram
  • Monitor for lymphedema
  • Monitor for family history change for new genetic counseling
  • Other imaging and labs as clinically indicated
Same as early stage Chemotherapy Hormonal Therapy
History and physical Every cycle Every 1–3 months
Every cycle Every 1–3 months
CT CAP Every 2–4 cycles Every 2–6 months
Bone scan Every 4 cycles Every 4–6 months
PET/CT Optional Optional

NOTES: *In addition to history and physical examination, and laboratory exams. CAP = chest abdomen pelvis; CDK = cyclin-dependent kinase; CT = computed tomography; ER/PR/HER2 = tumor markers; FDG = fluorodeoxyglucose (a positron-emitting substance injected for diagnostic purposes in conjunction with PET); MRI = magnetic resonance imaging; m-TOR = mechanistic target of rapamycin; PARP = poly (ADP-ribose) polymerase;

PET = positron emission tomography; PIK3CA = a protein coding gene; RT = radiation therapy. Routine lab studies/all CT and MRI imaging is with contrast unless otherwise designated. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019a.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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microscopic analysis of breast tissue is necessary for a diagnosis and to determine the stage and characterize the type of the disease. The tissue for microscopic analysis can be obtained from a needle biopsy (fine-needle or wider-core needle) or surgical excision. The diagnostic procedure for breast cancer differs according to multiple factors, including cancer stage, the size and location of the mass, and patient factors, preferences, and resources (ACS, 2017).

Hormone receptor tests should be ordered to provide insight into which treatment options would be most effective for the patient. Hormone receptor testing typically uses a specialized staining process on the breast tissue sample to see whether hormone receptors are present (NBCF, 2016). Although breast cancer generally has been referred to as a single disease, there are at least four different molecular subtypes which differ from one another in terms of risk factors, presentation, response to treatment, and outcomes (ACS, 2017). Gene expression profiling techniques have allowed for a better understanding of the molecular subtypes of breast cancers. Approximations of molecular subtypes have been identified using routinely evaluated biological markers, including the presence or absence of hormone (estrogen or progesterone) receptors (HR+/HR−) and excess levels of human epidermal growth factor receptor 2 (HER2, a growth-promoting protein) or extra copies of the HER2 gene (HER2+/HER2−) (ACS, 2017). Treatment is determined by testing of these biological markers.

Breast ultrasound is often used to evaluate abnormal findings from a mammogram or physical exam. For inflammatory and advanced breast cancers where the tumors might have metastasized to other parts of the body, other diagnostic tests should be performed, such as whole-body CT, PET, MRI, and bone scans. Another type of test called FDG (fluorodeoxyglucose) PET/CT may be used, where FDG, composed of fluoride and glucose, acts as a radiotracer to find cancer in lymph nodes, organs, and bones. This can be done simultaneously with the diagnostic CT (NCCN, 2019a). Genetic testing gives people the chance to learn whether their breast cancer or family history of breast cancer is due to an inherited gene mutation. FDG PET/CT is most helpful in situations where standard staging studies are equivocal or suspicious, especially in the setting of locally advanced (cancer that has spread from its origin to nearby tissue) or metastatic cancer. FDG PET/CT may also help identify unsuspected regional nodal disease or distant metastases in locally advanced breast cancer when used in addition to standard staging studies (NCCN, 2019a).

Treatments for Breast Cancer

The medical professionals involved in the care of individuals with breast cancer include surgeons, radiation oncologists, medical oncologists,

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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genetic counselors, rehabilitation physicians, physical therapists, occupational therapists, speech language pathologists, and exercise physiologists, in addition to the specialists noted in the “Medical Professionals Involved in the Care of Selected Cancers” section (NCCN, 2019a). The treatment settings include radiology facilities, surgery suites, radiation facilities, and outpatient infusion centers (NCCN, 2019a).

As with diagnosis, treatment for breast cancer differs according to the stage of the cancer and other factors such as the biological markers noted in the diagnostic criteria section. In general, the treatment involves either breast-conserving surgery (i.e., surgical removal of the tumor and surrounding tissue) or a mastectomy (i.e., surgical removal of the breast), depending on tumor characteristics (e.g., size and extent of spread) and patient preference (ACS, 2019b). Radiation to the breast is recommended for most patients having breast-conserving surgery. For women with early-stage breast cancer (without spread to the skin, chest wall, or distant organs), studies indicate that breast-conserving surgery plus RT results in long-term outcomes that are equivalent to a mastectomy. Although many patients undergoing total mastectomy do not need radiation, it is sometimes recommended when the tumor is large or the lymph nodes are involved. One or more underarm lymph nodes are usually evaluated during surgery to determine whether the tumor has spread beyond the breast. Women undergoing mastectomy who elect breast reconstruction typically have several options, including the type of tissue or implant used to restore breast shape. The reconstruction may be performed at the time of mastectomy (also called immediate reconstruction) or as a second procedure (delayed reconstruction), but it often requires more than one surgery (ACS, 2019b).

The treatment may also involve chemotherapy before (neoadjuvant therapy) or after (adjuvant) the surgery, hormone (anti-estrogen) therapy, or targeted therapy, or some combination of those, depending on the cancer stage, subtype, and anticipated benefits of each treatment component. Women with early-stage breast cancer that tests positive for hormone receptors benefit from treatment with hormone therapy for 5 or more years (ACS, 2019b). Tumor genomic analysis may predict the benefits of hormonal therapy alone or of adding chemotherapy or early-stage adjuvant therapy (Vieira and Schmitt, 2018).

Chemotherapy and other treatments that target cancer treat the invasive disease and improve survival, but they do not necessarily improve functioning. In fact, the treatment itself could reduce functioning.

Length of Treatment Time for Breast Cancer

A treatment using non-hormonal therapy for early or locally advanced disease that achieves complete remission is generally complete in 12 to 18

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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months, although hormonal therapy may be carried out for an additional period of time, which can be as much as 10 years (NCCN, 2019a).

Standard Measures of Outcomes for Breast Cancer

For early-stage as well as locally advanced breast cancers, the ideal outcome of cancer therapy is complete remission. For advanced-stage diseases, complete remission is rare; other possible outcomes of therapy include partial remission, stable disease, or progressive disease (NCCN, 2019a). Metastatic diseases are typically incurable.

Breast cancer patients with early-stage and locally advanced disease achieving complete remission should receive frequent (one to four times per year) physical examinations for the first 5 years post-treatment, then yearly physical examinations after the first 5 years to assess for possible metastatic recurrence and tolerance to ongoing therapies, and to monitor or treat any treatment effects. Patients should be monitored for lymphedema. Other imaging and laboratory tests should be conducted as determined by the patient’s treating physician. Those with advanced-stage cancer are likely undergoing chemotherapy or hormonal therapy, or both. The monitoring of those undergoing chemotherapy includes carrying out a history and physical and laboratory tests at every cycle of chemotherapy, performing a CT chest abdomen pelvis (CT CAP) scan every two to four cycles, and carrying out a bone scan every four cycles. Those undergoing hormonal therapy should receive a history and physical and laboratory tests every 1–3 months, a CT CAP every 2–6 months, and a bone scan every 4–6 months or as clinically indicated (NCCN, 2019a).

CUTANEOUS MELANOMA

Over the past several decades there has been a significant rise in cutaneous melanoma incidences in white populations, and it has grown from a very rare malignancy into a disease of considerable clinical importance (Canavan and Cantrell, 2016). Between 2007 and 2009, the overall melanoma incidence in the United States was 21.87 cases per 100,000 person-years, which was up significantly from the 13.94 cases per 100,000 person-years in 1989 to 1991. Men in the United States have a 1 in 33 lifetime risk for developing melanoma, compared with 1 in 52 for U.S. women. In contrast to non-melanoma skin cancers, malignant melanoma affects a younger population with the median age at diagnosis of 55 years. Melanoma is associated with significant morbidity and mortality; however, mortality has leveled over since 1990, though it remains high in those with metastatic disease (Canavan and Cantrell, 2016). Table 3-6 describes the diagnostics, therapy, outcome, and monitoring for cutaneous melanoma.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-6 Diagnostics, Treatment, Outcomes, and Monitoring for Cutaneous Melanoma

Early Stage Locally Advanced Advanced Stage
Diagnostics* Sentinel lymph node biopsy Tumor molecular testing Same as locally advanced stage
Treatment Primary tumor wide excision
  • Primary tumor wide excision
  • Regional lymph node dissection
  • Regional lymph node RT
  • Adjuvant immunotherapy or kinase inhibitor
  • Resection of limited metastases
  • Immunotherapy
  • Kinase inhibitor
  • Chemotherapy
  • Palliative RT
Disease outcomes of treatment Complete remission Recurrence Same as early stage
  • Complete remission
  • Partial remission
  • Progressive disease
Post-treatment monitoring History and physical every 6–12 months for 5 years and annually thereafter
  • History and physical every 3–6 months for 2 years, every 3–12 months for 3 years then as clinically indicated
  • Imaging every 3–12 months for 3 years
  • History and physical
  • Imaging (same length of follow-up as locally advanced if no evidence of disease after therapy)

NOTES: *In addition to history and physical examination, imaging, routine laboratory studies. RT = radiation therapy. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019b.

Professionally Accepted Diagnostic Criteria for Cutaneous Melanoma

A clinical suspicion of a melanoma is based on the visual appearance of a skin lesion. Skin lesion abnormalities raising suspicion include asymmetry, irregular borders, multiple colors, diameter, and change. An early melanoma diagnosis is essential for improving patient prognosis and survival. More superficial, thinner lesions are associated with improved clinical outcomes; therefore, early diagnosis with excisional biopsy is imperative. A full-thickness excisional biopsy is required at the time of initial biopsy in order to determine a potential melanoma’s Breslow thickness. Punch and shave biopsies provide insufficient histologic information and are not recommended (Canavan and Cantrell, 2016).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Treatments for Cutaneous Melanoma

Medical professionals involved in the care of individuals with melanoma include dermatologists, radiation oncologists, medical oncologists, plastic surgeons, and providers that help manage side effects of immunotherapy (e.g., endocrinologists, pulmonologists, gastroenterologists, and neurologists) (NCCN, 2019b). Treatment settings include surgery suites, radiation facilities, and outpatient infusion centers (NCCN, 2019b).

Treatment modalities are based on the stage at diagnosis. Early-stage disease is treated by primary tumor complete excision with a clear margin. Locally advanced disease may be identified by sentinel node biopsy and might also include dissection and RT of regional lymph nodes, adjuvant immunotherapy, or kinase inhibitors. Advanced-stage treatment can involve resection of limited metastases, immunotherapy, kinase inhibitors, chemotherapy, and RT of the brain (NCCN, 2019b).

Surgical excision with adequately conservative margins is the cornerstone of treatment for localized disease without lymph node involvement. Lymph node involvement that is identified clinically or through imaging is treated with lymph node dissection. Adjuvant therapy is an option for high-risk patients, the goal of which is to eliminate subclinical micrometastases. As the understanding of the molecular genetics of melanoma has expanded, there has been great interest in developing targeted treatments, and there are now numerous adjuvant treatment options. Some of the recently approved treatments have targeted BRAF V600E mutations (cobimetinib, trametinib, dabrafenib, and vemurafenib), some target the programmed cell death receptor (pembrolizumab and nivolumab), and others act through immunomodulation (ipilimumab) (Canavan and Cantrell, 2016).

Length of Treatment Time for Cutaneous Melanoma

Therapy for early-stage or locally advanced disease that achieves complete remission is generally complete in 12 to 18 months (NCCN, 2019b). Metastatic disease is typically incurable.

Standard Measures of Outcomes for Cutaneous Melanoma

For early-stage and locally advanced melanoma, the ideal outcome of cancer therapy is complete remission. For advanced-stage diseases, complete remission is rare; other possible outcomes of therapy include partial remission or progressive disease (NCCN, 2019b).

Patients with early-stage melanoma achieving complete remission should receive a history and physical examination every 6–12 months for the first 5 years and then annually thereafter. Those with locally advanced

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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and advanced-stage disease should receive a history and physical every 3–6 months for 2 years, then every 3–12 months for the next 3 years, and then as clinically indicated, as well as having imaging every 3–12 months for 3 years (NCCN, 2019b).

RENAL CANCER

Kidney cancer among adults consists of malignant tumors arising from the renal parenchyma and renal pelvis. Despite an overall increase in the incidence of renal cancers from 1992 to 2015, there has been a recent plateau in renal cancer incidence rates with a significant decrease in mortality (Saad et al., 2018).

Evidence suggests an etiologic role for physical activity, alcohol consumption, occupational exposure to trichloroethylene, and high parity among women. Genetic susceptibility and environmental exposures are believed to influence renal cell cancer risk, but limited studies based on gene approaches have not produced conclusive results. Large-consortium efforts employing genome-wide scanning technology are under way, and they hold promise for novel discoveries in renal carcinogenesis (Capitanio and Montorsi, 2016; Chow et al., 2010). Table 3-7 describes the diagnostics, therapy, outcome, and monitoring for renal cancer.

Professionally Accepted Diagnostic Criteria for Renal Cancer

With the expansion of routine imaging for many disorders, patients with renal cell carcinoma are increasingly being identified incidentally. Only 30 percent of patients are diagnosed on the basis of symptoms (Capitanio and Montorsi, 2016). Although renal cell carcinoma is frequently detected by abdominal ultrasound scanning, limitations in its specificity and accuracy make it necessary to use CT or MRI to confirm suspicious findings. The main goals of imaging are to characterize the mass and possible abdominal metastases, tumor extension, and venous involvement for the purpose of staging. If malignant renal cell carcinoma is suspected, additional imaging (e.g., thoracic and brain CT scan, total body bone scan) can be considered in symptomatic patients or in cases of bulky abdominal disease. New technologies for cancer detection and characterization are being investigated for renal cell carcinoma; for example, advanced MRI techniques, such as diffusion-weighted and perfusion-weighted imaging, are being explored for the assessment of renal masses (Capitanio and Montorsi, 2016).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-7 Diagnostics, Treatment, Outcomes, and Monitoring for Renal Cancer

Early Stage Locally Advanced Advanced Stage
Diagnostics*
  • Abdominal/pelvic CT or MRI
  • Chest X-ray
  • If clinically indicated: bone scan, chest CT, brain MRI
  • Consider needle biopsy if small lesion
Same as early stage Same as early stage
Treatment
  • Partial or radical nephrectomy
  • Ablative therapy (cryotherapy, radiofrequency ablation) for small lesions
  • Partial or radical nephrectomy
  • Adjuvant kinase inhibitor therapy for clear cell variety
  • Cytoreductive nephrectomy
  • Metastasectomy or stereotactic body RT for oligometastatic disease
  • Kinase inhibitor
  • Immunotherapy
  • Antiangiogenics
  • High-dose interleukin-2
Disease outcomes of treatment
  • Complete remission
  • Recurrence
Same as early stage
  • Partial remission
  • Complete remission (rare)
  • Stable disease
  • Disease progression
Post-treatment monitoring
  • Postoperative abdominal CT, MRI, or ultrasound and then annually for 3 years
  • Chest X-ray or CT annually for 5 years
Same as early stage
  • Chest, abdominal, pelvic CT or MRI imaging every 6–16 weeks
  • Head CT/MRI baseline and then as clinically indicated
  • Bone scan, spine MRI as clinically indicated

NOTES: *In addition to history and physical examination, routine and systemic therapy directed labs. CT = computed tomography; MRI = magnetic resonance imaging; RT = radiation therapy. Routine lab studies/all CT and MRI imaging is with contrast unless otherwise designated. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019c.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Treatments for Renal Cancer

Individuals with renal cancer are identified for treatment via imaging, including CT and MRI (NCCN, 2019c). The medical professionals involved in the care of individuals with renal cancer include surgeons, medical oncologists, and invasive radiology specialists (NCCN, 2019c). Treatment settings include invasive radiology facilities, surgery suites, and medical oncology clinics (NCCN, 2019c). Notwithstanding advances in the understanding of renal cell carcinoma biology, surgery remains the mainstay of curative treatment. Although radical nephrectomy was historically the standard of care for management of renal tumors, the detection of small renal lesions and accumulating evidence that surgically induced chronic kidney disease can increase patients’ morbidity have led to more conservative approaches. Specifically, nephron-sparing surgery, active surveillance, and minimally invasive techniques have been introduced into daily clinical practice. These approaches limit invasiveness, iatrogenic renal function impairment, and overtreatment (Capitanio and Montorsi, 2016).

Length of Treatment Time for Renal Cancer

Disease therapy for early disease is generally complete in 12 weeks, therapy for locally advanced disease that achieves complete remission with surgery is complete in 12 weeks, and clear-cell variety receiving adjuvant therapy is usually complete in 60 weeks (NCCN, 2019c).

Standard Measures of Outcomes for Renal Cancer

For early-stage and locally advanced renal cancer, the ideal outcome of cancer therapy is complete remission. For advanced-stage diseases, complete remission is possible but rare; partial remission is more probable (NCCN, 2019c). Eventual progression and death are likely for advanced disease.

Post-treatment monitoring for patients with early-stage and locally advanced renal cancers who achieve complete remission includes CT, MRI, or ultrasound immediately after operation, then annually for 3 years; a chest X-ray or CT should also be performed every 5 years. For those with advanced-stage disease, chest, abdominal, pelvic CT, or MRI imaging should be performed every 6–16 weeks. Head CT/MRI should be taken at baseline postoperatively and then as clinically indicated. A bone scan and a spine MRI should be performed as clinically indicated.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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HEAD AND NECK SQUAMOUS CELL CANCERS

Head and neck squamous cell cancers develop in the mucous membranes of the mouth, nose, and throat (NLM, 2019) and are classified by location: the mouth (oral cavity), the middle part of the throat near the mouth (oropharynx), the space behind the nose (nasal cavity and paranasal sinuses), the upper part of the throat near the nasal cavity (nasopharynx), the voicebox (larynx), or the lower part of the throat near the larynx (hypopharynx). Depending on the location, the cancer can cause abnormal patches or open sores (ulcers) in the mouth and throat, unusual bleeding or pain in the mouth, sinus congestion that does not clear, sore throat, earache, pain when swallowing or difficulty swallowing, a hoarse voice, difficulty breathing, or enlarged lymph nodes (NLM, 2019). Cancers of the brain, thyroid, and esophagus are separately categorized because these cancers are very different in their symptoms and treatment from the previously listed cancers of the head and neck (Cohen et al., 2016a). Head and neck cancers accounted for an estimated 61,760 new cancer cases in the United States in 2016. Currently, there are approximately 436,060 head and neck cancer survivors living in the United States, accounting for 3 percent of all cancer survivors, and long-term survival is becoming more common in this population. Tobacco use and alcohol consumption combine to account for an estimated 75 percent of head and neck cancer cases. In addition, the human papillomavirus (HPV) accounts for as many as 70 percent of oropharyngeal cancers. HPV-related head and neck cancer is a biologically and clinically distinct disease from tobacco-related head and neck cancer, with now well-described differences in molecular alterations, clinical presentation, and prognosis. Approximately 20 percent of the population is positive for exposure to high-risk HPV (Cohen et al., 2016a). An estimated 53,000 new cases of cancer of the oral cavity and pharynx (throat) are expected to be diagnosed in the United States in 2019. Incidence rates are more than twice as high in men as in women. Unlike most other cancer sites, stage IV head and neck cancers are still potentially curable (Cohen et al., 2016b). Table 3-8 describes the diagnostics, therapy, outcome, and monitoring for head and neck squamous cell cancers.

Professionally Accepted Diagnostic Criteria for Head and Neck Squamous Cell Cancer

The diagnostic criteria are the same for all stages of head and neck cancer and may include biopsy (such as fine-needle aspiration of the neck), HPV tissue testing for oropharynx cancer, Epstein-Barr virus (EBV) DNA testing for nasopharynx cancers, mirror and fiberoptic exams, CT/MRI or

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-8 Diagnostics, Treatment, Outcomes, and Monitoring for Head and Neck Squamous Cell Cancer

Early Stage Locally Advanced Advanced Stage
Diagnostics*
  • Biopsy (or FNA of neck)
  • HPV tissue testing (oropharynx)
  • EBV/DNA testing (nasopharynx)
  • Mirror and fiberoptic exam
  • Examination under anesthesia with endoscopy
  • CT/MRI of primary and neck
  • Dental evaluation
  • As clinically indicated: chest CT; PET/CT; nutritional, speech, swallowing evaluation/therapy
Same as early stage Same as early stage
Treatment
  • Primary resection
  • RT
  • Primary resection
  • Neck sentinel node biopsy
  • Neck node dissection
  • RT
  • Chemotherapy
  • Targeted agent therapy
  • Chemotherapy
  • Targeted agent therapy
  • Immunotherapy
Disease outcomes of treatment
  • Complete remission
  • Recurrence
  • Complete remission
  • Partial remission
  • Complete remission
  • Partial remission
  • Progressive Disease
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Early Stage Locally Advanced Advanced Stage
Post-treatment monitoring
  • History and physical (including mirror and fiberoptic exam)
    • Year 1: every 1–3 months
    • Year 2: every 2–6 months
    • Years 3–5: every 4–8 months
    • Years 5+: every 12 months
  • Neck RT: TSH every 6–12 months
  • Intraoral RT: dental monitoring
  • Nasopharyngeal: EBV DNA monitoring
  • Speech/hearing and swallowing evaluation and rehabilitation as clinically indicated
  • Repeat primary and neck baseline imaging within 6 months of therapy completion
  • Annual routine imaging if poor visualization of primary site
Same as early stage Same as early stage and routine CT or CT/PET imaging to monitor therapy response for metastatic disease

NOTES: *In addition to history and physical examination and laboratory tests. CT = computed tomography; EBV = Epstein-Barr virus; FNA = fine needle aspiration; HPV = human papillomavirus; MRI = magnetic resonance imaging; PET = positron emission tomography; RT = radiation therapy; TSH = thyroid-stimulating hormone. Routine lab studies/all CT and MRI imaging is with contrast unless otherwise designated. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019d.

the primary site and neck, and dental evaluation. As clinically indicated, diagnosis may also include chest CT, PET/CT, nutrition consultation, speech consultation, and swallowing evaluation and therapy.

Fine-needle aspiration is a common type of biopsy used in diagnosing head and neck cancer. This involves inserting a thin needle directly into the tumor or lymph node and then examining the cells under a microscope for cancer cells, in a process called a cytologic examination. The biopsy might include testing to see whether the person has HPV, which has been linked to a higher risk of head and neck cancers. In some cases, whether a person has HPV can help determine which treatments would be most effective (NLM, 2019). Molecular testing of the tumor may be done to identify specific

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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genes, proteins, and other factors unique to the tumor and also to help determine treatment options. A CT scan or MRI can be used to determine the tumor’s size. In addition, if swallowing is impaired, physicians may consult a nutritionist and speech language pathologist. A barium swallow study can help identify abnormalities in the swallowing passage (NLM, 2019).

Treatments for Head and Neck Squamous Cell Cancer

Medical professionals involved in the care of individuals with head and neck squamous cell cancer include surgeons, radiation oncologists, medical oncologists, and dentists (NCCN, 2019b). Therapy takes place is the surgery suite, radiation facilities, and outpatient infusion centers (NCCN, 2019d). RT or surgery or a combination of the two are standard treatments; chemotherapy is often added for high-risk or advanced disease. Chemotherapy or targeted therapy may be combined with radiation as an initial treatment in some cases. Immunotherapy is a newer option for advanced or recurrent cancer (ACS, 2019b).

Standard management of head and neck cancers is based largely on anatomic considerations and TNM (tumor, lymph nodes, metastasis) stage. Early-stage disease (stage I and II) is treated with a single modality—surgery or RT—depending primarily on the tumor’s location but also on the tumor’s extent, the anticipated cure rate, and functional and esthetic outcome. About 80 to 90 percent of early-stage patients will go into complete remission. Advanced-stage patients (stages III, IVa, and IVb) are treated with multimodal therapy, including surgery, RT, chemotherapy, and targeted agent therapy. The sequencing and combination of therapies are based on the stage, tumor location, expertise of treating physicians, and patient preference. Despite the use of more aggressive treatment for advanced-stage disease, cure rates remain low primarily because of locoregional recurrence. However, HPV-related head and neck cancer is associated with a significantly better prognosis even with stage IV disease, especially in never smokers. Cure rates, often based on 5-year survival rates, for HPV-related head and neck cancer in some large studies has approached 90 percent (Cohen et al., 2016a).

Much of the current research in head and neck cancers is focused on personalizing therapy based on molecular phenotypes, improving treatment efficacy, and reducing long-term morbidity. The latter is predominantly being studied in HPV-related head and neck cancer, where reductions in radiation dose or volume are being studied with the goal of reducing acute and chronic toxicities (Cohen et al., 2016a).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Length of Treatment Time for Head and Neck Squamous Cell Cancer

Disease therapy for early disease is complete in 12 weeks, and therapy for locally advanced disease that achieves complete remission with combination therapy is complete in 6 to 12 months (NCCN, 2019d).

Standard Measures of Outcomes for Head and Neck Squamous Cell Cancer

For all stages of head and neck cancer, the ideal outcome of cancer therapy is complete remission. For advanced-stage disease, partial remission is more probable, and progressive disease is also a possible result of cancer therapy (NCCN, 2019d).

Post-treatment monitoring for all stages of head and neck cancer in which complete remission has been achieved should include a history and physical examination that includes mirror and fiberoptic exam and which is performed every 1–3 months in the first year following treatment, every 2–6 months in the second year, every 4–8 months at 3–5 years post-treatment, and once per year after 5 years post-treatment (NCCN, 2019d).

Other factors to monitor depend on the site of the head and neck cancer. If RT is performed on the neck, TSH should be monitored every 6–12 months to look for radiation-induced hypothyroid, a toxicity of the radiation. Dental monitoring should be performed for those undergoing intraoral RT. EBV DNA monitoring should be performed for those treated for nasopharyngeal cancer. If the cancer resulted in impaired speech, hearing, or swallowing, those functions should be rehabilitated and monitored closely. Primary and neck baseline imaging should be performed within 6 months of therapy completion. Annual routine imaging should also be performed if there is poor visualization of the primary site of cancer. For those with advanced-stage head and neck cancer, routine CT or CT/PET imaging should also be performed to monitor therapy response for metastatic disease (NCCN, 2019d).

ADVANCED EPITHELIAL OVARY CANCER

Ovarian cancer is the most lethal gynecologic malignancy among women in the United States (Thrall et al., 2011). In 2019 an estimated 22,530 American women will be newly diagnosed with ovarian cancer and 13,980 women will die of the disease (ACS, 2020). Survival in epithelial ovarian cancer is strongly related to the stage of the disease, and the majority of patients present with advanced-stage (III/IV) disease at the time of diagnosis (Thrall et al., 2011). Although survival remains low for advanced epithelial ovary cancer (see Table 3-1), for a subset of patients

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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with certain biological characteristics, the disease is curable and long-term survival (of 10 or more years) is possible (Cress et al., 2015; Hilal et al., 2016). Researchers have theorized that individuals with advanced-stage ovary cancer who carry mutations in the tumor suppressor genes BRCA1 and BRCA2 respond better to chemotherapy than those who do not (Cress et al., 2015). Additionally, data show that younger women generally have better prognoses, partially due to a better ability to tolerate aggressive therapy (Cress et al., 2015). Table 3-9 describes the diagnostics, therapy, outcome, and monitoring for advanced epithelial ovary cancer.

Professionally Accepted Diagnostic Criteria for Advanced Epithelial Ovary Cancer

Diagnostics for advanced epithelial ovarian cancer include CT of the chest, abdomen, and pelvis using the CA-125 (carbohydrate antigen 125) marker and genetic counseling and testing (NCCN, 2019e; Pepin et al., 2014). CT of the abdomen and pelvis is the first-line imaging modality for staging, selecting treatment options, and assessing disease response in ovarian cancer (Sahdev, 2016). Genetic counseling and testing can play a role in screening for ovarian cancer (Neff et al., 2017). Recent advances in the hereditary understanding of this disease have shown a significant role for inherited BRCA1 and BRCA2 gene mutations. A positive test result for the BRCA gene mutations indicates a higher susceptibility to breast and ovarian cancers (Neff et al., 2017). A positive deleterious BRCA germline mutation also directs utilization of poly (ADP-ribose) polymerase (PARP) inhibitor therapy (NCCN, 2019e).

Treatments for Advanced Epithelial Ovary Cancer

The medical professionals involved in the care of individuals with advanced epithelial ovary cancer include gynecologic oncologists, surgeons, medical oncologists, and genetic counselors (NCCN, 2019e). Treatment settings include surgery suites and outpatient infusion centers (NCCN, 2019e). Optimal care for most patients with advanced ovarian cancer generally includes both surgery and chemotherapy (NCCN, 2019e; Thrall et al., 2011). People with advanced epithelial ovary cancer are identified for treatments via examination, imaging (ultrasound, CT, and MRI), and laparascopic examination (NCCN, 2019e). The treatment of newly diagnosed advanced epithelial ovarian cancer is rapidly evolving. Targeted therapies are now available based on positive phase III clinical trials (Monk et al., 2019). Current NCCN guidelines (2019e) recommend the following treatments:

  1. Total abdominal hysterectomy with bilateral salpingo-oophorectomy, surgical staging, and debulking, followed by (adjuvant) chemotherapy
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-9 Diagnostics, Treatment, Outcomes, and Monitoring for Advanced Epithelial Ovary Cancer

Advanced Stage
Diagnostics*
  • Chest, abdomen, pelvis CT
  • CA-125 marker
  • Genetic counseling and testing
Treatment
  • Total abdominal hysterectomy with bilateral salpingo-oophorectomy, surgical staging and debulking, followed by (adjuvant) chemotherapy (intravenous or intraperitoneal and intravenous) with or without antiangiogenics agent, maintenance antiangiogenics agent or targeted agent (PARP inhibitor)
  • Pre-operative chemotherapy (neoadjuvant) followed by same surgery and same adjuvant therapy
  • Chemotherapy with or without antiangiogenics agent for non-surgical candidate. Chemotherapy, targeted agent, hormonal therapy, immunotherapy, palliative RT for persistent/progressive disease
Disease outcomes of treatment
  • Complete or partial remission
  • Persistent and progressive disease
Post-treatment monitoring
  • Complete remission:
    • History and physical examination (including pelvic exam) every 2–4 months for 2 years, 3–6 months for 3 years, and then annually
    • CA-125 monitoring
    • Imaging and labs as clinically indicated
    • Genetic counseling if not done initially
  • Relapsed, progressive disease
    • Chest/abdomen/pelvic CT, MRI, PET/CT, or PET
    • CA-125 monitoring, labs as therapy and clinically indicated
    • Tumor molecular testing

NOTES: *In addition to history and physical examination (including pelvic exam). CA-125 = carbohydrate antigen 125 (a protein detected through blood test); CT = computed tomography; MRI = magnetic resonance imaging; PARP = poly (ADP-ribose) polymerase (a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death); PET = positron emission tomography; RT = radiation therapy. Routine lab studies/all CT and MRI imaging is with contrast unless otherwise designated. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019e.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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  1. (intravenous or intraperitoneal and intravenous) with or without antiangiogenics agent, maintenance antiangiogenics agent, or targeted agent (PARP inhibitor)

  2. Preoperative chemotherapy (neoadjuvant) followed by same surgery and same adjuvant therapy
  3. Chemotherapy with or without antiangiogenics agent for nonsurgical candidate. Chemotherapy, targeted agent, hormonal therapy, immunotherapy, palliative RT for persistent/progressive disease

The timing and extent of surgery has direct implications for the selection of subsequent treatment as well as for the patient’s prognosis. The newest class of agents approved by the U.S. Food and Drug Administration (FDA) to treat newly diagnosed advanced ovarian cancer are inhibitors of the enzyme poly (ADP ribose) polymerase, or PARP. PARP inhibitors are recommended for maintenance therapy after completion of chemotherapy for women identified with a BRCA1/2 mutation (Jiang et al., 2019). The early initiation of chemotherapy following surgery has been found to improve survival. One study of 1,718 patients with stage III and IV advanced ovarian cancer found that survival was adversely affected when chemotherapy was initiated more than 25 days following surgery (Tewari et al., 2016).

Length of Treatment Time for Advanced Epithelial Ovary Cancer

Early-stage or locally advanced disease therapy that achieves complete remission is usually complete in 12 to 18 months, with a possible extension with PARP-inhibitor therapy (NCCN, 2019e).

Standard Measures of Outcomes for Advanced Epithelial Ovary Cancer

For those with advanced epithelial ovary cancer, the ideal outcome of cancer therapy is complete remission, although partial remission and persistent and progressive disease are also possible (NCCN, 2019e).

For those in complete remission, a history and physical examination including a pelvic examination are recommended every 2–4 months for the first 2 years after treatment, then every 3–6 months for 3 years, then annually. CA-125 monitoring, imaging, laboratory tests, and genetic counseling should also be conducted as clinically indicated. For those with relapsed, progressive disease, CT, MRI, PET/CT, or PET should be performed in the chest, abdomen, and pelvis. Other post-treatment monitoring for those with relapsed, progressive disease includes tumor molecular testing and

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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laboratory tests (generally, a comprehensive metabolic panel and a complete blood count) as clinically indicated and depending on the type of therapy (NCCN, 2019e).

NON-SMALL-CELL LUNG CANCER

Lung cancer remains the leading cause of cancer deaths in the United States, with 5-year survival improving incrementally (see Table 3-2) given recent advances in therapy. Although survival for lung cancer remains low, for a subset of patients, long-term survival is possible (Davis et al., 2019). Lung cancer comprises small-cell lung cancer (SCLC; approximately 15 percent of all lung cancers) and NSCLC (approximately 85 percent) (Reck and Rabe, 2017). In the past decade, advances have been made in the science of NSCLC (Duma et al., 2019). Lung cancer screening has demonstrated early-stage detection resulting in reduced mortality. The National Lung Screening Trial found a lung cancer mortality benefit of 20 percent and a 6.7 percent decrease in all-cause mortality with the use of low-dose chest CT in high-risk individuals. The treatment of lung cancer has also evolved, with the introduction of several lines of tyrosine kinase inhibitors in patients with EGFR, ALK, ROS1, NTRK mutations, and BRAF V600 mutations and NTRK gene fusion. Similarly, ICIs have changed the landscape of NSCLC treatment. ICI therapy is recommended first-line therapy as either monotherapy or combined with chemotherapy for advanced disease that demonstrates overexpression of the PD-L1. ICI therapy is also recommended for stage III disease following the completion of combined chemotherapy and radiation (Duma et al., 2019). Table 3-10 describes the diagnostics, therapy, outcome, and monitoring for NSCLC.

Professionally Accepted Diagnostic Criteria for Non-Small-Cell Lung Cancer

Often, NSCLC is not diagnosed until advanced-stage disease is present. Cough, seen in 50 percent to 75 percent of patients, is the most common symptom, followed by hemoptysis, chest pain, and dyspnea. Other less common symptoms include laboratory abnormalities or paraneoplastic syndromes. Diagnosis requires a biopsy for histologic confirmation (Duma et al., 2019). Diagnosis also requires a determination of the extent of the tumor to define the TNM stage, which will ultimately guide cancer treatment options. Chest and upper abdomen CT, PET, and MRI can determine the stage, with CT scans being the most commonly used imaging modality for staging (Purandare and Rangarajan, 2015). On its own, the FDG/PET component does not have the optimal spatial resolution to

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-10 Diagnostics, Treatment, Outcomes, and Monitoring for Non-Small-Cell Lung Cancer

Early Stage Locally Advanced Advanced Stage
Diagnostics*
  • CT chest and upper abdomen, FDG PET/CT
  • Brain MRI
  • Bronchoscopy
  • EBUS/EUS
  • Mediastinoscopy
  • Biopsy
  • Pulmonary function tests
  • Same as early stage
  • MRI spine and thoracic outlet (for primary abutting spine or subclavian vessels)
  • Thoracentesis/pericardiocentesis
  • CT chest and upper abdomen
  • Brain MRI, FDG PET/CT
  • Biopsy, tissue molecular testing (broad molecular profiling) and PDL-1 testing
Treatment
  • Surgical resection
  • RT
  • Chemotherapy/RT
  • Adjuvant chemotherapy, radiation
  • Chemotherapy/RT
  • Post chemotherapy/RT immunotherapy
  • Pleural local therapy (thoracentesis, small catheter drainage, pericardial window)
  • Targeted agents, immunotherapy, chemotherapy, RT
  • Endobronchial stent/laser
  • Orthopedic bone stabilization, skeletal directed agents for bone metastases
Disease outcomes of treatment
  • Complete remission
  • Recurrence
  • Complete remission
  • Persistent disease
  • Complete remission
  • Partial remission, stable disease
  • Progressive disease
Post-treatment monitoring
  • History and physical and low-dose non-contrast chest CT annually
  • Chest CT every 6 months for 2–3 years
For complete remission: History and physical and chest CT every 3–6 months for 3 years, then every 6 months for 2 years, then history and physical and low-dose non-contrast chest CT annually
  • History and physical and labs every cycle
  • Imaging every three cycles

NOTES: *In addition to history and physical examination and laboratory tests. CT = computed tomography; EBUS/EUS = endobronchial ultrasound/endoscopic ultrasound; FDG = fluorodeoxyglucose; MRI = magnetic resonance imaging; PET = positron emission tomography; RT = radiation therapy. Routine lab studies/all CT and MRI imaging is with contrast unless otherwise designated. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019f.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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provide information about infiltration of adjacent structures and, thus, has limitations for staging. However, if FDG/PET is performed along with contrast-enhanced CT, then the integrated image has a similar accuracy to a CT scan (Purandare and Rangarajan, 2015). Any positive node on PET-CT must be sampled, as confirmed by the analysis of a secondary objective from another randomized study (Duma et al., 2019). Additionally, NCCN (2019f) recommends bronchoscopy for early and locally advanced stages. Broncoscopes, which can be rigid or flexible, aid clinicians in providing an accurate diagnosis and lymph node staging. Technologies such as endobronchial ultrasound, navigational bronchoscopy, and autofluorescence have improved the efficacy of endobronchial diagnosis and sample collection (Bauer and Berkheim, 2016). CT or MRI of the head is recommended for patients to be treated with curative intent or for those with signs or symptoms suggestive of brain metastasis (Duma et al., 2019).

Treatments for Non-Small-Cell Lung Cancer

The medical professionals involved in the care of individuals with NSCLC include surgeons, radiation oncologists, medical oncologists, pulmonologists, and radiologists (NCCN, 2019f). The treatment settings include radiology facilities, surgery suites, radiation facilities, and outpatient infusion centers (NCCN, 2019f). People with NSCLC are identified for treatment via imaging, broncoscopy, and mediastinoscopy (NCCN, 2019f). The treatment of NSCLC is stage specific. Patients with early-stage or locally advanced cancers should be treated with complete surgical resection when not contraindicated. Non-surgical patients should be considered for conventional or stereotactic RT (Duma et al., 2019). Chemotherapy and immunotherapy are also options if the surgical resection does not succeed (NCCN, 2019f). Lobectomy, the surgical resection of a single lobe, is generally accepted as the optimal procedure for early-stage NSCLC (Duma et al., 2019). Data regarding lobectomy versus sublobar resection are mixed but generally favor lobectomy. The rationale for adjuvant chemotherapy for patients with early-stage lung cancer is based on the observations that distant metastases are the most common site of failure after potentially curative surgery. Adjuvant therapy consists of cisplatin-based combination regimens and is indicated in patients with stage II and IIIA disease after surgical resection (Duma et al., 2019).

Immunotherapy has dramatically changed the landscape of NSCLC treatment (Duma et al., 2019). An essential role of the immune system is to recognize and destroy neoplastic cells before they become clinically meaningful. To limit damage to healthy cells, this process is highly regulated by a network of activating and inhibitory pathways in equilibrium. By altering this equilibrium, malignancies can escape immune surveillance and

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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thrive. This strategy has been proven to be an effective therapy option for many cancers, including NSCLC. One of the most attractive features of this type of treatment is that a subset of patients seems to have long-lasting benefits, with a subgroup of patients being alive 5 years after diagnosis, something that was unthinkable a decade ago (Duma et al., 2019).

A small subset of individuals with NSCLC have the potential to be cured, and survivorship depends largely on the type of treatment used. Davis and colleagues (2019) studied a cohort of patients with stage IV NSCLC in the SEER database who were diagnosed from 1991 to 2007 and followed through 2012. They found that the 10 percent of patients who were long-term survivors (defined as living 21 months or longer) had a median survival time of 10 times that of the remaining 90 percent and were more likely to be younger, female, and treated with surgery. Uhlig and colleagues (2019) studied patients in the National Cancer Database who were diagnosed with stage IV NSCLC from 2010 through 2015 and found those treated with surgery in addition to systemic therapy survived longer than those treated with systemic therapy alone. Xia and colleagues (2017) likewise found remarkable improvements in patients in the SEER database diagnosed with NSCLC from 1988 to 2008 who underwent curative surgical resection. Another study of patients in the SEER database diagnosed with NSCLC from 1999 to 2008 concluded that RT was correlated with greater survival, especially coupled with surgery (Cheng et al., 2019). Otaibi and colleauges (2019) studied patients in the National Cancer Database with stage IV NSCLC and found improved survival in patients who received immunotherapy. They also found that the use of immunotherapy rose from 1 percent of patients to 12 percent from 2004 to 2015.

Length of Treatment Time for Non-Small-Cell Lung Cancer

Disease therapy for early-stage disease requiring surgery is usually complete in 12 weeks, therapy for early-stage disease requiring adjuvant therapy is complete in 6 months, and therapy for locally advanced disease that achieves complete remission with combination therapy is complete in up to 15 months (NCCN, 2019f).

Standard Measures of Outcomes for Non-Small-Cell Lung Cancer

The ideal outcome of NSCLC therapy is complete remission. For locally advanced-stage cancers, persistent disease is a possible result of treatment. For advanced-stage diseases, complete remission is rare; other possible outcomes of therapy include partial remission, stable disease, or progressive disease (NCCN, 2019f).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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NSCLC patients with early-stage disease who achieve complete remission should receive a history and physical and chest CT every 6 months for 2–3 years post-treatment, then an annual history and physical with low-dose non-contrast chest CT. For those with locally advanced disease in complete remission, a history and physical and chest CT should be performed every 3–6 months for the first 3 years after treatment, then every 6 months for 2 years. After 2 years, a history and physical with low-dose non-contrast chest CT should be performed annually. For those with advanced-stage disease, a history and physical and laboratory tests including a comprehensive metabolic panel and a complete blood count should be performed at every cycle of chemotherapy. Imaging should be performed at every three cycles of chemotherapy (NCCN, 2019f).

DIFFUSE LARGE B-CELL LYMPHOMA

Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma in the United States, representing approximately 24 percent of new cases of non-Hodgkin lymphoma each year. The disease is aggressive, and patients typically present with rapidly enlarging lymphadenopathy and constitutional symptoms, necessitating immediate treatment (Liu and Barta, 2019). The disease is characterized by age, stage, the number of extranodal sites, performance status, and levels of serum lactate dehydrogenase. Recently, next-generation sequencing and comprehensive genomic analysis has allowed further subclassification of the disease by recurrent, high-frequency mutations, which provides a solid foundation for the development of novel targeted approaches (Liu and Barta, 2019). Table 3-11 describes the diagnostics, therapy, outcome, and monitoring for diffuse large B-cell lymphoma (excluding high-grade).

Professionally Accepted Diagnostic Criteria for Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is best diagnosed from an excisional biopsy of a suspicious lymph node, which shows sheets of large cells that disrupt the underlying structural integrity of the follicle center and stain positive for pan-B-cell antigens, such as CD20 and CD79a. The cell of origin is determined by immunohistochemical stains, while molecular features such as double-hit or triple-hit disease are determined by fluorescent in situ hybridization (FISH) analysis. Commercial tests for frequently recurring mutations are currently not routinely used to inform treatment (Liu and Barta, 2019). In parallel to cell-of-origin studies, the subtypes of diffuse large B-cell lymphoma based on molecular features such as genetic rearrangements have also been found to have prognostic

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-11 Diagnostics, Treatment, Outcomes, and Monitoring for Diffuse Large B-Cell Lymphoma (Excluding High-Grade)

Early Stage Advanced Stage Relapsed/Refractory
Diagnostics*
  • General blood laboratory studies, incisional or excisional biopsy
  • Tissue for immunohistochemistry, flow cytometry, PCR for IGH and TCR gene rearrangements, karyotype, FISH for major translocations, next-generation sequencing
  • Whole body PET/CT with or without C/A/P CT, bone marrow biopsy, International Prognostic Score calculation
  • Hep B testing, echocardiogram or MUGA scan, International Prognostic Index calculation
  • As clinically indicated: head CT/MRI, neck CT/MRI, HIV and hep C testing, beta-2 microglobulin level, lumbar puncture, pregnancy testing (as indicated)
Same as early stage Same as early stage
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Early Stage Advanced Stage Relapsed/Refractory
Treatment
  • Targeted monoclonal antibody
  • Chemotherapy
  • RT
  • Targeted monoclonal therapy, chemotherapy, RT
  • Intrathecal chemotherapy for leptomeningeal disease
  • High-dose methotrexate for parenchymal CNS disease
  • Targeted monoclonal therapy, chemotherapy, RT
  • Kinase inhibitor, immunomodulator, immunotherapy
  • High-dose chemotherapy with autologous stem cell rescue
  • Allogeneic hematopoietic cell transplant
  • Chimeric antigen receptor T-cell therapy
Disease outcomes of treatment
  • Complete remission
  • Recurrence
Complete remission Complete remission
Post-treatment monitoring
  • History and physical and labs every 3–6 months for 5 years, then annually or as clinically indicated
  • C/A/P CT with contrast only as clinically indicated
  • History and physical and labs every 3–6 months for 5 years, then annually or as clinically indicated
  • C/A/P CT with contrast every 6 months for 2 years, then as clinically indicated
  • History and physical and labs every 3–6 months for 5 years, then annually or as clinically indicated.
  • C/A/P CT with contrast every 6 months for 2 years, then as clinically indicated

NOTES: *In addition to history and physical examination (including pelvic exam). C/A/P = chest/abdomen/pelvis; CNS = central nervous system; CT = computed tomography; FISH = fluorescence in situ hybridization; IGH = immunoglobulin heavy chain; MUGA = multiple-gated acquisition scan; PCR = polymerase chain reaction; PET = positron emission tomography; RT = radiation therapy; TCR = T-cell receptor. Clinical trial therapy is also an option for treatment.

SOURCE: NCCN, 2019g.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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implications. These genetic rearrangements are identified by FISH. FISH studies should be done at the time of diagnosis and, ideally, again at the time of recurrence for prognostic and treatment implications (Liu and Barta, 2019). Whole-exome sequencing and the associated next-generation sequencing modalities have not yet been adopted into clinical practice, and tailored therapeutic approaches to these different subtypes have yet to be defined (Liu and Barta, 2019).

Treatments for Diffuse Large B-Cell Lymphoma

The medical professionals involved in the care of individuals with diffuse large B-cell lymphoma include radiation oncologists and medical oncologists (NCCN, 2019g). The treatment settings include radiation facilities and outpatient infusion centers (NCCN, 2019g). Patients with large B-cell lymphoma are identified for treatments via examination and imaging (CT, MRI, PET/CT) (NCCN, 2019g). NCCN (2019g) recommends targeted monoclonal antibody therapy, chemotherapy, and RT for all stages of diffuse large B-cell lymphoma. More advanced stages may require additional treatments, such as kinase inhibitors and immunotherapy.

The improved knowledge of the pathogenetic mechanisms underlying lymphomagenesis and the discovery of the critical role of tumor microenvironments have enabled the design of new drugs against cell targets and pathways. FDA has approved several monoclonal antibodies for targeted therapy in hematology (Crisci et al., 2019). Therapeutic monoclonal antibodies target specific antigen molecules, such as extracellular growth factors and transmembrane receptors. In some cases, monoclonal antibodies are conjugated with radioisotopes or toxins to allow the specific delivery of these cytotoxic agents to the tumor cell target (Crisci et al., 2019).

Length of Treatment Time for Diffuse Large B-Cell Lymphoma

Disease therapy that achieves complete remission is usually complete in 6 months (NCCN, 2019g). Therapy for disease that does not achieve complete remission will take a longer course.

Standard Measures of Outcomes for Diffuse Large B-Cell Lymphoma

The ideal outcome of diffuse large B-cell lymphoma therapy is complete remission (NCCN, 2019g). Monitoring for all stages of disease with complete remission includes a history and physical and laboratory tests (including a comprehensive metabolic panel and a complete blood count) every 3–6 months for the first 5 years post-treatment, then annually or

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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as clinically indicated. Chest/abdomen/pelvis CT is also recommended as clinically indicated for those with early-stage lymphoma and every 6 months for the first 2 years post-treatment or as clinically indicated for those with advanced-stage or relapsed/refractory disease.

DISABLING IMPAIRMENTS RELATED TO THE SELECTED CANCERS AND CANCER TREATMENTS

Cancer treatments are well known to cause morbidity in cancer survivors. Although the treatments have generally improved to the point that they are both more effective and less debilitating than previously, treatment-related impairments are still common and, in many instances, expected. Studies show that most types of cancers result in decreased work ability in patients, at least during active treatment or in its terminal phase, and that the decreased work ability is often associated not with the progression of the cancer itself, but rather with treatment, treatment-related side effects (also known as toxicities), and comorbidity with other health conditions (Munir et al., 2009). The adverse effects of some treatments can be profound, with serious implications for function and quality of life (QOL). At the core of cancer treatments are surgery, systemic therapy, and RT. Each of these modalities has evolved significantly in recent years. Systemic therapy, for instance, which historically centered on various combinations of cytotoxic chemotherapeutics, now includes hormonal and biologic (targeted, immune, and gene) therapies. The addition of these new agents has revolutionized the treatment of many types of cancer but has also introduced new types of functional morbidity.

For instance, fatigue and exhaustion are the most frequent problems reported by breast cancer survivors. Fatigue is one of the most important factors that prevent cancer survivors from rejoining the workforce or reduce their capability to work (Islam et al., 2014). Clinically relevant levels of CRF have been seen in approximately one-third of cancer survivors, lasting up to 6 years post-treatment, and this is associated with high levels of disability (Jones et al., 2016). A study by Cheville and colleagues (2008) of 163 patients with metastatic breast cancer found that 92 percent of the patients in the study had at least one physical impairment. Among the identified impairments, 92 percent required a physical rehabilitation intervention, and 88 percent required physical therapy or occupational therapy, or both.

The residual effects of cancer treatments can appear decades after treatment. Certain types of radiation and chemotherapy for breast cancer are associated with an increased risk of developing cardiovascular complications, which may not present until up to 20 years after the cancer treatments (Okwuosa et al., 2017). Use of cisplatin has been shown to

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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increase the risk of cardiovascular events even decades after treatment (Feldman et al., 2018; Herradó et al., 2017). About 58 percent of breast cancer survivors experience chemotherapy-induced peripheral neuropathy (CIPN), which can persist up to 1–3 years after treatment completion, with significant impairment of QOL (Bao et al., 2016). In some breast cancer survivors CIPN can result in permanent impairment. Likewise, cognitive impairment is common among colorectal cancer survivors who receive adjuvant chemotherapy. Associated impairments include processing speed, verbal memory, and attention or working memory. Studies have shown that the majority will improve after treatment completion (Vardy et al., 2014).

As described in Chapter 1, the definition of “impairment” and its relationship to disability and functioning varies across disciplines. In this section, the committee defines cancer-related impairments as sequelae of cancer that interfere with a person’s ability to function.

Time Course and Trajectory of Treatment Effects

The effects of cancer treatment vary profoundly. They may be local or systemic, transient or chronic, functionally irrelevant or profoundly disabling. Many are morbid, and some are mortal. Their natural histories range widely. Some resolve spontaneously over time, such as mucositis, anemia, and alopecia. Those that do not resolve can cause variable degrees of permanent tissue changes that differ in functional impact. The majority of durable treatment effects can be clinically mitigated but not eliminated. Lacking an accepted taxonomy, these treatments effects on healthy tissue are variably referred to as treatment toxicities, side effects, long-term effects, and late effects. Unfortunately, these terms have not been formally defined, a situation that has resulted in inconsistent usage. The situation is made more complex by the fact that some treatment effects engender secondary effects. For example, a hip joint contracture due to radiation-induced scarring may stress the contralateral hip, accelerating the development and progression of osteoarthritis. For clarity and consistency in the chapter, the committee defines acute side effects as those that develop during treatment but are transient, long-term side effects as those that develop during treatment but are chronic, late effects as those that develop after completion of treatment, and secondary effects as those that are engendered as a result of acute and long-term side effects.

The need for precise categorical definitions is particularly critical in identifying disabling conditions that may improve with treatment. Most cancer survivors develop multiple effects in all of the aforementioned categories, with their net impact changing progressively over time. Figure 3-4 presents theoretical trajectories for each effect category. By examining

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Image
FIGURE 3-4 Theoretical trajectories for acute, long-term, late, and secondary effects of cancer.

various time points on the x-axis, it becomes apparent that multiple evolving processes may co-occur and contribute to an individual’s residual treatment burden. Acute side effects may lessen, long-term side effects stabilize, late effects emerge, and secondary effects develop. Determining the relative contributions of each on an individual’s ability to engage in gainful employment may be challenging for even seasoned clinicians, particularly as some effects are symptoms that fluctuate over time, such as pain, fatigue, and insomnia.

The impact of any single effect can be dramatically altered by the nature and number of co-occurring effects. Cross-sectional reports demonstrate that the number of physical impairments and the presence of symptoms potently mediate disability to a greater degree than the presence of any specific impairment (Cheville et al., 2011). Among disease-free cancer survivors, disablement is less often due to a single symptom or impairment than to the toxic interplay and reinforcing effects of multiple mild to moderate issues (Sarfarti et al., 2016). Each effect tends to further erode a survivor’s functional reserve, making it difficult for the survivor to engage in or benefit from treatment. For example, fatigue and pain often amplify the impact of weakness and limit patients’ participation in rehabilitation treatments (Alfano et al., 2016). More recent models of function and disability, such as the World Health Organization’s International Classification of Functioning, Disability and Health (WHO, 2002), acknowledge the web of

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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dynamic, interacting factors that drive disability and highlight the difficulty in attributing functional loss to a single toxicity or impairment.

A full accounting of adverse cancer treatment effects is beyond the scope of this report; however, a limited group of impairments and symptoms are common disabling factors across diverse cancer types and stages. The presence and severity of these treatment effects—pain, CRF, cardiotoxicity, CIPN, lymphedema, pulmonary dysfunction, and CD—are key determinants of whether a survivor is likely to functionally improve with treatment. Anticipating whether a survivor is likely to resume gainful employment and estimating the interval before he or she can do so requires a comprehensive inventory of residual treatment effects with consideration given to the natural history and treatment responsiveness of each. Table 3-12 presents a matrix of cancers with their associated impairments.

Table 3-13 shows a matrix of impairments related to particular cancer therapies.

The following sections describe key symptoms and impairments that have been empirically implicated in cancer-related disablement.

TABLE 3-12 Selected Cancers and Associated Impairments Caused by Cancer or Cancer Treatment

Impairments
Cancers Pain Lymphedema Fatigue Cardiotoxicity Cognitive Dysfunction Pulmonary Dysfuction Nerve Dysfunction
Advanced epithelial ovary
Cutaneous melanoma
Diffuse large B-cell lymphoma
Head and neck
Invasive breast
Non-small-cell lung
Renal

NOTE: Many impairments are mediated by cancer treatments and are not caused by the cancers themselves (see Table 3-13).

SOURCES: Gamper et al., 2015; Kim et al., 2010; Pachman et al., 2012; Runowicz et al., 2016; Silver et al., 2013.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-13 Selected Cancer Therapies and Associated Impairments

Impairments
Therapy Pain Lymphedema Fatigue Cardiotoxicity Cognitive Dysfunction Pulmonary Dysfuction Nerve Dysfunction
Chemotherapy
Hormone therapy
Immune modulators * *
Radiation therapy
Surgery
Targeted therapy

NOTE: *Indicate that the literature does not show a clear linkage at the time of this report.

SOURCES: Amir et al., 2011; Chamberlain, 2010; Giglio and Gilbert, 2010; Glare et al., 2014; Kim et al., 2010; Livshits et al., 2014; Piperis et al., 2012; Stone et al., 2000; Vasiliadis et al., 2014; Wang et al., 2017; Warren et al., 2014; Wilkes, 2018; Wu and Amidi, 2017.

PAIN

Pain is unfortunately prevalent and potentially damaging at all stages of cancer. The most common causes of cancer-related pain are local and remote tumor effects and the cancer treatment itself, although many other causes exist. Chronic musculoskeletal and other types of “benign,” noncancer pain are frequently exacerbated among survivors due to stress, altered kinetics, and deconditioning, among the many other unwelcome changes that characterize the cancer experience. Pain has well-documented erosive effects on all QOL domains. Physical and cognitive functions are particularly susceptible to the damaging effects of pain, which affects survivors’ ability to work.

Professionally Accepted Diagnostic Criteria for Pain

The diagnosis of cancer-related pain is most commonly made through patient report. Pain assessments are administered to patients via diverse modes including verbal, print, and telephonic questioning as well as via tablets at point-of-care and through web-based platforms and portals. The data collected through these assessments are frequently recorded in patients’ medical records, increasingly as structured elements. However, some pain

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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assessments may be solely accessible as unstructured data in providers’ notes. Common pain assessment tools include 11-point numerical rating scales, the Brief Pain Inventory (BPI) and the three-item PEG questionnaire that was derived from it, the PROMIS pain short forms, and computer adaptive tests (Kean et al., 2016). In addition, many multi-domain QOL assessment tools such as the Functional Assessment of Cancer Therapy (FACT) and the European Organisation for Research and Treatment of Cancer QOL Core Questionnaire 30 include pain-related items that may allow the calculation of pain subdomain scores (Iravani et al., 2018; Kean, 2016).

Thresholds at which pain is considered moderate or severe vary across assessment tools. The BPI has been most studied with respect to score strata that indicate pain significant enough to cause problems. For this tool ratings of 1–3 are considered mild, 4–7 moderate, and 8–10 severe (Cleeland, 2009). One report noted that pain greater than 5 was sufficiently severe to negatively affect patients’ function (Zalon, 2014).

Concern that pain may reflect cancer spread or recurrence frequently leads providers to evaluate pain loci with imaging and other tests. Imaging may include plain films, MRI, bone scans, PET, CT, or some combination of these, depending on the pain distribution and quality. Focal neuropathic pain, particularly with co-occurring sensory and motor deficits, may indicate the need for nerve conduction studies and electromyography. More diffuse neuropathic pain may additionally require laboratory tests to assess for a paraneoplastic syndrome. In some cases invasive testing, including biopsy and lumbar puncture, may be needed to determine whether cancer recurrence or progression contributes to a patient’s pain. All evaluations strive to identify treatable sources of pain, rather than to inform estimates of pain intensity or its functional interference.

The post-mastectomy pain syndrome occurs more frequently in younger survivors (Tait et al., 2018). Other instances of cancer-related pain that are more common in age- or gender-defined subgroups have not been widely reported.

Cancer pain is treated by medical, radiation, and surgical oncologists. Supportive and palliative care practitioners including nurses, hospice and palliative medicine physicians, rehabilitation service providers (physical medicine and rehabilitation, physical therapists, and occupational therapists), and pain management specialists frequently contribute to pain care among cancer populations. Psychologists and social workers may be available at some centers to provide cognitive behavioral therapy, mindfulness training, and other behavioral pain management strategies. Primary care providers may coordinate pain management, with the assistance of the aforementioned professionals, among disease-free cancer survivors who

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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are no longer in regular contact with their cancer care teams (Nersesyan and Slavin, 2007).

Treatments for Pain

The treatment patterns, clinical responsibility, and team constituencies for the management of persistent pain among cancer survivors are not well defined. The shortage of oncologists (Yang et al., 2014) and a burgeoning population of cancer survivors makes it clear that there is a need to shift survivorship care from oncology to primary care clinicians. However, this shift has been operationalized with varying degrees of success, making it difficult to determine which discipline is most likely to coordinate pain care. Depending on availability, the clinical disciplines involved in the management of cancer pain may include, in addition to oncology specialties and primary care, physical and occupational therapists, physiatrists, pain management specialists, and orthopedists (Ashburn and Staats, 1999).

Medications are the most commonly used way to treat pain (Paice et al., 2016). As concern has grown about the harms associated with-long term opioid exposure, analgesic use among disease-free survivors has shifted to non-opioid analgesics such as acetaminophen, non-steroidal anti-inflammatory drugs, and topical formulations and to co-analgesics such as anti-convulsants and antidepressants with pain-relieving properties (Swarm and Dans, 2018). Rehabilitative approaches have the potential to concurrently address pain and enhance function among survivors, but reports suggest persistent under-use (Cheville et al., 2018). Interventional analgesic procedures, including local nerve blocks, neuro-axial drug delivery, and spinal cord stimulation, are therapeutic options; however, their use and effectiveness among disease-free cancer survivors is not well characterized. Reports are largely restricted to pilot studies (Karmakar et al., 2014; Wijayasinghe et al., 2016). Multimodal chronic pain management programs have been proven effective in reducing pain and opioid use among diverse clinical populations, including cancer survivors (Pollak et al., 2018). Behavioral pain management approaches, including cognitive behavioral therapy and mindfulness-based stress reduction, achieve pain relief for some patients. A growing body of evidence suggests that exercise can be effective in relieving pain. For example, three randomized controlled trials show that exercise improved outcomes for women with breast cancer who used exercise to treat their aromatase inhibitor-induced arthralgias (Arem et al., 2016; Baglia et al., 2019; Nyrop et al., 2017).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Length of Time to Improvement for Pain

The effectiveness of pain treatments may become rapidly apparent. Blocks take effect immediately, or in days to weeks if steroids or botulinum toxin are instilled, respectively. Rehabilitative therapies achieve more gradual effects, but they are generally not continued if the benefit is not apparent within 1–2 months. Medications are more variable. Opioids and non-opioid analgesics, if appropriately titrated, offer rapid benefit. Co-analgesics may require more protracted titration, but the treatment response should be evident within 2–3 months. Often analgesics are combined to capitalize on their complementary mechanisms of action. Optimizing the doses of a combined analgesic regimen may require a longer interval, though seldom more than 6 months. Opioid use in pain treatment is also discussed in Chapter 2. Patients’ responses to behavioral therapies are typically more gradual, and improvement may take 1 or more months. Multimodal pain management programs take a similar amount of time for improvement.

Data are not currently available regarding differences in responsiveness to pain management approaches across age groups. Younger women are more likely to develop post-mastectomy pain, but it remains unclear whether they are more or less likely to respond to treatment (Tait et al., 2018).

Standard Measures of Outcomes for Pain

Cancer pain among survivors is similar to other pain in that it is ultimately a subjective experience that requires reporting by the patient to assess the pain’s severity and the response to treatment. The persistence and durability of cancer pain cannot be directly associated with imaging finding or tumor markers. Although imaging is frequently used to identify cancer sites that cause pain, imaging findings may not correlate with pain intensity. Despite clear evidence that patient-reported outcomes accurately and precisely measure pain, they are not routinely captured during the care of cancer survivors, making it difficult to define an individual’s trajectory over time and thus challenging to define a length of time from start of treatment until functioning improves. Pain’s adverse effects on other QOL domains make assessment of these domains a reasonable surrogate for gauging treatment response when pain ratings are not available. Specifically, mood, sleep quality, function, and social role participation generally improve or deteriorate in parallel with pain intensity (Tavoli et al., 2008; Whibley et al., 2019). Other indicators of treatment response are the types and dosages of pain medicine that an individual consumes during a defined time interval (e.g., 1 day or 1 week).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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CANCER-RELATED FATIGUE

CRF is common among those treated for cancer, especially patients undergoing treatment with RT and chemotherapy, with an estimated prevalence of 28 percent to 91 percent (Runowicz et al., 2016). The NCCN guidelines define CRF as “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning” (NCCN, 2019h). Compared with the fatigue experienced by healthy individuals, CRF is more severe, more distressing, and less likely to be relieved by rest. An often profound but subjective sense of tiredness is a key feature of CRF, as is its interference with the usual activities of daily living (NCCN, 2019h). CRF is more common with certain malignancies such as pancreatic and breast cancer and lymphoma and is also more common during treatment (Ebede et al., 2017). While gender differences in the incidence of CRF have not been well studied, it is known that older adults report more CRF than younger adults (Butt et al., 2010; Miaskowski, 2004).

CRF is by far the most common symptom affecting people with cancer and is nearly universal in those receiving cytotoxic chemotherapy, RT, bone marrow transplantation, or a treatment with biological response modifiers. It is notoriously under-reported, under-diagnosed, and under-treated. In a survey of 1,569 patients with cancer, CRF was found in 80 percent of individuals undergoing chemotherapy or RT or both (Henry et al., 2008). In patients with metastatic disease undergoing any type of therapy the prevalence of CRF exceeded 75 percent (Curtis et al., 1991; Portenoy et al., 1994; Ventafridda et al., 1990). Moderate or severe fatigue was found in 45 percent of patients undergoing active outpatient treatment and in 29 percent of patients with complete remission from breast, prostate, colorectal, or lung cancer (Wang et al., 2014). A meta-analysis that examined 27 studies of 12,237 breast cancer survivors found that both a more advanced disease stage (II or III versus 0 or I) and chemotherapy treatment were predictors of severe fatigue (Abrahams et al., 2016).

Cancer survivors report that fatigue persists months or even years after the treatment ends (NCCN, 2019h). Persistent CRF affects the QOL, as patients become too tired to participate in daily activities that make life meaningful (Behringer et al., 2016; Crom et al., 2005; Janda et al., 2000). CRF may influence the time it takes to return to work following treatment (Islam et al., 2014). Because of the successes in cancer treatment, health care professionals are now more likely to see patients with prolonged states of fatigue related to the late effects of treatment. Disability-related issues are especially relevant and challenging for patients with cancer who

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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are cured of their malignancy and have continued fatigue (Morrow et al., 2002).

Professionally Accepted Diagnostic Criteria for Cancer-Related Fatigue

Fatigue is a subjective experience that should be systematically assessed using patient self-reports and other data sources. Because it is a symptom perceived by the patient, it can be described most accurately by self-report. Patients should be screened for the presence and severity of fatigue at their initial clinical visit, at regular intervals during and following cancer treatment, and as clinically indicated (Berger et al., 2015). There are multiple instruments available to assess fatigue in the clinical setting (NCCN, 2019h). The Visual Analogue Fatigue Scale is one such instrument that can be quick and easy to administer even in a busy clinical setting (Glaus, 1993). Patients with fatigue should be evaluated for treatable contributing conditions such as pain, depression, anxiety, anemia, sleep disturbance, nutritional deficits, cardiac dysfunction, pulmonary dysfunction, infection, etc. (NCCN, 2019h).

All members of the oncology and rehabilitation teams, including medical oncologists, oncologic surgeons, radiation oncologists, rehabilitation physicians, nurses, physical therapists, occupational therapists, social workers, and psychologists, should take an active part in screening for CRF. Physicians have the responsibility of identifying and treating conditions that can mimic or contribute to CRF such as anemia, depression, and recurrent cancer. Physical therapists, occupational therapists, and exercise physiologists are responsible for designing and optimizing exercise programs, teaching energy conservation techniques, etc. Social workers and psychologists can teach cognitive behavior techniques and other mindfulness techniques (NCCN, 2019h).

Treatments for Cancer-Related Fatigue

Managing fatigue is integral to the comprehensive management of cancer patients. An interdisciplinary approach that includes not only oncology clinicians but also practitioners from rehabilitation (physiatry, physical therapy, occupational therapy), nursing, social work, nutrition, psychology, exercise physiology, and other disciplines is often key to optimizing patient outcomes (Escalante et al., 2001; NCCN, 2019h). Multiple pharmacologic and non-pharmacologic treatments for CRF have been tested in trials. A meta-analysis of 11,525 patients in 113 studies demonstrated that nonpharmacologic interventions, specifically exercise and psychosocial interventions, improved CRF (Mustian et al., 2017).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Length of Time to Improvement for Cancer-Related Fatigue

Relatively little is known about the length of time from the start of a treatment until the person’s functioning improves to the point where CRF is no longer disabling. Studies investigating CRF have generally ranged from 4–12 weeks in duration (Bower, 2014). By contrast, CRF is well known to persist for years following treatment, with approximately 25–30 percent of patients experiencing symptoms up to 5 years or longer following the successful completion of oncologic treatment (Ebede et al., 2017).

Standard Measures of Outcomes for Cancer-Related Fatigue

As noted above, patients with CRF should be screened at regular intervals throughout cancer treatment and into survivorship. Tools such as the Visual Analogue Fatigue Scale are useful in monitoring patient improvement (Charalambous et al., 2016).

CARDIOTOXICITY

A number of cancer treatments, including anthracyclines, trastuzumab and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors, angiogenesis inhibitors, checkpoint inhibitors, and thoracic irradiation, are associated with significant cardiotoxicity (Jain et al., 2017). Cardiac problems such as heart failure, pericarditis, coronary heart disease, hypertension, arrhythmias, and valve disease can occur.

Anthracycline-based chemotherapy, specifically the use of doxorubicin, is a common component of many cancer treatment regimens and is associated with significant dose-dependent cardiotoxicity. A prospective study of 2,625 patients receiving anthracycline chemotherapy demonstrated cardiotoxicity in 9 percent, with 98 percent of the cases occurring in the first year following treatment. Only 11 percent of the patients recovered fully; 71 percent had only a partial recovery (Cardinale et al., 2015). The HER2-targeted therapy trastuzumab is also associated with cardiotoxicity. Between 0 and 4.1 percent of patients receiving trastuzumab-containing regimens experienced Common Terminology Criteria for Adverse Events (CTCAE)grade III/IV heart failure or cardiac-related death. The alkylating agent cyclophosphamide at the therapeutic dose of 170–180 mg/kg causes dose-related cardiotoxicity in 7–28 percent of patients, with 11–43 percent of them experiencing mortality (Iqubal et al., 2019). Tyrosine kinase inhibitors can cause cardiac toxicity ranging from asymptomatic subclinical abnormalities such as electrocardiographic changes and reduced left ventricular ejection fraction to life-threatening conditions such as heart failure and acute coronary syndromes (Orphanos et al., 2009). Angiogenesis inhibitors

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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such as the vascular endothelial growth factor inhibitors can cause left ventricular dysfunction, among other issues (Tocchetti et al., 2013). Multiple cases of myocarditis and fatal heart failure have been reported in patients treated with ICIs, either alone or in combination (Varricchi et al., 2017). In Hodgkin lymphoma survivors, RT to the mediastinum is well known to cause a variety of cardiac abnormalities, including coronary heart disease, valvular heart disease, heart failure, and pericarditis (Van Leeuwen and Ng, 2016). RT for breast cancer can cause coronary heart disease in a dose-dependent fashion with the risk increasing linearly as the dose to the heart increases (Jacobse et al., 2019). A variety of new radiation techniques have been developed to treat breast cancer, including deep inspiration breath hold, gating, accelerated partial breast irradiation, and the use of modern three-dimensional planning with the intention of avoiding or minimizing radiation cardiac toxicity (Yeboa and Evans, 2016).

Professionally Accepted Diagnostic Criteria for Cardiotoxicity

The evaluation and management of cancer treatment–related cardiotoxicity is an emerging field. Cardiovascular evaluation with radionuclide imaging, advanced echocardiography, and magnetic resonance imaging is helpful in the early detection of cardiotoxicity and the prevention of overt heart failure (Jain et al., 2017). There is limited evidence to guide clinical decision making with respect to the detection and management of cancer treatment–related cardiotoxicity (Conway et al., 2015). In general, medical management of the various cardiac toxicities resulting from cancer treatment follows the principles used to treat analogous disorders resulting from other etiologies.

Oncology clinicians, including medical oncologists, surgical oncologists, and radiation oncologists, as well as non-oncologic health professionals such as internists, primary care physicians and nurse practitioners, and rehabilitation physicians are instrumental in the identification of cardiac dysfunction in the cancer setting. The medical management generally falls to cardiologists, internists, or primary care physicians. Rehabilitation management is often a combination of efforts between a rehabilitation physician and some combination of physical therapists, occupational therapists, and exercise physiologists (Alfano et al., 2016).

Treatments for Cardiotoxicity

A comprehensive program of cardiac rehabilitation should include risk factor modification and patient education in addition to exercise and strengthening and psychosocial support. The effectiveness of rehabilitation for patients with coronary artery disease in the non-cancer population has been well established (Simon et al., 2018). The emergence of home-based

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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cardiac rehabilitation may improve access and availability. One study demonstrated that women with breast cancer and treatment-related heart failure who participated in a cardiac rehabilitation program had similar gains in the volume of oxygen uptake during peak exercise (VO2peak) and similar completion rates to those with coronary disease from other causes (Bonsignore et al., 2017).

Length of Time to Improvement for Cardiotoxicity

There are no data concerning the interval between the onset of treatment and functional improvement. And while cardiac disease is generally more common with advancing age (Strait and Lakatta, 2013), little is known about whether there are certain ages where improvement is more probable.

Standard Measures of Outcomes for Cardiotoxicity

The expected benefits of a comprehensive cancer rehabilitation program include improvements in exercise tolerance, skeletal muscle strength, psychological status, and QOL. Though little literature exists for patients with cardiac disease resulting from cancer treatment, it is likely that similar benefits would be conferred by cardiac rehabilitation (Bonsignore et al., 2017). Cardiotoxicity in the cancer setting is often permanent and progressive (Virizuela et al., 2019). However, cardiotoxicity due to HER2-directed agents is typically reversible (Dong and Chen, 2018).

CHEMOTHERAPY-INDUCED PERIPHERAL NEUROPATHY

Neuropathy, or peripheral neuropathy, is defined as the condition arising from the damage and dysfunction of the peripheral nerves—the motor, sensory, and autonomic nerves that connect the brain and spinal cord to the rest of the body (Stubblefield et al., 2009). CIPN is peripheral neuropathy that is caused by exposure to neurotoxic chemotherapeutic agents. It is one of the most common side effects of cancer treatment, with a prevalence of 19 percent to 85 percent (Zajaczkowska et al., 2019). In addition to the pain and functional limitations it causes, CIPN can be a major dose-limiting toxicity for many chemotherapeutic agents (Stubblefield et al., 2009).

The signs and symptoms of CIPN range from mild to disabling with significant implications for function and QOL (Stubblefield et al., 2009). Abnormal sensations including tingling, numbness, and pain are common. Weakness, difficulty with gait, and falls can occur. Patients may have trouble with the activities of daily living. Autonomic dysfunction, including bowel and bladder dysfunction and orthostatic hypotension, can be seen in the more severe cases. CIPN may not resolve; one study found that after an

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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average of 6 years following treatment, nearly half (47 percent) of women treated for breast cancer still reported CIPN (Winters-Stone et al., 2017). Among women with CIPN, those with symptoms were 1.8 times more likely to fall than those without (Winters-Stone et al., 2017).

Chemotherapeutic drugs and anticancer biologics that are frequently reported as associated with symptomatic neuropathy include platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib), and immunomodulatory drugs (thalidomide) (Argyriou et al., 2014; Zajaczkowska et al., 2019). Many of these medications (e.g., paclitaxel and cisplatin) are used to treat a variety of cancers. For most regimens, the severity of the neuropathy increases with dose and duration until the cessation of the treatment. A notable exception is the platinum agents, for which symptoms may progress for weeks to months after treatment completion—a phenomenon known as the coasting effect (Stubblefield et al., 2009). Another exception to the typical pattern of CIPN is oxaliplatin, which is unique in that two patterns have been observed: acute transient (cold-induced) and cumulative persistent (dose-limiting) neuropathy. For most drugs the symptoms of CIPN usually subside with time, although long-term sequelae can occur (Stubblefield et al., 2009).

Professionally Accepted Diagnostic Criteria for Chemotherapy-Induced Peripheral Neuropathy

The diagnosis of CIPN is generally made on clinical grounds. When patients develop the expected signs and symptoms of CIPN in the setting of a known neurotoxin, no additional investigation is generally needed. If the signs and symptoms are outside the norm in terms of clinical features, severity, or the temporal relationship to neurotoxin exposure that is expected for a given agent, then electrodiagnostic studies or appropriate laboratory investigations may be indicated (England et al., 2009). Pre-existing or emerging neuropathy from other causes, such as diabetes or B12 deficiency, and disorders that mimic CIPN, such as carpel tunnel syndrome or radiculopathy, should be excluded (Stubblefield et al., 2009). If further evaluation is warranted, the treating oncology clinician will generally request consultation with a neurologist and physical medicine and rehabilitation physician.

The primary functional issues seen in CIPN can be categorized as sensory (pain, tingling, numbness, loss of proprioceptive sense), motor (weakness), autonomic (orthostatic hypotension, bowel and bladder dysfunction, sexual dysfunction), or a combination of impaired modalities (gait dysfunction, falls, mobility issues, impaired activities of daily living). While older adults are more likely to develop CIPN, they generally report less pain and interference with activity despite having worse light touch and impairment in sensing cold and vibration (Argyriou et al., 2006; Wong et

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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al., 2019). Gender differences in the development of CIPN have not been observed. However, regional studies have found a higher prevalence of CIPN in women than in men (Molassiotis et al., 2019; Shah et al., 2018). This difference might be because gynecologic and breast cancers often receive neurotoxic chemotherapies (Zanville et al., 2016).

Because CIPN symptoms may worsen with accumulating exposure, close monitoring is necessary during chemotherapy. In severe cases, a dose reduction or treatment discontinuation may be indicated at the discretion of the treating oncologist, but this must be weighed against the oncologic risks (Stubblefield et al., 2009).

All members of the oncology and rehabilitation teams, including medical oncologists, oncologic surgeons, radiation oncologists, neurologists, rehabilitation physicians, nurses, physical therapists, and occupational therapists, should take an active part in screening for signs and symptoms of CIPN. Physicians have the responsibility of identifying and treating conditions that can mimic or contribute to CIPN such as diabetic neuropathy, lumbar polyradiculopathy, and carpal tunnel syndrome, among others. Physicians can also treat neuropathic and other pain disorders with medications, injections, and other modalities. Physical therapists can design custom programs to improve balance, gait, transfers, endurance, and other capabilities with the goal of improving function and QOL. Occupational therapists can improve hand dexterity, coordination, and the ability to perform the activities of daily living (Stubblefield et al., 2009).

Treatments for Chemotherapy-Induced Peripheral Neuropathy

The treatment of neuropathy is based on the functional issues present. There are no medications to treat motor abnormalities, but pain and other positive neuropathic symptoms (paresthesias, dysesthesias, allodynia, etc.) may improve with certain medications. A comprehensive outpatient assessment by a physician knowledgeable in the evaluation and management of neuropathy should be done to exclude contributing medical issues. The prescription of physical therapy or occupational therapy to improve strength, mobility, gait, and participation in the activities of daily living is indicated unless a safety issue precludes it. Various pharmacologic agents have been evaluated in the prevention and treatment of CIPN. Drugs that have been approved by FDA have been approved largely based on their efficacy in reducing pain and producing other positive neuropathic symptoms in diabetic neuropathy and post-herpetic neuralgia. With the exception of duloxetine, most clinical trials on the use of medications to prevent or treat CIPN have failed to yield positive findings (Majithia et al., 2016; Smith et al., 2013). To date, no agent has been approved specifically for treating CIPN (Stubblefield et al., 2009). Table 3-14 lists the medications

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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TABLE 3-14 Common Agents for Pain Management in Neuropathy

Drug Starting Dose Titration Maximum Dose Duration of Adequate Trial Potential Side Effects
Duloxetine 20–30 mg/day No evidence that higher dose is more effective 120 mg/day 2 weeks Nausea, xerostomia, constipation, diarrhea
Gabapentin* 100–300 mg nightly or 100–300 mg 3 times/day Increase by 100–300 mg 3 times/day, every 1–7 days 3,600 mg (depending on absorption) 1–2 week at max tolerated dose Somnolence, dizziness, GI symptoms, mild edema, cognitive impairment (elderly), exacerbation of gait problems
5 percent lidocaine patch Maximum of three patches daily Non-applicable Three patches 2 weeks Rash/erythema
Opioids (oxycodone, morphine, methadone) 5–15 mg every 4 hours Convert to long-acting after 1 week, ti-trate based on breakthrough use No ceiling effect 4–6 weeks Constipation, nausea, vomiting (self-limited), sedation, confusion, respiratory depression
Pregabalin 25–50 mg 3 times/day Increase by 50 mg/dose after 1 week 200 mg 3 times/day Unclear (likely 2–4 weeks) Dizziness, somnolence, xerostomia, edema, blurred vision, decreased concentration
Tramadol 50 mg 1–2 times/day Increase by 50–100 mg/day, individual doses every 3–7 days 400 mg/d (100 mg 4 times/day); elderly 300 mg/day 4 weeks Dizziness, constipation, nausea, somnolence, orthostatic hypotension, increased risk of seizure, serotonin syndrome
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Drug Starting Dose Titration Maximum Dose Duration of Adequate Trial Potential Side Effects
Tricyclic antidepressants (amitriptyline,* nortriptyline,* desipramine) 10–25 mg nightly Increase by 10–25 mg every 3–7 days 75–150 mg; may increase if blood level of drug plus metabolite <100 ng/mL 6–8 weeks; 1–2 weeks at max dose Cardiovascular disease (needs screening), anticholinergic effects, interact with drugs metabolized by cytochrome P450 2D6 (e.g., cimetidine, phenothiazine)

NOTES: *Negative results in randomized controlled clinical trials on chemotherapy-induced peripheral neuropathy. GI = gastrointestinal.

SOURCE: Stubblefield et al., 2009. Reproduced with permission.

commonly used off-label to relieve pain and produce positive neuropathic symptoms in CIPN.

Length of Time to Improvement for CIPN

The length of time from the start of a treatment to when functioning improves to the point of which the condition is no longer disabling has not been defined for CIPN. The duration of intervention and assessment in pain treatment studies ranges from 1–8 weeks. Physical therapy intervention durations of 6 weeks have been reported for CIPN, but the time is likely to vary significantly depending on the patient’s needs (Kleckner et al., 2018). Signs and symptoms of CIPN can persist for years or indefinitely in many patients (Winters-Stone et al., 2017).

Standard Measures of Outcomes for CIPN

Pain associated with CIPN can be assessed over time using a visual analog scale for pain. Patient-reported outcome measures such as the Karnofsky Performance Scale (KPS) or the CTCAE are commonly used to assess patient function (Kaplow and Iyere, 2017; Miaskowski et al., 2018).

LYMPHEDEMA

Lymphedema is a late or long-term side effect of cancer that is caused by the compromise of lymph nodes or vessels during cancer treatment. The

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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condition is characterized by progressive swelling of one or more body parts. Lymphedema is incurable but can be indefinitely managed with treatment. Left untreated, lymphedema tends to progress leading to pain, disability, and medical morbidities, including recurrent cellulitic infections and unhealing wounds. The progression is due to the accumulation of proteinaceous debris in the interstitium, which in turn sequentially produces inflammation, scarring, and worsened lymphatic obstruction. As lymphedema progresses, it is marked by the enlargement and eventual hardening (keratinization) of the affected tissues. Lymphedema-related functional loss might impede the ability to work for some patients, depending on the affected body parts, the patient’s occupation, and the severity. For example, an inability to stand for extended periods without exacerbating the condition may severely restrict the employment options of patients with leg lymphedema. Additionally, patients who develop recurrent cellulitis may be unable to hold jobs due to frequent and unplanned medical absences.

While many factors have been associated with the onset and progression of lymphedema, the surgical removal and irradiation of lymph nodes to stage or locally control cancer are its principal cause in the context of cancer treatment (Armer et al., 2019; Nguyen et al., 2017; Rockson, 2018). Cancer survivors develop lymphedema in predictable distributions based on the location and degree of their lymphatic compromise. Because specific lymph node beds are commonly targeted in the treatment of particular cancers, lymphedema occurs in consistent distributions among survivors of breast, prostate, and gynecologic cancers as well as melanoma, lymphoma, and some sarcomas. Secondary lymphedema is also a frequent late effect in patients with head and neck cancer (Deng et al., 2012, 2019; Smith et al., 2015). For example, patients treated for melanoma of the legs typically undergo removal of their inguinal lymph nodes, which places them at risk for lymphedema of the leg and of the external genitalia. The degree to which lymphedema conforms to an anticipated distribution based on cancer type has prognostic significance. Swelling outside the implicated lymph drainage territory suggests an alternative, possibly systemic, etiology and a lower likelihood of response to lymphedema therapy (Sleigh and Manna, 2019).

The current understanding of cancer-related lymphedema’s natural history derives largely from observational studies of patients with breast cancer. This subgroup has proven conducive to study because they are numerous and generally have an uninvolved upper extremity for comparison. Incidence rates vary contingent on the lymphedema diagnostic criteria and cancer treatment specifics, ranging from 5 percent, after sentinel node procedures to as high as 25–40 percent following full axillary dissection with radiation (Armer and Stewart, 2005; Norman et al., 2009). Robust reports suggest that lymphedema develops within 3 years of breast cancer

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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treatment, with a majority of patients presenting by 2 years (Garza et al., 2017; Norman et al., 2009). Some patients develop lymphedema during cancer treatment, but for many acute swelling occurs only transiently after surgery, if at all.

Incidence rates also vary by the type and extent of cancer treatment, with the use of radiation and the number of lymph nodes surgically removed being principal risk factors. Many patients (e.g., those with gynecologic and prostate cancers) have undergone removal of their pelvic lymph nodes and are therefore at risk for lymphedema involving both legs, their lower trunks, and genitalia. Accelerated lymphedema progression in legs versus arms is due to the increased demands of vertically transporting metabolic waste from the large lower extremity muscle groups against gravity (Vagas and Ryan, 2003).

Functional morbidity associated with lymphedema following cancer treatment varies considerably and depends on a host of factors. Research has not yet identified lymphedema characteristics that are consistently associated with functional morbidity. As a consequence, the current understanding that late-stage lymphedema is more functionally morbid derives from anecdotal clinical experience. Lymphedema of the lower extremities, because of its more rapid progression to advanced stages, causes a higher frequency of cellulitis, wounds, and other morbidities and is therefore assumed to be more disabling. Patients with comorbid vascular insufficiency or obesity are also more likely to develop morbid, late-stage lymphedema and, presumably, disability.

Professionally Accepted Diagnostic Criteria for Lymphedema

Symptoms of heaviness and aching characterize the initial onset of lymphedema, particularly following activity. The symptomatic period that precedes objective swelling is referred to as stage 0 lymphedema and may be exceedingly brief or prolonged. The eventual appearance of soft-tissue swelling indicates progression to stage 1 lymphedema. The swelling initially fluctuates, often with transient periods of complete resolution. It is common for lymphedema to involve limited portions of an affected extremity or body part. Breast cancer–related lymphedema of the arm, for example, often involves the dorsum of the hand and tissue around the elbow with relative sparing of the intervening areas. Ultimately, swelling becomes constant and progresses to stage 2 lymphedema. The transition from stage 1 to stage 2 indicates the presence of subdermal fibrosis and scarring and can be discerned by the presence of rubbery tissue deposits that do not alter with changes in swelling. Progression to stage 3, the most advanced, is characterized by keratinized, thickened skin, often appearing first over the most involved portions of a limb (Sleigh and Manna, 2019).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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The hallmark of lymphedema is the presence of enlarged or redundant soft tissue overlying the affected body part and associated with skin changes and symptoms of heaviness and aching. Because limb volume is relatively straightforward to measure, volume measurements are a principal means by which lymphedema may be diagnosed. However, absent pre-treatment volume measurements that allow for an estimation of change over time, reliance on volume as a sole diagnostic criterion may lead to under-diagnosis. A physical examination by an experienced clinician to screen for changes in tissue texture, pitting, deviation from normal limb contour and architecture, and thickening and hardening of the skin, also referred to as dermal metaplasia, is arguably the most accurate means of diagnosis. Diagnostic testing may include evaluations to identify alternative causes of swelling such as venous obstruction and insufficiency. Lymphoscintigraphy to assess lymph flow is the most widely available means of assessing lymphatic function. An abnormal lymphoscintigram confirms lymphedema in most cases.

A higher proportion of women develop cancer-related lymphedema, principally because they develop cancers (i.e., breast and gynecological) whose treatment involves lymph node removal. There is currently no evidence of a gender difference in lymphedema incidence among patients for head and neck cancer or melanoma, malignancies whose treatment also requires lymph node removal. The age of lymphedema onset is tightly linked to the age of the cancer diagnosis. Some reports have associated advanced age with lymphedema risk, but this finding has not been consistent.

Lymphedema treatments are most often delivered by certified lymphedema therapists and physical therapists with lymphedema therapy training. Ideally these individuals should have undergone training and received certification from the Lymphology Association of North America. Physicians may participate in lymphedema management, but specialists are few and generally situated at specialty centers. Most often, the physician’s role is restricted to excluding diagnoses that can mimic lymphedema, confirming a diagnosis of lymphedema, and referring patients to therapy. Because lymphedema receives scant attention in medical training, physicians may be unaware of the importance of identifying therapists with complex decongestive therapy (CDT) training (Garza et al., 2017). A positive notation of lymphedema in a physician’s documentation is generally an accurate reflection of the diagnosis. However, an absence of mention or a negative mention does not necessarily rule out a diagnosis of lymphedema. Primary care physicians, physical medicine and rehabilitation physicians, and vascular surgeons as well as cancer care providers may oversee lymphedema management. Some medical centers have survivorship clinics staffed by cancer care providers, internists, and advanced practice providers, among other clinicians who participate in lymphedema detection and treatment. Apart from lymphedema therapists and physical therapists, clinicians do

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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not generally administer lymphedema treatments. Plastic surgeons who perform lymphovenous bypass and vascularized lymph node transplant surgeries are an exception (Garza et al., 2017).

Treatments for Lymphedema

Lymphedema can be managed but not cured (Shaitelman et al., 2015). The current international standard of care is a two phase treatment system that involves reduction (phase 1) and maintenance (phase 2), which is referred to as complete or complex decongestive therapy. When it is detected early, survivors’ lymphedema may only require maintenance care. Maintenance generally involves the daytime use of compression garments of appropriate type, size, and pressure. Because such garments are not consistently covered by federal and commercial payers, many patients either go without or replace their garments infrequently. Survivors who are initially diagnosed with advanced lymphedema require initial intense lymphedema therapy (i.e., complete decongestive therapy [phase 1]). Although it is remarkably effective when delivered at optimal intensity (1–2 times daily for up to 2 weeks), reductive CDT treatment commonly occurs at less frequent intervals, often only twice per week for up to 4–8 weeks. Therefore, while lymphedema, irrespective of the body part, improves with guideline-concordant treatments, these are not available to a majority of patients. Treatment should also include cellulitis prevention, which is done by reducing microbial skin growth, and, in case of recurrent infections, antibiotic prophylaxis. Various types of pneumatic pumps have been used as adjuncts to CDT. Their use as sole treatment is generally regarded as inappropriate and inferior to CDT. However, pumps may improve CDT outcomes for some patients when used as adjunctive treatments (Aldrich et al., 2017; Szuba et al., 2002). Exercises done against resistance to improve muscle bulk and quality in the affected territory are also a common adjunct.

At present medications are not indicated in the treatment of lymphedema. Diuretics are commonly prescribed to patients, particularly with lower extremity lymphedema, but their use is not guideline endorsed or evidence based. Several microsurgeries, including lymphovenous bypass and vascularized lymph node transplant, have gained traction over the past decade as a means of further temporizing lymphedema. These surgeries do not necessarily cure lymphedema or obviate the requirement that patients wear compression garments (Garza et al., 2017). Long-term surgical outcomes are currently being studied, and these surgeries are not endorsed by current guidelines (Garza et al., 2017).

Lymphedema treatments are most often delivered at physical therapy and occupational therapy facilities, which may or may not be affiliated with larger health systems. Increasingly, oncology care providers are mandated

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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to ensure that patients are able to access rehabilitation services (Silver et al., 2018). However, it is not yet clear whether this will lead to an increase in their onsite provision of lymphedema services. Plastic surgeons who perform lymphedema surgeries are often situated in large medical centers to ensure sufficient volume for their specialty practices.

Cancer survivors are identified for treatment through various routes. Some cancer centers screen for lymphedema using volume measurements or patient-reported outcomes, but this is not a standardized practice. Patients with cancer are increasingly educated about the possibility of developing lymphedema. As a consequence, many self-refer to lymphedema specialists if they note swelling or else bring the swelling to the attention of their primary or oncological care teams.

Length of Time to Improvement for Lymphedema

Volume reduction typically occurs rapidly, over 2–4 weeks, when CDT is appropriately administered at adequate frequency, once to twice daily. The resolution of dermal keratinization and interstitial fibrosis typically lag, but some improvement should be expected within 2–4 weeks of initiating appropriate CDT.

Standard Measures of Outcomes for Lymphedema

Treatment response is typically monitored using changes in limb volume, estimated either by a formula that incorporates serial limb circumference measurements or by optoelectric or water displacement volumetry (Deltombe et al., 2007). Bioimpedance is used to detect and assess lymphedema of the arms and, more recently, the legs. However, the cost of the necessary equipment has been an impediment to broad uptake. A physical examination to characterize normalization of limb contour, improvements in tissue texture, and resolution of dermal metaplasia is essential to a comprehensive assessment. A physical examination may additionally evaluate improvements in wounds, lymphorrhea (seepage of lymph through intact skin), and microbial skin colonization. An additional marker of treatment response is the frequency of cellulitic infections, which should reduce with effective therapy (Al-Niaimi and Cox, 2009).

Several patient-reported outcomes have been validated to assess the function and QOL in individuals with lymphedema. However, their use has, similarly, not been mainstreamed. When available they may reflect treatment success or failure. Generic and cancer-specific patient-reported outcomes, which are routinely collected in some oncologic and rehabilitation practices, evaluate domains (e.g., pain and function) that may improve with lymphedema treatment. Absent lymphedema-specific tools,

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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these patient-reported outcomes may help to clarify whether a patient has improved with treatment.

PULMONARY DYSFUNCTION

Chronic lower respiratory disease is the fourth-leading cause of death in the United States behind heart disease, cancer, and unintentional injuries (Murphy et al., 2018). Because of this high prevalence, pre-existing pulmonary disease is present in many cancer patients and may develop or worsen during treatment and survivorship. Lung cancer is the second most common cancer for both men and women and the leading cause of cancer-related death for both sexes (ACS, 2019b). Additionally, the lungs are a primary site for metastatic disease. Lung metastases can be seen in 57–77 percent of breast cancer patients and nearly half of colorectal cancer patients who succumb to their disease (Kindler and Shulman, 2001).

A number of cancer treatments can cause pulmonary dysfunction with severity ranging from mild to life threatening (Stubblefield, 2018). Toxicity includes bronchospasm, interstitial lymphocytic or eosinophilic pneumonitis, non-cardiogenic pulmonary edema due to increased vascular permeability, and late pulmonary fibrosis. The time course of toxicity is generally divided into early (immediate to 2 months after therapy) and late (2 or more months following completion of chemotherapy) (Garipagaoglu et al., 1999). The best known cause of pulmonary fibrosis is bleomycin, which causes toxicity in about 10 percent of treated patients with a mortality rate of 1–2 percent (Abid et al., 2001). Tyrosine kinase inhibitors, a relatively new treatment modality for many cancers, are associated with pulmonary toxicity with an incidence ranging from 0.2 percent to 10.9 percent (Peerzada et al., 2011). RT can cause extrinsic (kyphoscoliosis, chest wall fibrosis, phrenic nerve paralysis) or intrinsic lung disease. Acute radiation-induced lung injury manifests as radiation pneumonitis. Radiation pneumonitis develops in approximately 5–15 percent of patients who receive high-dose radiation for lung cancer and in 10–20 percent of individuals receiving chest radiation for other tumors (Garipagaoglu et al., 1999; Roach et al., 1995). Late radiation-induced lung injury typically presents as pulmonary fibrosis (Hanania et al., 2019). The incidence of serious radiation-induced pulmonary complications has decreased secondary to advances in radiation delivery techniques. An understanding of the relationship between when and how radiation was delivered and the clinical manifestations will help distinguish radiation-induced injury from other etiologies. The treatment of acute pneumonitis is dependent on its clinical severity, and it typically responds completely to corticosteroids. Identifying and effectively treating patients who may progress to fibrosis remains a challenge (Hanania et al., 2019).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Professionally Accepted Diagnostic Criteria for Pulmonary Dysfunction

The diagnosis of cancer and treatment-related pulmonary dysfunction is initially based on the patient’s history, symptoms, physical examination, and diagnostic testing. An evaluation of blood gases is useful in assessing oxygen and carbon dioxide levels. Imaging, such as chest X-ray and CT, is often helpful for identifying tumors, effusions, and fibrosis. Pulmonary function tests are a non-invasive method of testing such lung functions as volume, capacity, flow rates, and gas exchange, facilitating the diagnosis of obstructive and restrictive disorders. Bronchoscopy allows for a direct visualization and biopsy of lung tissue (NCCN, 2019g).

Oncology physicians, including medical oncologists, surgical oncologists, and radiation oncologists, as well as non-oncologic physicians such as internists, primary care physicians, and rehabilitation physicians, are instrumental in the identification of pulmonary dysfunction in the cancer setting. The medical management of pulmonary dysfunction generally falls to pulmonologists, internists, or primary care physicians. Rehabilitation management is often a combination of efforts between a rehabilitation physician and some combination of physical therapists, occupational therapists, and exercise physiologists.

Treatments for Pulmonary Dysfunction

The treatment of cancer and treatment-related pulmonary disease varies considerably by type. A pulmonologist with knowledge and experience in evaluating and managing such complications is generally best equipped to help cancer survivors achieve optimal outcomes. Pulmonary rehabilitation (PR) is an evidence-based, multidisciplinary comprehensive exercise program designed to benefit patients with symptomatic chronic respiratory dysfunction (Rivas-Perez and Nana-Sinkam, 2015). The goal of PR is to optimize pulmonary function and improve a patient’s ability to function despite the disease. PR integrates education and exercise that is individualized to the patient’s needs. A standard protocol for PR includes three 30-to 90-minute sessions per week of aerobic exercise and strength training carried out for 6–8 weeks. Training modalities may include a treadmill, a stationary bicycle, NU-Step, upper body resistance training, and training in breathing techniques. Evidence suggests that PR is safe and effective before, during, and after lung cancer treatment (Rivas-Perez and Nana-Sinkam, 2015). While PR has been found to improve exercise capacity and QOL in idiopathic pulmonary fibrosis patients, the benefits of PR in radiation-induced pulmonary fibrosis have not been well evaluated (X. Yu et al., 2019).

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Length of Time to Improvement for Pulmonary Dysfunction

The length of time from the start of treatment for cancer and treatment-related pulmonary disease to where a patient’s functioning improves to the point where the condition is no longer disabling has not been specifically evaluated. In many cases, pulmonary disease resulting from cancer and its treatment is permanent and progressive.

Standard Measures of Outcomes for Pulmonary Dysfunction

Pulmonary function tests provide an objective measure of pulmonary function that can be monitored over time. Patients’ self-reports of overall function can be measured with the KPS. The CTCAE is also often used by oncologists to monitor patient pulmonary function.

COGNITIVE DYSFUNCTION

CD is a common consequence of cancer and its treatment. CD is often the presenting symptom of a brain tumor (Ozawa et al., 2018). More than 90 percent of patients with gliomas will demonstrate significant cognitive deficits in at least one domain (Tucha et al., 2000). CD can result from direct brain involvement by primary CNS lymphoma, brain metastases, or leptomeningeal disease. In addition, neurologic complications associated with brain cancer, including seizures, increased intracranial pressure, hydrocephalus, and stroke, can cause CD.

It is widely accepted that cancer treatments can also result in CD. The overall incidence of CD in cancer survivors without central nervous system involvement, including breast, prostate, cervical, and colorectal cancers, ranges from 17–75 percent (Jean-Pierre and McDonald, 2016). CD in cancer survivors was previously thought to be caused by psychological distress or by cancer side effects such as fatigue because chemotherapy was not believed to cross the blood–brain barrier. However, recent evidence controlling for psychological factors and cancer side effects—and, more recently, functional neuroimaging studies—have found evidence for persistent cognitive changes following chemotherapy and other forms of cancer treatment (Ahles and Saykin, 2007). This phenomenon is known colloquially as “chemo brain.” RT is also well known to cause CD (Wilke et al., 2018).

Attention, memory, and executive functioning are the most frequently identified cognitive domains affected by cancer and its treatment (Pendergrass et al., 2018). Cognitive symptoms have a profound impact on function, independence, and QOL and are often cited by patients and caregivers as having the greatest negative impact on QOL when compared with physical or other neurologic symptoms.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Professionally Accepted Diagnostic Criteria for Cognitive Dysfunction

Following the exclusion and treatment of medical causes of CD, neuropsychological evaluation is helpful in identifying CD, assessing its severity, and determining the specific impairments so that treatments can be targeted effectively.

All members of the oncology and rehabilitation teams, including medical oncologists, oncologic surgeons, radiation oncologists, rehabilitation physicians, nurses, physical therapists, occupational therapists, social workers, and psychologists, should take an active part in screening for CD. Physicians have the responsibility of identifying and treating conditions that can mimic or contribute to CD, such as cerebrovascular disease, dementia, depression, and brain metastases, among others. Neuropsychologists and others can perform detailed neurocognitive assessments. Rehabilitation programs designed to adapt to cognitive deficits can be performed by neuropsychologists, occupational therapists, speech language pathologists, and social workers.

Treatments for Cognitive Dysfunction

A cognitive rehabilitation program is intended to enhance patients’ neurocognitive functioning, specifically their memory, attention, language, visuospatial, and executive function abilities (Weller et al., 2014). Cognitive behavioral therapy and neuropsychological/cognitive training may help improve symptoms of CD in cancer survivors (Fernandes et al., 2019; Sleight, 2016). In addition to neuropsychologists, occupational therapists and speech language pathologists are often trained to evaluate and treat CD in cancer survivors.

Length of Time to Improvement for Cognitive Dysfunction

The time from initiation of treatment until persons with cancer or treatment-related CD improve to where they are no longer disabled has not been defined. Cognitive rehabilitation programs generally run for several weeks and, although generally helpful, might not return a cancer survivor to their pre-treatment level of cognitive functioning.

Standard Measures of Outcomes for Cognitive Dysfunction

A variety of neurocognitive assessments are available to assess improvement or deterioration of cognitive function in cancer survivors (Lange and

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Joly, 2017). Cognitive functioning can be assessed objectively with cognitive tests and subjectively with self-report questionnaires. Cognitive complaints can be assessed by the FACT–Cognitive Function questionnaire, which was developed from interviews with expert clinicians and oncology patient focus groups. The International Cognition and Cancer Task Force recommends using some neuropsychological tests that assess the most objective impaired cognitive domains in patients with cancer. However, in practice these tests are rarely able to establish the differential diagnosis between chemotherapy-related cognitive impairment and neurodegenerative disease (Lange and Joly, 2017). Another instrument to measure CD is the physician-reported Everyday Cognition scale (Oh, 2017); this questionnaire has been validated for use in the assessment of dementia, and is not commonly used in cancer research and practice (Farias et al., 2011).

NEW AND DEVELOPING CANCER TREATMENTS

The development of anticancer drugs has changed radically from designing chemotherapies to maximize damage to cancer cells to developing therapeutics based on our greater understanding of tumor biology. Current strategies hope to remove the basic function of the cancer cells while sparing normal cells and limiting toxicities. New approaches for drug discovery now involve immunomodulatory agents and drugs that target proliferation, angiogenesis, and growth-signaling pathways as well as targeted therapies that can be used as single agents or in combination with chemotherapeutic agents and RT (Ramaswami et al., 2013). The most recent advances in cancer treatment now involve genetic profiling, targeted medicine, and immunotherapy. Contemporary tumor profiling techniques tend to be in the area of “precision” or “personalized” medicine.

Precision Medicine

Breakthroughs in technology have dramatically improved our understanding of many molecular etiologies of cancer, including genomic, transcriptional, proteomic, and epigenetic aberrations and immune mechanisms. This research has led to the concept of “precision medicine” based on a personal approach to treatment. Precision medicine, also known as “personalized medicine,” allows oncologists to select treatments that are most likely to help patients based on a genetic understanding of their disease (NCI, 2019c). Specific treatments are designed to individualize care using the genetic changes in a patient’s own tumor.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Genetic Therapy

Genomic profiling is increasingly used in the management of cancer. One of the first studies to use personalized medicine for treating cancer was the IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy) study, a precision medicine program at the University of Texas MD Anderson Cancer Center for patients with advanced cancer (ASCO, 2018). The approach involves the use of tumor molecular profiling and treating patients with matched targeted therapy. Results have been encouraging in terms of the rates of response, progression-free survival, and overall survival compared with non-matched therapy (Tsimberidou, 2017; Tsimberidou et al., 2017). Using next-generation sequencing to profile the tumor, the therapy can be optimized to provide treatment for patients with difficult-to-treat cancers. In the IMPACT study, the targeted therapy resulted in slower cancer growth and prolonged survival across a diverse set of cancer types, including gastrointestinal cancer, gynecologic cancer, breast cancer, melanoma, lung cancer, and thyroid cancer (ASCO, 2018).

Although treatment for breast cancer has evolved significantly in the past several decades, gene therapy has emerged as a promising treatment strategy as research has explored the possibility of correcting defective genes and modulating gene expression (McCrudden and McCarthy, 2014; Stoff-Kahlili et al., 2006). In a review of gene therapy’s potential to affect breast cancer research, Bottai and colleagues (2017) noted that further efforts will be required to increase the clinical application of RNA interference-based therapeutics, especially in combination with conventional treatments. Innovative strategies, including genome editing and stem cell-based systems, may contribute to translating gene therapy into clinical practice. Major challenges involving safety, the efficiency of delivery systems, immunogenicity, and functionalization must still be overcome before considering gene therapy as a concrete option for the treatment of cancer patients.

Targeted Therapy

Research in the field of targeted therapy has most frequently involved a very specific tumor type identified for a very specific treatment. For example, targeted therapies for NSCLC have included the gene for EGFR. Therapies targeting genes including EGFR have consistently demonstrated improved response rate (56–83 percent) and progression-free survival (9–14 months) than standard chemotherapy in patients with advanced disease (Maemondo et al., 2010; Mitsudomi et al., 2010; Sequist et al., 2013). It has been suggested that targeted therapies could be used as single agents or, in some cases, in combination with chemotherapeutic agents and RT

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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(Ramaswami et al., 2013). Ultimately, access to molecular testing and treatment will be the key to realizing the benefits of precision oncology—the premise that treatment choices tailored to individual patients using personalized cancer genomic data may markedly improve outcomes—at a population level (Del Rivero et al., 2016).

To address some of the limitations of targeted gene therapy, including its high toxicity and high cost as well as the genetic heterogeneity of tumors that can lead to drug resistance, efforts have been made to identify broad-spectrum therapies (Block et al., 2015). This involves the development of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. While still in development, approaches using natural products and phytochemicals may play an important role in integrative oncology to improve patients’ QOL as well as their lifespan.

Immunotherapy

Immunotherapy, which was briefly described earlier as it is becoming a more common practice, refers to a biological treatment (using substances made from living organisms to treat cancer) that helps an individual’s own immune system fight cancer (NCI, 2019d). These treatments can either help the immune system attack cancer directly or stimulate the immune system in a more general way. The National Cancer Institute lists several types of immunotherapies:

  • Checkpoint inhibitors are drugs that work by releasing the “brakes” that are keeping T cells (lymphocytes that play a central role in immune response) from killing cancer cells, thus interfering with the ability of cancer cells to avoid immune system attack.
  • Adoptive cell transfer attempts to boost the natural ability of T cells to fight cancer. T cells are removed from a tumor, and the most aggressive ones are grown in the lab to be returned to the patient as an active agent.
  • Monoclonal antibodies, also known as therapeutic antibodies, are immune system proteins produced in the lab. These antibodies are designed to attach to specific targets found on cancer cells. Some monoclonal antibodies mark cancer cells so that they will be better seen and destroyed by the immune system, and this is a type of immunotherapy. Other monoclonal antibodies that are used in cancer treatment do not cause a response from the immune system. Such monoclonal antibodies are considered to be targeted therapy, rather than immunotherapy.
Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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  • Treatment vaccines, which work against cancer by boosting one’s immune system’s response to cancer cells. Treatment vaccines are different from the ones that help prevent disease.
  • Cytokines, primarily interferons (IFNα, IFNβ, and IFNγ) and interleukins (ILs), are proteins that enhance the immune system’s ability to respond to cancer. IFNα and IFNβ are involved in innate immune response and increase the resistance of normal cells to natural killer cells and make cancer cells more vulnerable to killing by cytotoxic T cells. Interleukin-2 (IL-2) stimulates activity of T cells to enhance their antitumor activity (Chemoth.com).

Immunotherapy, particularly antibody-based treatments, has revolutionized the medical approach to NSCLC therapies for a small number of individuals with curable disease (Corrales et al., 2018; Guillon et al., 2017; Somasundaram and Burns, 2017). Since the first monoclonal antibody was approved in the mid-2000s (Sandler et al., 2006), new therapies have continued to emerge, improving survival for patients (Guillon et al., 2017). In November 2016 the results of the KEYNOTE-024 trial showed for the first time the superiority of immunotherapy over chemotherapy as a first-line treatment for NSCLC (Reck et al., 2016). In this phase 3 trial, a humanized monoclonal antibody against programmed death was tested in patients who had previously untreated advanced NSCLC. The clinical trial was stopped by the safety monitoring committee on the basis of the substantial clinical benefit of the immunotherapy. In addition, two classes of ICIs have been found to be effective against a variety of malignancies (Schvartsman et al., 2016). Another type of drug that shows promise, CAR-T cell therapy, takes the adoptive cell transfer approach. Until recently, the use of CAR-T cell therapy has been restricted to small clinical trials of patients with advanced blood cancers. These therapies have had remarkable responses in patients for whom other treatments proved ineffective. In 2017, two CAR T-cell therapies were approved by FDA—one for adults with advanced lymphomas, and another for children with acute lymphoblastic leukemia (NCI, 2019d).

Immunotherapies have also been shown to be effective in treating melanomas, including disseminated melanoma for which there is currently no single or combination chemotherapy that has been shown to prolong survival. Several studies have found ICIs, particularly the CTLA-4 and PD-1 blocking antibodies, to act by blocking an innate negative regulation of T-cell activation and response, allowing the immune system to attack the tumor, although serious toxicities may occur (Hodi et al., 2010; Larkin et al., 2015; Robert et al., 2015a,b). As there is growing evidence that tumor mutational burden is a strong independent predictive factor for the efficacy of immunotherapies (Hugo et al., 2016; McGranahan et al., 2016;

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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Snyder et al., 2014), researchers are now addressing the effect of immunotherapy regimens in patients with melanoma with specific germlines such as CDKN2A mutations (Helgadottir et al., 2018). Other strategies have been to combine ICIs to improve melanoma outcomes (Khair et al., 2019). Similarly, combining immunotherapies with targeted therapies has also been recommended (C. Yu et al., 2019).

Recent advances in immunotherapies, specifically checkpoint-based treatments, have also been made in breast cancer, especially in difficult to treat types. In 2018, the results of the IMpassion130 trial showed a substantial overall survival benefit in patients with PD-L1-positive (PD-L1+) metastatic or inoperable locally advanced triple-negative breast cancer through the addition of the anti-PD-L1 agent atezolizumab to first-line chemotherapy (Schmid et al., 2018).

FDA has approved several new immunotherapies for use in cancer patients in the past year, including atezolizumab combination for lung cancer and triple-negative breast cancer, and pembrolizumab for head and neck cancer, first-line treatment of lung cancer, and pre-surgical treatment for advanced melanoma (CRI, 2020). The success of precision medicine to date provides the promise of strategies to come that will increase response, remission, survival, and QOL for cancer patients.

VARIATIONS IN TREATMENT RESPONSE

The response to treatments and the periods of disability caused by cancer progression or by toxicities of cancer treatment will differ considerably by cancer site, cell subtype, treatment, and individual characteristics. Some patients with cancer will die quickly with a short period of disability. Others will experience disability associated with their treatment or go into remission and not experience symptoms for some period of time. As an example of variation by cancer site, thyroid cancers and skin cancers were given as examples of cancers in the committee’s Statement of Task but were not among the committee’s selected cancers as they are unlikely to be disabling. Studies show a very low risk of disabling effects for patients with thyroid cancer, a recurrence rate of less than 1 percent, and a low chance of needing treatment. In fact, a paper published by Nikiforov et al. in 2016 recommended renaming “thyroid cancer” to “noninvasive follicular thyroid neoplasms with papillary-like nuclear features.” Most people with melanoma, the most disabling type of skin cancer, are cured by their initial surgery. Invasive melanoma accounts for 1 percent of all skin cancers diagnosed (ACS, 2019c). Nonmelanoma skin cancer, also known as keratinocyte carcinoma (KC), is the most common type of skin cancer. The incidence of KC is difficult to estimate because cases are not required to be reported to cancer registries. Almost all cases of KC can be cured (ACS,

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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2019c). On the other hand, metastatic pancreatic adenocarcinoma is highly lethal and disabling, and was not among the committee’s selected cancers as it is unlikely to improve with treatment. Few effective treatments exist for this malignancy, and many patients die within 5 years of diagnosis (Rossi et al., 2014).

Importantly, the originating organ system of the cancer often does not predict the amount or duration of disability an individual patient should experience. Within cancers of a specific organ system, there are differences by specific cancer cell type and by cancer stage. For example, triple-negative2 invasive breast cancer is much more aggressive and has lower survival rates than other invasive breast cancer cell types. Another example is that although most thyroid cancer is detected at an early stage and the long-term survival is high, anaplastic thyroid cancer is very aggressive with limited treatment options and thus results in a short life expectancy. Other causes of variance are the different treatments available for each cancer and the fact that patients react differently to available treatments for a variety of reasons.

Newer, more effective treatments in the paradigm of precision medicine work on specific subsets of cancer with genomic alterations not shared by all cancers of that category. Three to 5 percent of all NSCLC carry an ALK gene mutation and respond to a targeted agent crizotinib. The committee considered new treatments that may improve life expectancy and functioning. These treatments result in sustained benefit for only a subset of patients.

Variation in Treatment Response by Age

The committee’s Statement of Task included an item on “specific ages where improvement is more probable” for the treatments discussed. There is a small literature documenting differences in response to cancer treatment by age. This section describes the few studies that the committee identified related to this topic. One therapy that does show variation in response by age is immunotherapy, which is not surprising, given that aging is associated with profound changes to the immune system (Weyand and Goronzy, 2016). However, the direction of the relationship appears to vary by treatment and cancer site. A study by Kugel and colleagues (2018) found in an analysis of more than 500 patients at different cancer centers with metastatic melanoma treated with the ICI pembrolizumab that older people with melanoma appeared to respond more efficiently to treatment than younger people. More people aged 62 or older had tumor shrinkage or

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2 “Triple negative” refers to cancer tumors lacking the three most common types of receptors related to breast cancer–estrogen, progesterone, and the HER2/neu gene.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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stable disease after pembrolizumab treatment than did people younger than 62. For every decade of age, the probability that a patient was resistant to pembrolizumab dropped by 13 percent, with no difference by gender. The researchers then followed up with a study in mice to observe the physiologic pathways. The results of the mouse study mirrored that of the observational study in human patients and suggested that the pattern might be in part due to an age-related shift in the types of immune cells found in melanoma tumors (Kugel et al., 2018). Another team of researchers (Sceneay et al., 2019) used mouse models to study the implications of age on the results of immune checkpoint blockade therapy in patients with triple-negative breast cancer. The study found that age had a significant effect on response to immunotherapy—young mice experienced greater reduction in tumor growth and better overall survival rates in response to treatment than those who did not receive the treatment; on the other hand, the immunotherapy treatment did not significantly benefit the aged mice compared with the aged mice who did not receive treatment.

A study by Lee and colleagues (2019) observing patients in the National Cancer Database with stage II and III rectal adenocarcinoma (not one of the selected cancers) treated with neoadjuvant chemoradiation found a strong stepwise relationship between age and response to treatment. Younger patients had a lower rate of treatment response, specifically of pathologic complete response and nodal clearance. Researchers Shah and Boucai (2018) studied the effects of age on response to therapy in 320 patients with thyroid cancer at high risk of recurrence. The patients had a median age of 49 years and were receiving thyroid-stimulating hormone-suppressive therapy and had at least one neck ultrasound during the first 2 years of follow-up. They found that age did affect response to therapy, with patients younger than 55 years significantly more likely to have an excellent response to the treatment than older patients.

These studies suggest that the directionality of treatment response variation by age depends on the cancer site and treatment, among other factors. Additional research would need to be conducted to draw more conclusive inferences.

RETURN TO WORK AFTER CANCER

While this chapter addresses the effect of cancer treatments on disease status and functional ability, there is not a clear linkage to return to work. This section reviews reports studying the effects of surviving cancer on long-term employment and return to work. The committee found a few papers on this topic that studied individuals with breast cancer. Cocchiara and colleagues (2017) performed a systematic review of papers on return to work after breast cancer. Of the 26 articles they reviewed, they found that

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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the studies primarily addressed factors affecting return to work, interventions to enhance return to work, qualitative data on experiences of cancer survivors returning to work, and the economic aspects of cancer survivors returning to work. A 2019 systematic review performed by McLennan and colleagues analyzed 47 studies of prostate patients, comprising 20,083 individuals with a mean age of 61 years, and found a high overall return-to-work rate, with lower rates among those with physically demanding or low-paid jobs, comorbid conditions, and poor physical functioning.

Several studies reviewed return-to-work data across cancer survivors of multiple cancer sites. Moran and colleagues (2011) analyzed data from the Penn State Cancer Survivor Study and compared those with data from a comparison group drawn from the Panel Study of Income Dynamics, which focused on younger workers (ages 28–54 years). The researchers found that as long as 2–6 years after diagnosis, cancer survivors have lower employment rates and work fewer hours than other similarly aged adults. The difference in employment rate, averaged across survivors who remain cancer-free and those with new cancers, was 7–8 percentage points. The average reduction in usual hours per week was about 3.5 hours for female survivors and about 5.5 hours for male survivors, including those who stopped working. The reappearance of cancer added considerably to the long-term effects of the disease on the employment of survivors, and younger male survivors were particularly hard hit by recurrences and second cancers.

A 2013 study by Mehnert and colleagues summarized return-to-work data from several review articles analyzing U.S. and European cancer survivors and found that return-to-work rates averaged 64 percent among the studies, with a range of 24 percent to 94 percent, noting that a meta-analysis by de Boer et al. (2009) found that the unemployment risk was 1.48 times higher in the United States than in European countries. Overall, Mehnert et al. (2013) noted that studies indicate a steady increase in return to work with increasing time intervals after a cancer diagnosis, based on data from populations with early-stage breast cancer, gynecologic cancers, and gastrointestinal, blood, and urologic cancers. The percentage of patients with these cancers returning to work at 6 months after diagnosis averaged 40 percent, increasing to 89 percent at 24 months after diagnosis. Mehnert et al. (2013) also reported that, based on results from six studies, a risk of unemployment was associated with extensive surgery and advanced tumor stage.

Roelen and colleagues (2011) found, in a study of employees with breast cancer, genital cancer, gastrointestinal cancer, lung cancer, skin cancer, and blood cancers in the Netherlands, that 2 years after a cancer diagnosis the highest percentage of patients who fully returned to work were those with female genital cancer, male genital cancer, skin cancer, and breast cancer. The lowest percentage of patients returning to work were those with

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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lung cancer and gastrointestinal cancer. Advanced cancer stages and palliative treatment intention were associated with lower return-to-work rates.

A 2008 study by Short and colleagues analyzed data from the Penn State Cancer Survivor Study and the Health and Retirement Study data to quantify the increase in work disability attributable to cancer in a cohort of adult survivors who were an average of 46 months post-diagnosis. The sample included 647 survivors of ages 55–65, diagnosed at four medical centers in Pennsylvania and Maryland, and 5,988 similarly aged subjects without cancer in the Health and Retirement Study. The study found that even for cancer-free survivors, the disability rate was significantly higher than in adults with no chronic conditions (female odds ratio [OR]=1.94; male OR=1.89).

SUMMARY AND CONCLUSIONS

Cancer is the second leading cause of death in the United States and a major cause of disability. In recent years, because of the development of new treatments such as immunotherapy and CAR T-cell therapy, there has been an increase in the overall survival of patients with cancers that would historically have had a poor prognosis. The committee notes the following cancers are likely to be disabling for a length of time (usually around the time of diagnosis) but might improve with treatment, particularly with recent developments in cancer therapy: breast cancer (excluding DCIS), melanoma, renal cancer, head and neck cancers, advanced epithelial ovary cancer, NSCLC, and diffuse large B-cell lymphoma. The committee acknowledges that other cancers might also fit the criteria.

In addition to the effects of the medical condition itself, cancer treatments are well known to cause morbidity in cancer survivors. Although treatments have generally improved to the point that they are both more effective and less debilitating, treatment-related impairments are still common and, in many instances, expected. Studies show that most types of cancers result in decreased work ability in patients, at least during active treatment or in its terminal phase, and that the decreased work ability is often associated not with the progression of the cancer itself, but rather with treatment, treatment-related side effects (also known as toxicities), and comorbidity with other health conditions. The adverse effects of some treatments can be profound, with serious implications for function and QOL. At the core of cancer treatments are surgery, systemic therapy, and RT. Each of these modalities has evolved significantly in recent years. Systemic therapy, for instance, which historically centered on various combinations of cytotoxic chemotherapeutics, now includes hormonal and biologic (targeted, immune, and gene) therapies. The addition of these new agents has revolutionized the treatment of many types of cancer but has

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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also introduced new types of morbidity. Treatment-related impairments include pain, fatigue, cardiotoxicity, peripheral neuropathy, lymphedema, pulmonary dysfunction, and CD. The residual effects of cancer treatments can present decades after treatment. Studies have shown that the majority will improve after treatment completion although the time course is patient specific.

The most significant recent advance in our understanding of cancers that are likely to improve with treatment has been achieved through an influx of promising new pharmaceuticals. Improved prognoses for some cancers have been realized through the integration of novel targeted immune checkpoint and PARP inhibitors (pharmacological inhibitors of the enzyme poly ADP ribose polymerase), among others. The impact of these agents has been nothing short of revolutionary for some cancers (i.e., achieving durable remissions in cancers that were previously considered imminently mortal). Their effects on metastatic melanoma have been particularly remarkable, for instance. The effective practice of precision medicine permitted by these agents is exciting and will doubtlessly expand precipitously as it is extended across different types and stages of cancer as well as being expanded through the addition of new agents to an already formidable arsenal. However, much uncertainty remains regarding the toxicities of these treatments, and only patients whose tumors express targetable molecules are eligible for these therapies. Common, functionally morbid toxicities with the potential to affect all body systems have been attributed to these agents. Consequently, the body of evidence regarding their harms and benefits continues to evolve. Additional advances in cancer care that have improved treatment outcomes include enhanced imaging, earlier detection capabilities, and enhanced supportive care, among others.

Cancers are a very heterogeneous class of medical conditions, with impairments and recovery that are hard to generalize over the course of the disease. The committee developed three overall conclusions regarding its review of specific selected cancers. First, variation in the ability of a cancer to improve with treatment exists within cancers of a particular organ system, not only by stage, but also by cancer cell type and molecular and genomic characteristics. Prognosis and treatment decisions are likewise based on the cancer site, stage, cell type, and molecular and genomic characteristics. For example, triple-negative invasive breast cancer (breast cancer with tumors lacking estrogen, progesterone, and the HER2 gene) is much more aggressive and has lower survival rates than many other invasive breast cancer cell types. Another example is that recent phase III trials show that targeted therapies demonstrate superior efficacy to chemotherapy in NSCLC patients with an activating EGFR mutation and in patients with ALK rearrangements. Patients’ ultimate survival varies dramatically based

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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on the treatments available for their specific cancer sites, stage of disease, cell types, and molecular and genomic markers as well as their individual characteristics, including comorbid disease, functional status, and the social determinants of health. Additionally, a few studies suggest that for certain combinations of cancer site and treatment, response varies by age; however, the direction of the relationship varies among the studies reviewed.

Second, success in cancer treatment does not predict improved functional outcomes. Long-term cancer survivors often experience multiple comorbidities and impairments related to the toxic effects of cancer therapies, including surgery, radiation, and systemic therapy (chemotherapy, biologic therapy). These impairments, which are a major cause of morbidity, have their own trajectories, treatments, and treatment response considerations. They can be acute side effects that develop during treatment but are transient, long-term side effects that develop during treatment but are chronic, late effects that develop after completion of the treatment, or secondary effects that result from acute and long-term side effects. The committee suggests that the following common cancer-related impairments can be disabling for a period of time, but managed, though not necessarily cured, with treatment: pain, CRF, cardiotoxicity, CIPN, lymphedema, pulmonary dysfunction, and CD. Additionally, the committee notes that improved functional outcomes do not predict return to work.

Finally, it is important to consider the recursive nature of cancer, cancer treatments, and impairments. Cancer is a dynamic process, and as cancer patients survive longer, they experience a higher probability of disease relapse, which can reset an episode of treatment. Given that cancer treatments commonly result in functional impairment, and disease relapse is highly probable, the question of how long it takes from initiation of cancer treatment until functioning improves is a complex one. The committee suggests that the length of time from the start of cancer treatment until a person’s functioning improves to the point at which the condition is no longer disabling involves two timeframes: (1) the time to remission of the cancer, and (2) the time to recovery from the toxicities, symptoms, and functional impairments caused by either the cancer or the treatment. The committee notes that a cancer patient’s disease status, more so than the cancer site and stage, is an appropriate indicator of whether the patient’s functional status should be assessed for improvement. If a patient’s cancer achieves complete remission, functional status improvement is probable, and it is reasonable to reevaluate the patient’s functional status 12 months after achieving complete remission. If a patient’s cancer achieves a stable partial remission, functional status improvement is possible, and it is reasonable to reevaluate the patient’s functional status 12 months after achieving stable partial remission. If the patient has no response to treatment or experiences a progression of the disease, then functional improvement is unlikely.

Suggested Citation:"3 Cancer." National Academies of Sciences, Engineering, and Medicine. 2020. Selected Health Conditions and Likelihood of Improvement with Treatment. Washington, DC: The National Academies Press. doi: 10.17226/25662.
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The Social Security Administration (SSA) administers two programs that provide disability benefits: the Social Security Disability Insurance (SSDI) program and the Supplemental Security Income (SSI) program. SSDI provides disability benefits to people (under the full retirement age) who are no longer able to work because of a disabling medical condition. SSI provides income assistance for disabled, blind, and aged people who have limited income and resources regardless of their prior participation in the labor force. Both programs share a common disability determination process administered by SSA and state agencies as well as a common definition of disability for adults: “the inability to engage in any substantial gainful activity by reason of any medically determinable physical or mental impairment which can be expected to result in death or which has lasted or can be expected to last for a continuous period of not less than 12 months.” Disabled workers might receive either SSDI benefits or SSI payments, or both, depending on their recent work history and current income and assets. Disabled workers might also receive benefits from other public programs such as workers’ compensation, which insures against work-related illness or injuries occurring on the job, but those other programs have their own definitions and eligibility criteria.

Selected Health Conditions and Likelihood of Improvement with Treatment identifies and defines the professionally accepted, standard measurements of outcomes improvement for medical conditions. This report also identifies specific, long-lasting medical conditions for adults in the categories of mental health disorders, cancers, and musculoskeletal disorders. Specifically, these conditions are disabling for a length of time, but typically don’t result in permanently disabling limitations; are responsive to treatment; and after a specific length of time of treatment, improve to the point at which the conditions are no longer disabling.

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