7

Selected Topics in Other Cancers

In 2019 the U.S. Social Security Administration (SSA) received more than 114,000 disability claims that listed some form of cancer as the primary diagnosis (see Chapter 2). Although diagnoses for breast cancer and lung cancer together make up almost 30% of these claims, other cancers are also prominent, particularly colorectal cancers, which account for 12% of claims. Other cancers among the top 10 cancer diagnoses in claims occur with a frequency of 3–5% (see Table 2-1). Together the top 10 cancer diagnoses, including breast cancer and lung cancer, constitute 70% of all SSA cancer disability claims. Given the prevalence of these other cancers and the committee’s task of providing “an overview of the current status of the diagnosis, treatment, and prognosis of adult cancers including, but not limited to, breast cancer and lung cancer,” this chapter presents epidemiologic and other new information for the following selected cancers:

• Gastrointestinal cancers—colorectal cancer, pancreatic cancer, and liver and bile duct cancers;
• Hematologic cancers—leukemias, lymphomas, and multiple myeloma/plasma cell cancers;
• Ovarian cancer;
• Head and neck cancers; and
• Melanoma.

This chapter does not attempt to review comprehensively the epidemiology, diagnosis, treatment, and prognosis for all the cancers for which SSA receives large numbers of claims, but rather focuses on those cancers

for which changes in the risk factors, incidence, treatment, and outcomes may affect the number and type of disability claims received by SSA in the future. For example, head and neck cancers are increasingly diagnosed in working-age adults as a result of the increasing prevalence of human papillomavirus (HPV)-associated cancers, and HPV-associated cancers have better prognoses than other types of head and neck cancers. Hematologic cancers (e.g., leukemia, lymphoma, and myeloma) have seen substantial developments in systemic treatments, which have had a favorable impact on prognosis. The committee included melanoma in this chapter because, while it is not among the top 10 cancers for which SSA receives disability claims, it is the fifth most commonly diagnosed cancer in the United States and its incidence has been rising. Since 2014 new treatments have resulted in a decrease in the mortality rate of metastatic melanoma (SEER, n.d.-h). The committee excluded discussion of nervous system cancers, although SSA commonly receives disability claims for these cancers, because there have not been notable changes in their incidence, treatment, or prognosis that are likely to affect SSA disability claims in the near future. Information on the functional impairments associated with the cancers discussed in this chapter can be found in Chapter 9.

GASTROINTESTINAL CANCERS

Gastrointestinal cancers are among the most frequent cancer diagnoses received by SSA in disability claims. The three most common types of gastrointestinal cancer are colorectal cancer, pancreatic cancer, and liver and bile duct cancers, and each of these cancer types is represented in the 10 most frequent cancer diagnoses seen in SSA disability claims (see Chapter 2). The committee assesses each of these cancer types, and highlights new information on their incidence, diagnosis, and treatment.

Colorectal Cancer

Colorectal cancer is the third most commonly diagnosed cancer in both men and women (9% and 8% of all cancers, respectively, in 2020; see Chapter 3, Figure 3-1), and as with many other cancers, its incidence increases with age. Colorectal cancer also has the third highest mortality rate for men and women among cancers (Siegel et al., 2020; see Chapter 3, Figure 3-6). Siegel et al. (2017), in an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) program, found that for adults aged 55 years and older, incidence rates for colon cancer have generally declined since the mid-1980s and that for rectal cancer there has been a decline since 1974. However, the incidence of colorectal cancer has been increasing among young adults and is the second most frequently diagnosed cancer in

both men and women aged 30–49 years (Bhandari et al., 2017). Between 1995 and 2014 there was a 2.4% annual increase in incidence among adults aged 25–29 years (Sung et al., 2019). Other evidence suggests that individuals born around 1990 (now aged about 30 years) have double the risk of colon cancer and quadruple the risk of rectal cancer during their lifetimes compared with those born around 1950 (now aged about 70 years) (Siegel et al., 2017). This increase in colorectal cancer incidence may be due to the increasing prevalence of overweight and obese individuals, lack of physical activity, smoking, alcohol consumption, and a diet heavy with animal products and fewer fruits and vegetables (Araghi et al., 2019; Arnold et al., 2017). In particular, a sedentary lifestyle, regardless of exercise or diet, appears to be a risk factor for colorectal cancer for those aged 25–42 years (Nguyen et al., 2018).

Colorectal cancer is more frequently diagnosed among Blacks than among Whites, Asian/Pacific Islanders, or Hispanic men and women (see Figure 3-5). However, these patterns differ somewhat in younger adults. For example, Rahman et al. (2015) analyzed SEER data for 1973–2009 and found that compared with non-Hispanic Whites, other race/ethnic groups were two to three times more likely to be diagnosed with colorectal cancer before age 50 years. The study also found a more advanced stage at diagnosis for minority groups compared with non-Hispanic Whites.

Much of the overall decline in colorectal cancer incidence in older adults can be attributed to increased screening of asymptomatic people with colonoscopy or flexible sigmoidoscopy. During these procedures, precancerous polyps can be removed when present, thus preventing the development of subsequent cancers. Colorectal cancer screening typically begins at age 50 for average-risk adults, as recommended by the U.S. Preventive Services Task Force. However, the American Cancer Society now recommends starting colorectal cancer screening in adults over the age of 45 (see Chapter 4, Table 4-1). The common symptoms of colorectal cancer at presentation include blood in stools, straining to move bowels, abdominal pain, and weight loss. Whether an individual is presenting for a positive screening test or for symptoms, most colorectal cancers are diagnosed with biopsy during a colonoscopy or flexible sigmoidoscopy. Once a diagnosis of colon or rectal cancer is confirmed, staging is performed with a computed tomography (CT) scan of the chest, abdomen, and pelvis to evaluate for distant metastatic disease. Patients with rectal cancer typically have magnetic resonance imaging (MRI) of the pelvis (or an endorectal ultrasound) to better evaluate the primary rectal tumor and local lymph nodes.

Although often grouped together, colon and rectal cancer are diagnosed and treated somewhat differently. Colon cancers make up roughly two-thirds of colorectal cancer cases, with rectal cancers making up the other third.

The treatment of colon cancer without distant metastases usually starts with surgical resection of the affected part of the colon. If pathologic examination shows cancer in surgically removed local lymph nodes or if other high-risk clinical features are present, then adjuvant (postoperative) chemotherapy is generally recommended and is given over 3 to 6 months.

The treatment of nonmetastatic rectal cancer is distinct from and more complex than the treatment of colon cancer. While patients with very early-stage rectal cancer may be treated with up-front surgery, many patients are treated initially with radiation (with or without concurrent chemotherapy, depending on the radiation approach) followed by surgery and adjuvant chemotherapy. Other treatment approaches being increasingly used for localized rectal cancer include “total neoadjuvant therapy” (receipt of both chemotherapy and radiation prior to surgery) (Cercek et al., 2018; Fokas et al., 2019) and even non-operative “watch and wait” approaches (Smith et al., 2019). In the “watch and wait” approach, sometimes referred to as an “organ preservation” strategy, patients with a complete clinical response after chemotherapy and radiation can enter a surveillance program instead of undergoing surgery. Patients with cancer recurrence identified during surveillance can be evaluated for additional surgery for curative intent, and at least some patients will have long-term, cancer-free survival without ever undergoing surgery.

Morbidities related to the treatment of nonmetastatic colon and rectal cancers include adverse effects of the chemotherapy, surgery, and radiation. Oxaliplatin-related peripheral neuropathy is the most common and challenging long-term adverse effect of adjuvant chemotherapy for colorectal cancer. Oxaliplatin-related peripheral neuropathy is characterized by numbness and a loss of sensation in the fingers, toes, and feet and can sometimes lead to debilitating difficulty with fine motor skills, balance, and ambulation. Up to 15% of patients experience severe neuropathy (grade ≥3) during treatment (Grothey et al., 2018) although the neuropathy improves over time in most patients. Morbidities related to surgery include frequent and irregular loose bowel movements and fecal incontinence. Patients receiving surgery for rectal cancer may require a temporary or permanent ostomy, which can affect body image and social function. See Chapter 9 for more information on treatment-related functional impairments.

Metastatic colon and rectal cancers are treated primarily with chemotherapy. Patients with oligometastatic cancer (i.e., those with an anatomically limited extent of metastatic disease) may receive surgery, radiation, or ablation as part of their treatment; infrequently, patients can achieve long-term disease-free survival with these local therapy approaches. The median survival time for metastatic colorectal cancer has improved over the past decade to approximately 25–30 months among patients enrolled in clinical trials, although survival may be less for patients in the general

population (Cremolini et al., 2015; Heinemann et al., 2014; Venook et al., 2017). Most patients with metastatic colorectal cancer will receive intermittent chemotherapy for 1 or more years after diagnosis. Depending on certain characteristics, patients with metastatic colorectal cancer may also be treated with targeted therapies (often in combination with chemotherapy) or, less commonly, with immunotherapy. Long-term treatment with systemic therapies may result in substantial difficulty with maintaining prior levels of function as the adverse effects of treatment include fatigue, nausea, diarrhea, neuropathy, and increased infection risk, as well as the need for frequent oncology office visits during the course of treatment.

Pancreatic Cancer

Pancreatic cancer accounts for 3% of new cancer diagnoses and nearly 8% of cancer deaths in the United States (SEER, n.d.-l). Pancreatic cancers can develop from two kinds of cells in the pancreas: exocrine cells and neuroendocrine cells. Pancreatic adenocarcinomas, which arise from exocrine cells, are the most common type of pancreatic cancer. Pancreatic adenocarcinomas are usually diagnosed at an advanced stage, when the cancer has already spread beyond the pancreas. Pancreatic neuroendocrine tumors are less common and have a better prognosis (PDQ® Adult Treatment Editorial Board, 2020a). As with several other cancers, pancreatic cancer becomes more common with increasing age, with a median age at diagnosis of 72 years; however, nearly one-third of cases are diagnosed in individuals younger than 65 years. Pancreatic cancer is slightly more common in men than women (14.9 cases/100,000 persons and 11.6 cases/100,000 persons, respectively) and it is slightly more common in Blacks than in Whites or other racial or ethnic groups (SEER, n.d.-l) (see Chapter 3, Figure 3-5).

There are no effective general population screening approaches for pancreatic cancer, and most pancreatic cancers are diagnosed at an advanced stage, where distant metastasis or local encasement of major abdominal blood vessels renders surgical resection infeasible. Accordingly, the 5-year survival rate for localized pancreatic cancer is 37%, falling to 3% for patients diagnosed with advanced cancer (Siegel et al., 2020; see Figure 3-10). Even when the cancer is diagnosed at an early stage, surgical resection of pancreatic cancer carries a high morbidity. Most patients will experience a cancer recurrence even after surgery and adjuvant chemotherapy (Conroy et al., 2011).

Pancreatic cancer often presents with abdominal pain, low back pain, weight loss, or jaundice (yellowing of the skin and the sclera of the eyes). Abdominal imaging to investigate the presenting symptom generally demonstrates a pancreatic mass, with or without the presence of distant metastases to the liver, peritoneum, lungs, or other sites. The biopsy of a

pancreatic head mass is usually accomplished via endoscopic retrograde cholangiopancreatography. In other cases, the biopsy of a metastatic site (e.g., the liver) in addition to the abdominal imaging may be sufficient to confirm the diagnosis of pancreatic cancer.

In patients with nonmetastatic pancreatic cancer, an evaluation by a multidisciplinary treatment team is recommended to identify patients who are candidates for surgical resection (Tempero et al., 2017). Such candidates must be healthy enough to safely undergo extensive surgery, and the pancreatic mass must not encase major abdominal blood vessels. Following successful pancreatic cancer surgery, adjuvant chemotherapy can help reduce the risk of cancer recurrence. Patients who are candidates for pancreatic cancer resection are increasingly treated with neoadjuvant chemotherapy. Radiation therapy may also be used for neoadjuvant or adjuvant treatment of surgically resectable pancreatic cancer, although the practice varies substantially across cancer treatment centers.

Morbidity after pancreatic cancer surgery is common. Many patients develop diabetes mellitus due to the loss of insulin-producing pancreatic islet cells (Burkhart et al., 2015; Salvatore et al., 2015). Weight loss is also common after pancreatic cancer surgery, as pancreatic exocrine insufficiency can lead to malabsorption of dietary fat and fat-soluble vitamins.

In patients with metastatic or locally advanced, unresectable pancreatic cancer, systemic chemotherapy may be used to prolong survival and improve or maintain the quality of life. Median survival in patients with metastatic pancreatic cancer is generally 1 year or less, although newer chemotherapy regimens are leading to an increased survival of 1 year or more for patients with a good response to first-line palliative chemotherapy (Conroy et al., 2011; Von Hoff et al., 2013). Common problems for patients living with metastatic pancreatic cancer include fatigue, pain, weakness, and neuropathy, depending on the specific chemotherapy treatments they receive.

Patients with pancreatic neuroendocrine tumors make up a special subset of patients with pancreatic cancer. Pancreatic neuroendocrine tumors are rare compared with the more common adenocarcinoma of the pancreas, but they carry a substantially better prognosis, even after the development of distant metastases (Jarufe et al., 2005).

Liver and Bile Duct Cancers

Liver and bile duct cancers are not among the top 10 common cancers in the United States based on incidence (see Chapter 3, Figure 3-1), but they are responsible for an increasing share of cancer deaths, accounting for an estimated 5% of cancer deaths in 2020 (SEER, n.d.-g). These cancers were the ninth most common cancer diagnoses received by SSA

for disability claims. Major risk factors for liver and bile duct cancers include alcohol use, chronic liver disease from hepatitis B and hepatitis C, and non-alcoholic fatty liver disease as well as obesity and smoking (ACS, 2019a). Hepatocellular cancer is the most common form of liver cancer; hepatocellular cancers arise from hepatocytes, the primary cell type of the liver parenchyma. Bile duct cancer, or cholangiocarcinoma, is another form of cancer that can affect the liver and the bile duct system. While bile duct cancers share similar risk factors with hepatocellular cancers, they are treated differently (ACS, 2019b).

Hepatocellular cancer has a median age at diagnosis of 64 years, is more common in men than women, and is diagnosed more frequently among Asian/Pacific Islanders, American Indian/Alaska Native, and Hispanic populations for both sexes than among Whites or Blacks (SEER, n.d.-g) (see Figure 3-5). Yang et al. (2018) saw a similar incidence in 2009–2013 in California where Asians/Pacific Islanders and Hispanics had double the incidence rate (11.7/100,000 persons and 10.6/100,000 persons, respectively) seen in Whites (5.2), with the highest rates among Vietnamese, Cambodian, and Laotians. There has been a small but steady increase in the incidence of liver and hepatic bile duct cancers (1.6% from 2008–2017) among people born after 1965 (Howlader et al., 2020), which is associated with the increased rates of obesity in this population (Sung et al., 2019).

Hepatocellular cancer may be diagnosed during a screening test for high-risk patients or as part of a symptom evaluation. Screening with ultrasound, CT scan, or MRI is recommended in patients with known liver cirrhosis, who are at substantially higher risk for hepatocellular cancer. There are many distinct approaches for treating liver-limited hepatocellular cancer. Biopsy is not always performed, as MRI findings may be considered sufficient for a definitive diagnosis. Many patients, but not all, will present with an elevated alpha-fetoprotein, measured by a blood draw (Bialecki and Di Bisceglie, 2005).

Patients with one to three small liver tumors from hepatocellular cancer may be treated with surgical resection. In patients with advanced cirrhosis of the liver, liver transplant can be used to treat liver cancer and cirrhosis concurrently if a transplant organ is available. In patients with more than three liver tumors or other high-risk factors or in patients with a high risk of surgical morbidity or mortality, hepatocellular cancer may be treated with ablation, embolization, or radiation. Tumors of 3 cm or less may be good targets for microwave ablation. Larger tumors are frequently treated with different types of embolization. Many patients with liver-limited hepatocellular cancer will have multiple liver-directed treatments over time (Viveiros et al., 2019).

In patients with metastatic hepatocellular cancer or with cancer that is refractory to liver-directed therapies, survival is usually 1 year or less.

However, newer systemic therapies—including targeted therapies and, in particular, immunotherapies—have led to an increasing number of patients who may live longer than 1 year after a diagnosis of metastatic hepatocellular cancer (Finn et al., 2020).

Bile duct cancers may affect the bile ducts within the liver (intrahepatic cholangiocarcinoma) or the extrahepatic bile duct system, which carries bile from the liver to the gallbladder and small intestine, traversing the head of the pancreas (extrahepatic cholangiocarcinoma and gall bladder cancer). Because bile duct cancers are adenocarcinomas, like many other solid tumors, it can be difficult to distinguish intrahepatic bile duct cancers from liver metastases arising from an occult tumor site; this makes intrahepatic bile duct cancer a diagnosis of exclusion when liver tumors are found in the absence of another suspected primary cancer site. Extrahepatic bile duct cancers often present with jaundice because of tumor obstruction of the extrahepatic bile duct.

When feasible, bile duct cancers are treated with surgical resection and, sometimes, with adjuvant radiotherapy. When complete surgical resection cannot be accomplished, bile duct cancers can be treated with chemotherapy, with a median survival time that is generally less than 1 year (Valle et al., 2010). However, some forms of bile duct cancer may be responsive to targeted therapies, such as intrahepatic cholangiocarcinomas, which are characterized by relatively frequent translocations involving the FGFR2 gene (Borad et al., 2015).

HEAD AND NECK CANCERS

SSA includes soft tissue cancers of the head and neck in its listings (SSA, 2015), and these are SSA’s fifth most frequently diagnosed cancer in disability claims (see Chapter 2). The SSA listing includes inoperable or unresectable, persistent or recurring disease after anticancer therapy, metastases beyond the regional lymph nodes, and small-cell (oat cell) carcinoma. Head and neck cancers may develop in the mucous membranes of the mouth, nose, and throat (NLM, 2020) and are classified by anatomical location.

Soft tissue cancers originating in the head and neck arise from various anatomic sites including oropharyngeal, hypopharyngeal, laryngeal, lip, metastatic squamous neck, nasopharyngeal, paranasal sinus, and nasal cavity. Cancer of the oral and pharyngeal cavity is the eighth most common cancer diagnosed in men but is not among the top 10 cancers diagnosed in women (SEER, n.d.-j) (see Chapter 3, Figure 3-1). Head and neck cancers are more than twice as common in men than in women and are most frequently diagnosed in Whites (see Figure 3-5), and the risk factors include tobacco or heavy alcohol use and infection with HPV (SEER, n.d.-j).

Tobacco use and alcohol consumption combined account for an estimated 75% of head and neck cancer cases overall (Hashibe et al., 2009), while HPV, particularly HPV-16, accounts for as much as 70% of oropharyngeal cancers (Saraiya et al., 2015). Oropharyngeal cancers are now the most common HPV-related cancer (Jemal et al., 2013). HPV-related oropharyngeal cancers are diagnosed at younger ages than oropharyngeal cancers that are not related to HPV (mean age at diagnosis, 61.0 and 63.8 years, respectively) (Chaturvedi et al., 2008). The incidence of HPV-related oropharyngeal cancers has been increasing (Stein et al., 2015), particularly among White men aged 40–59 years (Chaturvedi et al., 2008; Mehta et al., 2010), whereas the incidence of non-HPV related oropharyngeal cancers is declining. Age-adjusted rates for new oral cavity and pharynx cancer cases increased an average of 0.8% annually from 2008 to 2017 and the annual death rate also increased slightly by about 0.5% over the same period (SEER, n.d.-j). HPV-related oropharyngeal cancers have a better prognosis than oropharyngeal cancers that are not HPV-related.

Early-stage disease (stages I and II) is treated with a single modality—surgery or radiation therapy—depending on the tumor’s location and extent. Advanced-stage disease (i.e., stages III, IVa, and IVb) is treated with multimodal therapy, including surgery, radiation therapy, chemotherapy, and targeted therapy. Unlike cancers in most other sites, stage IV head and neck cancers are potentially still curable, and long-term survival is becoming more common in this population (Pulte and Brenner, 2010). Immunotherapy is a newer option for advanced or recurrent cancer (Cohen et al., 2019). There are three currently approved immunotherapy options for head and neck cancers: the monoclonal antibody cetuximab and two immune checkpoint inhibitors, nivolumab and pembrolizumab (Cohen et al., 2019).

HEMATOLOGIC CANCERS

Hematologic (blood) cancers include leukemias, lymphomas, and myelomas. Leukemias and lymphomas account for a significant proportion of disability claims for cancer, at 5% each, while myelomas are not among the top 10 cancers for which SSA receives disability claims (see Chapter 2). For each of the hematologic cancers, patients may experience morbidity and mortality from both the cancer itself and its associated treatments. Late-onset effects from chemotherapy and radiation therapy may occur years and even decades after the conclusion of treatment. Examples of late effects include the risk of new primary cancers, neurocognitive changes, and organ-specific toxicity, such as heart disease. This section provides an overview of new developments in the treatment of hematologic cancers along with established treatments.

Leukemias

There are approximately 60,000 new cases of leukemia diagnosed annually in the United States (SEER, n.d.-b). Leukemias may be broadly classified into acute and chronic leukemias, a classification also used by SSA. Leukemia is among the 10 most commonly diagnosed cancers in the United States (3.5% of all newly diagnosed cancers in 2019); 9th for men (4%) and 10th for women (3%) (SEER, n.d.-b) (see Chapter 3, Figure 3-1). Leukemia occurs most frequently in adults older than 55 years of age (median age at diagnosis is 67 years) and is more common among Whites than other racial or ethnic groups (SEER, n.d.-b) (see Figure 3-5).

Acute Leukemias

Acute leukemias consist primarily of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) (SEER, n.d.-c,-d). AML is the most common type of leukemia diagnosed in adults, with 19,940 new cases expected in 2020 (ACS, 2020a). ALL is diagnosed in approximately 6,000 patients annually, with more than half of new cases occurring in pediatric patients (SEER, n.d.-c). Acute leukemias are inherently very aggressive, and if left untreated they are usually fatal within weeks to months. The median age at diagnosis for AML is 68 years. In contrast, ALL is most frequently diagnosed in children and is less common than AML in adults.

Treatment for acute leukemias typically consists of several cycles of aggressive cytotoxic chemotherapy with or without novel agents. The goal of the initial treatment is to achieve remission. Depending on the specific subtype of leukemia, patients are stratified into different risk categories based on likelihood of cancer recurrence and response to conventional chemotherapy. Risk is determined by such factors as leukemia subtype, cytogenetics, and somatic mutations. For some AML patients, chemotherapy without hematopoietic stem cell transplant (HSCT; see Chapter 4 for a description of this treatment) is the standard of care because their risk of morbidity and mortality from a transplant exceeds their risk of dying from AML; the treatment may entail 6 months of aggressive chemotherapy. New targeted treatments are now available for a subset of AML patients with specific mutations, such as gilterinitib and midostaurin which target Flt3LG, a gene involved in the proliferation of early hematopoietic cells. Other targeted therapies for AML include enasidenib, ivosidenib, and venetoclax.

For ALL, the risk stratification takes into account whether a patient has a specific genetic abnormality called the Philadelphia chromosome. For young adults (ages 18–39) with no Philadelphia chromosome, treatment consists of cytotoxic chemotherapy without HSCT (Stock et al., 2019).

For these ALL patients, chemotherapy may be necessary for 2–2.5 years. Because chemotherapy kills both cancer and healthy cells in the bone marrow, patients with AML and ALL are at risk for life-threatening infections and bleeding. Thus, patients are often admitted to the hospital for inpatient cycles of chemotherapy and treatment of the resulting complications of low blood counts and other toxic effects.

HSCT is recommended for two types of patients: those with acute leukemias who are considered to be at higher risk of disease relapse, in which case HSCT is administered after initial chemotherapy when a patient is in complete remission, and those who relapse after treatment with initial chemotherapy. In the latter case it is recommended that patients undergo HSCT after receiving treatment for their relapse so that the bone marrow has minimal or no leukemia cells present prior to HSCT. The goals of HSCT are to replace a patient’s unhealthy bone marrow cells with a donor’s healthy bone marrow and to allow the donor’s healthy cells to attack and remove microscopic leukemia cells that may remain in a patient’s system after the transplant. HSCT is associated with significant risks of morbidity and mortality which may be related to pretransplant conditioning (i.e., the chemotherapy, with or without radiation treatments, that prepare the patient’s body to receive donor cells), to toxicity associated with long-term immunosuppression (e.g., the increased risk of opportunistic infections and organ toxicity), and to graft-versus-host disease, which occurs when the patient’s healthy tissues recognize the donor cells as foreign and react negatively (Bhatia, 2011) (see Chapter 9 for more information on graft-versus-host disease). Patients who undergo HSCT at a young age are at risk of reduced functional status and impairments for many years, even decades, as a consequence of their prior chemotherapy and radiation treatments and are also at risk of complications from those treatments. The impairments are caused by the chronic comorbidities that result after HCST, which include organ dysfunction due to graft-versus-host disease which may affect almost any organ in the body, new primary malignancies, musculoskeletal changes, cataracts, and neuropsychological effects (Inamoto and Lee, 2017). Together, the HSCT treatment itself and late-onset effects may result in accelerated aging with resulting frailty among younger patients (Cupit-Link et al., 2018).

Finally, for patients who undergo HSCT there is always the risk of disease recurrence and the development of new primary cancers. Treatment options for those with recurrent disease are generally few, and these patients’ prognosis is poor, with most of them succumbing to the disease. For younger patients with recurrent ALL, chimeric antigen receptor (CAR) T-cell therapy may be a newly available option (see Chapter 4 for discussion of CAR T-cell therapy).

Chronic Leukemias

Chronic leukemias—chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)—grow much more slowly than acute leukemias and are generally considered to be treatable chronic diseases. As of 2020 CLL represents 1.2% of all new cancer cases in the United States (SEER, n.d.-e). Although predominantly a disease of older adults, about one-third of new cases of CLL are diagnosed in adults aged 20–64 years (SEER, n.d.e). CLL is more common in men than women, particularly White men, and the median age at diagnosis is 70 years. Blacks and Asians/Pacific Islanders have a significantly lower incidence for CLL than Whites in nearly every age group and for both males and females (Yamamoto and Goodman, 2008).

CML is rare and represents 0.5% of new cancer cases in 2020 (SEER, n.d.-f). It is more common in older adults (median age at diagnosis is 65 years) and in men; however, almost half of all patients newly diagnosed with CML in 2020 are estimated to be 20–64 years of age (SEER, n.d.-f). CML has similar incidence in most races, though there is a significantly lower incidence in Asian/Pacific Islanders until age 80 (SEER, n.d.-f; Yamamoto and Goodman, 2008). CLL is more common than CML (estimated number of new cases 21,040 for CLL versus 8,450 new cases for CML in 2020), representing 1.2% of all new cancer cases in 2020 (SEER, n.d.-e). Like CML, CLL is more common in adults (median age at diagnosis 70 years), men, and Whites (SEER, n.d.-e).

Patients with CML have seen significant improvement in their outcomes with the development of tyrosine kinase inhibitors, with most patients having near-normal life expectancies (Bower et al., 2016). Patients may experience chronic low-level toxicity, including fatigue, muscle pain, and gastrointestinal distress. Additionally, serious toxicity may occur, including cardiac arrhythmias, pleural effusions, and blood clots (Medeiros et al., 2019). Managing toxicities and impairments is critical to ensuring long-term adherence to tyrosine kinase inhibitors. The treatment paradigm for CLL has been evolving, with the introduction of new oral targeted agents, including ibrutinib, venetoclax, idelalisib, duvelisib, and acalabrutinib, and there are several other novel agents in development. CAR T-cell therapy is also being explored as a treatment for refractory CLL. As CLL often is associated with a relapsing and remitting disease course, the development of new drugs may result in better long-term survival; however, there are few data on the long-term and late-onset effects of these newer agents.

Lymphomas

Lymphomas may best be classified into non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. SSA (2015) includes the following types

of lymphoma in its listing: non-Hodgkin lymphoma (aggressive and indolent); Hodgkin lymphoma; lymphoma following bone marrow or stem cell transplantation; and mantle cell lymphoma. NHL is diagnosed in many more patients annually (77,240 estimated new diagnoses in 2020) than Hodgkin lymphoma (8,480 new cases in 2020) (SEER, n.d.-a,-i).

Non-Hodgkin Lymphoma

NHL is the seventh most frequently diagnosed cancer in the United States, representing 5% and 4% of new cancer cases in men and women in 2019, respectively (see Chapter 3, Figure 3-1). It is most frequently diagnosed in people aged 65–74 years with a median age at diagnosis of 67 years (SEER, n.d.-i), however, it also has a substantial occurrence in young adults aged 20–39 years (ACS, 2020b; Bleyer et al., 2006).

NHL encompasses numerous B-, T-, and natural-killer-cell lymphomas. NHL may present in any lymph node as well as in extranodal organs, including the central nervous system. Historically, NHL has been treated with conventional chemotherapy, and HSCT if appropriate; in recent years, however, targeted therapies (e.g., ibrutinib) and antibody-based therapies (e.g., monoclonal antibodies) have been introduced. For patients with recurrent or refractory disease, new therapies such as CAR T-cell therapy may be used if the disease does not respond to chemotherapy. Perhaps the most noteworthy recent development for NHL has been U.S. Food and Drug Administration (FDA) approval of two CAR T-cell treatments for recurrent or refractory B-cell NHL—axicabtagene ciloleucel and tisagenlecleucel (Kansagra et al., 2020). CAR T-cell therapy provides an option for patients whose NHL is refractory to traditional chemotherapy and who may experience a cancer recurrence after an autologous HSCT. CAR T-cell therapy offers the potential of long-term disease control, albeit with minimal knowledge about the development of long-term and late-onset effects (see Chapter 8).

Hodgkin Lymphoma

Hodgkin lymphoma is rare and represents 0.5% of all new cancer cases in 2020 (SEER, n.d.-a). Hodgkin lymphoma, in contrast to NHL, is most commonly diagnosed in adults aged 20 to 34 years (the median age at diagnosis is 39.5 years old), with 31% of cases being diagnosed in people aged 20–34 (SEER, n.d.-a; Shanbhag and Ambinder, 2018). Hodgkin lymphoma has a higher incidence rate in men than in women (2.9 versus 2.3) and is less common in Asian/Pacific Islanders and American Indian/Alaska Natives than in Whites and Blacks (SEER, n.d.-a) (see Figure 3-5).

Hodgkin lymphoma is one of the success stories of oncology, with a 5-year overall survival rate of 87.4% as of 2016 (Howlader et al., 2020).

Traditionally, patients receive cytotoxic chemotherapy with or without radiation as the initial treatment. For those with recurrent disease, high doses of cytotoxic chemotherapy are administered, followed by autologous HSCT (Linch et al., 1993; Schmitz et al., 2002). Despite the excellent survival rates, however, Hodgkin lymphoma survivors are at risk for the development of significant late-onset effects as they may live for decades after their cancer diagnosis. Late-onset effects seen in adult survivors who had Hodgkin lymphoma as children may include heart disease, new primary malignancies, fatigue, pulmonary impairments, and thyroid disease (Castellino et al., 2011). For example, a patient who received radiation to the chest lymph nodes and anthracycline chemotherapy for bulky disease¹ is at risk for the development of breast cancer and cardiac disease even several years after completion of treatment (PDQ® Adult Treatment Editorial Board, 2020b). These late-onset effects may lead to impairments in functional status. In recent years, novel agents for Hodgkin lymphoma, such as brentuximab vedotin, have been introduced, but there are few data on the long-term toxicity of these agents.

Multiple Myeloma

Multiple myeloma is a hematologic cancer for which available therapies are rapidly changing. Standard-of-care treatment for myeloma can include chemotherapy, autologous HSCT, and in some cases watchful waiting. While multiple myeloma is not included in the top 10 cancers associated with SSA disability claims, the introduction of novel therapies such as carfilzomib and daratumumab has improved survival outcomes. CAR T-cell therapy is also being investigated for patients with recurrent or refractory multiple myeloma, and it may be available for this population in the near future.

Multiple myeloma is unusual in the sense that African Americans are two to three times more likely to be affected than Whites, with the racial disparity in incidence more pronounced in patients younger than 50 years (Waxman et al., 2010). SEER data from 1973–2006 showed that over this period Blacks had better disease-specific and relative survival rates than Whites (Waxman et al., 2010). Research has demonstrated that in closed health care systems such as the U.S. Department of Veterans Affairs, African Americans have better overall survival rates than Whites, given equal access to novel therapies (Fillmore et al., 2019).

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¹ The term “bulky disease lymphoma” is used to describe tumors in the chest that are at least half as wide as the chest or tumors in other areas that are at least 10 cm (about 4 in) across. Bulky disease is especially important for stage II lymphomas because it may require more intensive treatment (ACS, 2018).

Multiple myeloma is associated with significant morbidity from both the disease and its treatment. Disease-related morbidity includes organ dysfunction such as bone fractures and kidney failure. Treatment-related morbidity includes the risk of cytopenia, cardiomyopathy from anthracyclines, and neuropathy. Patients may also develop late-onset effects and impairments from chronic steroid use, including osteoporosis and cataracts.

OVARIAN CANCER

Ovarian cancer is relatively rare and is not among the estimated 10 most frequently diagnosed cancers in 2020 for U.S. women (SEER, n.d.-k). This cancer has a median age at diagnosis of 63 years and is most common in White women (SEER, n.d.-k) (see Figure 3-5). It is the most lethal gynecologic cancer among U.S. women (Thrall et al., 2011), with an overall 5-year survival of 48% (Siegel et al., 2020). Survival is strongly related to the stage at diagnosis, and most women are diagnosed with advanced stage (stage III–IV) disease (Thrall et al., 2011), which has a 5-year survival rate of 30% (Siegel et al., 2020), as there are no effective screening tests and the symptoms of ovarian cancer are nonspecific. However, there is a subset of women with certain biological characteristics, particularly younger age, for whom the disease is curable even at advanced stages and for whom long-term survival of 10 years or more is possible (Cress et al., 2015; Hilal et al., 2016). This improved survival may be the result of more favorable tumor biology and the woman’s greater ability to tolerate aggressive therapy (Cress et al., 2015). Efforts are under way to improve the detection of early disease; in particular, new biomarkers, including human epididymis protein 4, autoantibodies, and circulating tumor DNA, may help detect not only primary ovarian cancer but recurrent disease (Yang et al., 2017).

Optimal care for most patients with advanced ovarian cancer generally includes both surgery and chemotherapy (NCCN, 2019; Thrall et al., 2011). The timing and extent of surgery has direct implications for the selection of subsequent treatment as well as for the patient’s prognosis, with an early initiation of chemotherapy following surgery improving overall survival (Tewari et al., 2016). Targeted therapy, anti-angiogenic therapy, and immunotherapy are new treatment options for women with recurrent ovarian cancer (García-Martínez et al., 2020; Kim et al., 2017; Wang et al., 2020; Yang et al., 2017).

One of the newest additions to the treatment armamentarium for ovarian cancer is poly (ADP ribose) polymerase (PARP) inhibitor therapy (Mirza et al., 2020; NCCN, 2019; see also Chapter 8). PARP inhibitors were used initially for partially responsive or resistant disease, and they were later approved as maintenance therapy to be used after the completion of chemotherapy in women who have a BRCA 1/2 mutation. The goal of

this maintenance therapy is to prolong survival and delay disease recurrence (Coleman et al., 2019; González-Martín et al., 2019; Lorusso et al., 2018).

MELANOMA

The committee included melanoma of the skin in this chapter because, although it is not among the most common cancers for which SSA receives disability claims, there are advances in new therapies that are improving mortality and increasing the likelihood that some survivors with incurable, metastatic melanoma will be able to resume many of their daily activities.

Melanoma is the fifth most commonly diagnosed cancer in the United States and represents 5.6% of all new cancers (SEER, n.d.-h; see Chapter 3, Figure 3-1). The median age at diagnosis is 65 years (SEER, n.d.-h). The annual incidence of melanoma of the skin has been slowly increasing since 2008 at about 1.2% per year (SEER, n.d.-h); however, mortality rates have been falling—on average, by 2.9% each year from 2008–2017 (SEER, n.d.h) and dropping by almost 18% between 2013 and 2016 (Berk-Krauss et al., 2020)—as a result of improvements in screening and breakthroughs in immunotherapy. The 5-year relative survival rate for localized melanoma is 99.0%, although only 27.3% for metastatic disease (SEER, n.d.-m).

Melanoma is a cancer of the pigmented cells of the skin—the keratinocytes. Typically melanoma presents at an early stage as an irregularly shaped or growing pigmented lesion that may be associated with ulceration. Melanoma is more common in men than women, in people with fair complexions, and in those who have been exposed to natural or artificial sunlight (such as tanning beds) for long periods of time. In most cases it is a disease of chronic sun exposure, but it can also appear in areas not exposed to the sun. There are more new cases among Whites than any other racial/ethnic group, and it is rare in Blacks and Asian/Pacific Islanders (SEER, n.d.-h).

Melanoma is typically diagnosed by an examination of the skin and a biopsy of any unusual skin lesions. More superficial, thinner lesions are associated with improved clinical outcomes; therefore, early diagnosis with surgical removal of the lesion is important for improving the patient’s prognosis and survival. As with many cancers, the treatment for melanoma is based on the stage of the disease and may include surgical excision, chemotherapy, radiation therapy, immunotherapy, and targeted therapy. The majority of cases present as stage I/II (incidence of 17.6 per 100,000 individuals, compared with 1.9 and 1.0 for diagnoses of regional and distant stages) (SEER, n.d.m), and most are curable with surgery alone. Stage IV cancer is diagnosed with a positron emission tomography scan and brain MRI.

Historically the treatment of metastatic melanoma with conventional chemotherapy has been largely ineffective and has been associated with

significant morbidity and mortality (Canavan and Cantrell, 2016). However, the last decade has seen breakthroughs in immunotherapies and targeted therapies which have become standard of care. Immunotherapy with checkpoint inhibitors—cytotoxic T-lymphocyte associated protein 4 (CTLA4), programmed death cell-1(PD-1), or both—have improved survival and cured patients with metastatic melanoma. These immunotherapies have achieved response rates of 50%, and randomized studies with combination immunotherapy of CTLA4 and PD-1 have achieved 5-year survival rates of 52% (Dzienis and Atkinson, 2014; Larkin et al., 2019; Robert et al., 2017). Anti-CTLA4 therapy shows that 10-year survival for metastatic melanoma is possible (Schadendorf et al., 2015), and recent data on PD-1 inhibitors is even more promising (Larkin et al., 2019). Accordingly, these immunotherapy advances have been extended to adjuvant treatment where CTLA has shown improved recurrence-free survival in stage III melanoma (Eggermont et al., 2015), as has PD-1 therapy (Eggermont et al., 2018).

Another strategy in the treatment of metastatic melanoma is the targeting of BRAF mutations that occur in almost half of patients with metastatic melanoma. Initially, BRAF V600E was targeted with single-agent BRAF inhibitors (Chapman et al., 2011), but the dual inhibition of both BRAF and MEK in the RAS/RAF/MEK/ERK signaling pathway was more effective. FDA has approved three combinations that affect this pathway, including dabrafenib/tramentinib (Robert et al., 2019), vemurafenib/cobimetinib, and encorafenib/binmetinib (Hamid et al., 2019).

FINDINGS AND CONCLUSION

Findings

1. Colorectal cancer is a relatively common cancer among the U.S. population and SSA claimants. Although most colorectal cancers are diagnosed at early stages as a result of recommended screening and have a good prognosis, patients may experience long-term effects of chemotherapy, surgery, and radiation, particularly neuropathy and bowel symptoms such as frequent and irregular bowel movements and fecal incontinence. Furthermore, younger people are being diagnosed with more advanced colorectal cancer as they are not typically screened for the disease.
2. Most pancreatic cancers are diagnosed at an advanced stage, making surgery infeasible. This cancer has a generally poor prognosis because there are few treatment options with durable effectiveness.
3. Cancers of the liver and bile duct are increasing in frequency and are associated with increases in liver cirrhosis related to

3. alcohol use, hepatitis, and non-alcoholic fatty liver disease. New treatments, including immunotherapies, have led to improved survival.
4. Head and neck cancers are typically treated with surgery and radiation, which often lead to substantial long-term impairments. Immunotherapies are improving prognosis for head and neck cancers. Oropharyngeal cancers, which are highly associated with human papilloma virus infection, are increasing in frequency among younger adults; however, these cancers generally have a favorable prognosis.
5. Hematologic cancers include leukemia, lymphoma, and myeloma. These cancers cause substantial impairments resulting not only from the cancers themselves but also from their treatment. Treatment advances for chronic leukemias, myeloma, and some lymphomas have substantially improved prognosis for these cancers. Patients with some hematologic cancers may benefit from hematopoietic stem cell transplant, which improves outcomes but has substantial late-onset adverse effects, including graft-versus-host disease.
6. Ovarian cancer is typically diagnosed at advanced stage resulting in poor prognosis. Treatment advances, including PARP inhibitor therapy for ovarian cancers with specific genetic mutations, are expected to improve long-term outcomes.
7. Localized melanoma of the skin is a frequently diagnosed cancer with a good prognosis as a majority of these cancers are treatable with surgery. Mortality from metastatic melanoma has declined substantially in recent years, which is attributed to the effectiveness of targeted therapies and immunotherapies.
8. The morbidity associated with these cancers can be substantial.

Conclusion

1. In addition to the improvements previously described in the treatment of breast and lung cancer, there have been important improvements in the treatment of other common cancers for which SSA receives disability claims. These treatments are prolonging the survival for many people with these cancers. In particular, immunotherapies and, to a lesser extent, targeted therapies are being more widely used for these cancers with improved outcomes. However, there is little evidence on the long-term impairments associated with these newer treatments.

REFERENCES

Cercek, A., C.S.D. Roxburgh, P. Strombom, J.J. Smith, L.K.F. Temple, G.M. Nash, J.G. Guillem, P.B. Paty, R. Yaeger, Z.K. Stadler, K. Seier, M. Gonen, N.H. Segal, D.L. Reidy, A. Varghese, J. Shia, E. Vakiani, A.J. Wu, C.H. Crane, M.J. Gollub, J. Garcia-Aguilar, L.B. Saltz, and M.R. Weiser. 2018. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncology 4(6):e180071.

Chapman, P.B., A. Hauschild, C. Robert, J.B. Haanen, P. Ascierto, J. Larkin, R. Dummer, C. Garbe, A. Testori, M. Maio, D. Hogg, P. Lorigan, C. Lebbe, T. Jouary, D. Schadendorf, A. Ribas, S.J. O’Day, J.A. Sosman, J.M. Kirkwood, A.M.M. Eggermont, B. Dreno, K. Nolop, J. Li, B. Nelson, J. Hou, R.J. Lee, K.T. Flaherty, and G.A. McArthur. 2011. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. New England Journal of Medicine 364(26):2507–2516.

Chaturvedi, A.K., E.A. Engels, W.F. Anderson, and M.L. Gillison. 2008. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. Journal of Clinical Oncology 26(4):612–619.

Cohen, E.E.W., R.B. Bell, C.B. Bifulco, B. Burtness, M.L. Gillison, K.J. Harrington, Q.-T. Le, N.Y. Lee, R. Leidner, R.L. Lewis, L. Licitra, H. Mehanna, L.K. Mell, A. Raben, A.G. Sikora, R. Uppaluri, F. Whitworth, D.P. Zandberg, and R.L. Ferris. 2019. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). Journal for ImmunoTherapy of Cancer 7(1):184.

Coleman, R.L., G.F. Fleming, M.F. Brady, E.M. Swisher, K.D. Steffensen, M. Friedlander, A. Okamoto, K.N. Moore, N. Efrat Ben-Baruch, T.L. Werner, N.G. Cloven, A. Oaknin, P.A. DiSilvestro, M.A. Morgan, J.H. Nam, C.A. Leath, 3rd, S. Nicum, A.R. Hagemann, R.D. Littell, D. Cella, S. Baron-Hay, J. Garcia-Donas, M. Mizuno, K. BellMcGuinn, D.M. Sullivan, B.A. Bach, S. Bhattacharya, C.K. Ratajczak, P.J. Ansell, M.H. Dinh, C. Aghajanian, and M.A. Bookman. 2019. Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer. New England Journal of Medicine 381(25):2403–2415.

Conroy, T., F. Desseigne, M. Ychou, O. Bouché, R. Guimbaud, Y. Bécouarn, A. Adenis, J.L. Raoul, S. Gourgou-Bourgade, C. de la Fouchardière, J. Bennouna, J.B. Bachet, F. Khemissa-Akouz, D. Péré-Vergé, C. Delbaldo, E. Assenat, B. Chauffert, P. Michel, C. Montoto-Grillot, and M. Ducreux. 2011. Folfirinox versus gemcitabine for metastatic pancreatic cancer. New England Journal of Medicine 364(19):1817–1825.

Cremolini, C., F. Loupakis, C. Antoniotti, C. Lupi, E. Sensi, S. Lonardi, S. Mezi, G. Tomasello, M. Ronzoni, A. Zaniboni, G. Tonini, C. Carlomagno, G. Allegrini, S. Chiara, M. D’Amico, C. Granetto, M. Cazzaniga, L. Boni, G. Fontanini, and A. Falcone. 2015. FOLFOXIRI plus bevacizumab versus FLOFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: Updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study. The Lancet Oncology 16(13):1306–1315.

Cress, R.D., Y.S. Chen, C.R. Morris, M. Petersen, and G.S. Leiserowitz. 2015. Characteristics of long-term survivors of epithelial ovarian cancer. Obstetrics & Gynecology 126(3):491–497.

Cupit-Link, M.C., A. Mukta, W.A. Wood, and S.K. Hashmi. 2018. Relationship between aging and hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation 24(10):1965–1970.

Dzienis, M.R., and V.G. Atkinson. 2014. Response rate to vemurafenib in patients with B-RAF-positive melanoma brain metastases: A retrospective review. Melanoma Research 24(4):349–353.

Eggermont, A.M., V. Chiarion-Sileni, J.J. Grob, R. Dummer, J.D. Wolchok, H. Schmidt, O. Hamid, C. Robert, P.A. Ascierto, J.M. Richards, C. Lebbé, V. Ferraresi, M. Smylie, J.S. Weber, M. Maio, C. Konto, A. Hoos, V. de Pril, R. K. Gurunath, G. de Schaetzen, S. Suciu, and A. Testori. 2015. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncology 16(5):522–530.

Eggermont, A.M.M., C.U. Blank, M. Mandala, G.V. Long, V. Atkinson, S. Dalle, A. Haydon, M. Lichinitser, A. Khattak, M.S. Carlino, S. Sandhu, J. Larkin, S. Puig, P.A. Ascierto, P. Rutkowski, D. Schadendorf, R. Koornstra, L. Hernandez-Aya, M. Maio, A.J.M. van den Eertwegh, J.-J. Grob, R. Gutzmer, R. Jamal, P. Lorigan, N. Ibrahim, S. Marreaud, A.C.J. van Akkooi, S. Suciu, and C. Robert. 2018. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. New England Journal of Medicine 378(19):1789–1801.

Fillmore, N.R., S.V. Yellapragada, C. Ifeorah, A. Mehta, D. Cirstea, P.S. White, G. Rivero, A. Zimolzak, S. Pyarajan, N. Do, M. Brophy, and N.C. Munshi. 2019. With equal access, African American patients have superior survival compared to White patients with multiple myeloma: A VA study. Blood 133(24):2615–2618.

Finn, R.S., S. Qin, M. Ikeda, P.R. Galle, M. Ducreux, T.-Y. Kim, M. Kudo, V. Breder, P. Merle, A.O. Kaseb, D. Li, W. Verret, D.-Z. Xu, S. Hernandez, J. Liu, C. Huang, S. Mulla, Y. Wang, H.Y. Lim, A.X. Zhu, and A.-L. Cheng. 2020. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New England Journal of Medicine 382(20):1894–1905.

Fokas, E., M. Allgäuer, B. Polat, G. Klautke, G.G. Grabenbauer, R. Fietkau, T. Kuhnt, L. Staib, T. Brunner, A.L. Grosu, W. Schmiegel, L. Jacobasch, J. Weitz, G. Folprecht, A. Schlenska-Lange, M. Flentje, C.T. Germer, R. Grützmann, M. Schwarzbach, V. Paolucci, W.O. Bechstein, T. Friede, M. Ghadimi, R.D. Hofheinz, and C. Rödel. 2019. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. Journal of Clinical Oncology 37(34):3212–3222.

García-Martínez, E., A. Redondo, J.M. Piulats, A. Rodríguez, and A. Casado. 2020. Are antiangiogenics a good “partner” for immunotherapy in ovarian cancer? Angiogenesis 23:543–557.

González-Martín, A., B. Pothuri, I. Vergote, R. DePont Christensen, W. Graybill, M.R. Mirza, C. McCormick, D. Lorusso, P. Hoskins, G. Freyer, K. Baumann, K. Jardon, A. Redondo, R.G. Moore, C. Vulsteke, R.E. O’Cearbhaill, B. Lund, F. Backes, P. Barretina-Ginesta, A.F. Haggerty, M.J. Rubio-Pérez, M.S. Shahin, G. Mangili, W.H. Bradley, I. Bruchim, K. Sun, I.A. Malinowska, Y. Li, D. Gupta, and B.J. Monk. 2019. Niraparib in patients with newly diagnosed advanced ovarian cancer. New England Journal of Medicine 381(25):2391–2402.

Grothey, A., A.F. Sobrero, A.F. Shields, T. Yoshino, J. Paul, J. Taieb, J. Souglakos, Q. Shi, R. Kerr, R. Labianca, J.A. Meyerhardt, D. Vernerey, T. Yamanaka, I. Boukovinas, J.P. Meyers, L.A. Renfro, D. Niedzwiecki, T. Watanabe, V. Torri, M. Saunders, D.J. Sargent, T. Andre, and T. Iveson. 2018. Duration of adjuvant chemotherapy for stage III colon cancer. New England Journal of Medicine 378(13):1177–1188.

Hamid, O., C.L. Cowey, M. Offner, M. Faries, and R.D. Carvajal. 2019. Efficacy, safety, and tolerability of approved combination BRAF and MEK inhibitor regimens for BRAFmutant melanoma. Cancers 11(11):1642.

Hashibe, M., P. Brennan, S.-C. Chuang, S. Boccia, X. Castellsague, C. Chen, M.P. Curado, L. Dal Maso, A.W. Daudt, E. Fabianova, L. Fernandez, V. Wünsch-Filho, S. Frances-chi, R.B. Hayes, R. Herrero, K. Kelsey, S. Koifman, C. La Vecchia, P. Lazarus, F. Levi, J.J. Lence, D. Mates, E. Matos, A. Menezes, M.D. McClean, J. Muscat, J. Eluf-Neto, A.F. Olshan, M. Purdue, P. Rudnai, S.M. Schwartz, E. Smith, E.M. Sturgis, N. Szeszenia-Dabrowska, R. Talamini, Q. Wei, D.M. Winn, O. Shangina, A. Pilarska, Z.-F. Zhang, G. Ferro, J. Berthiller, and P. Boffetta. 2009. Interaction between tobacco and alcohol use and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer epidemiology consortium. Cancer Epidemiology, Biomarkers & Prevention 18(2):541–550.

Heinemann, V., L.F. von Weikersthal, T. Decker, A. Kiani, U. Vehling-Kaiser, S.E. Al-Batran, T. Heintges, C. Lerchenmüller, C. Kahl, G. Seipelt, F. Kullmann, M. Stauch, W. Scheithauer, J. Hielscher, M. Scholz, S. Müller, H. Link, N. Niederle, A. Rost, H.G. Höffkes, M. Moehler, R.U. Lindig, D.P. Modest, L. Rossius, T. Kirchner, A. Jung, and S. Stintzing. 2014. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncology 15(10):1065–1075.

Hilal, Z., B. Schultheis, F. Hartmann, A. Dogan, C. Cetin, H. Krentel, S. Schiermeier, and C.B. Tempfer. 2016. What characterizes long-term survivors of recurrent ovarian cancer? Case report and review of the literature. Anticancer Research 36(10):5365–5371.

Howlader, N., A.M. Noone, M. Krapcho, D. Miller, A. Brest, M. Yu, J. Ruhl, Z. Tatalovich, A. Mariotto, D.R. Lewis, H.S. Chen, E.J. Feuer, and K.A. Cronin. 2020. SEER cancer statistics review, 1975–2017. https://seer.cancer.gov/csr/1975_2017 (accessed September 1, 2020).

Inamoto, Y., and S.J. Lee. 2017. Late effects of blood and marrow transplantation. Haematologica 102(4):614–625.

Jarufe, N.P., C. Coldham, T. Orug, A.D. Mayer, D.F. Mirza, J.A. Buckels, and S.R. Bramhall. 2005. Neuroendocrine tumours of the pancreas: Predictors of survival after surgical treatment. Digestive Surgery 22(3):157–162.

Jemal, A., E.P. Simard, C. Dorell, A.M. Noone, L.E. Markowitz, B. Kohler, C. Eheman, M. Saraiya, P. Bandi, D. Saslow, K.A. Cronin, M. Watson, M. Schiffman, S.J. Henley, M.J. Schymura, R.N. Anderson, D. Yankey, and B.K. Edwards. 2013. Annual report to the nation on the status of cancer, 1975–2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. Journal of the National Cancer Institute 105(3):175–201.

Kansagra, A., S. Farnia, and N. Majhail. 2020. Expanding access to chimeric antigen receptor T-cell therapies: Challenges and opportunities. American Society of Clinical Oncology Educational Book 40:e27–e34.

Kim, J.Y., C.H. Cho, and H.S. Song. 2017. Targeted therapy of ovarian cancer including immune check point inhibitor. Korean Journal of Internal Medicine 32(5):798.

Larkin, J., V. Chiarion-Sileni, R. Gonzalez, J.-J. Grob, P. Rutkowski, C.D. Lao, C.L. Cowey, D. Schadendorf, J. Wagstaff, R. Dummer, P.F. Ferrucci, M. Smylie, D. Hogg, A. Hill, I. Márquez-Rodas, J. Haanen, M. Guidoboni, M. Maio, P. Schöffski, M.S. Carlino, C. Lebbé, G. McArthur, P.A. Ascierto, G.A. Daniels, G.V. Long, L. Bastholt, J.I. Rizzo, A. Balogh, A. Moshyk, F.S. Hodi, and J.D. Wolchok. 2019. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. New England Journal of Medicine 381(16):1535–1546.

Linch, D.C., D. Winfield, A.H. Goldstone, D. Moir, B. Hancock, A. McMillan, R. Chopra, D. Milligan, and G.V. Hudson. 1993. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: Results of a BNLI randomised trial. Lancet 341(8852):1051–1054.

Lorusso, D., E. Tripodi, G. Maltese, S. Lepori, I. Sabatucci, G. Bogani, and F. Raspagliesi. 2018. Spotlight on olaparib in the treatment of BRCA-mutated ovarian cancer: Design, development and place in therapy. Drug Design, Development and Therapy 12:1501.

Medeiros, B.C., J. Possick, and M. Fradley. 2018. Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: Strategies for monitoring, detecting, and managing. Blood Reviews 32(4):289–299.

Mehta, V., G.P. Yu, and S.P. Schantz. 2010. Population-based analysis of oral and oropharyngeal carcinoma: Changing trends of histopathologic differentiation, survival and patient demographics. Laryngoscope 120(11):2203–2212.

Mirza, M.R., R.L. Coleman, A. González-Martín, K.N. Moore, N. Colombo, I. Ray-Coquard, and S. Pignata. 2020. The forefront of ovarian cancer therapy: Update on PARP inhibitors. Annals of Oncology 31(9):1148–1159.

NCCN (National Comprehensive Cancer Network). 2019. NCCN clinical practice guidelines in oncology: Ovarian cancer including fallopian tube cancer and primary peritoneal cancer, version 1.2019. https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf (accessed April 30, 2020).

Nguyen, L.H., P.H. Liu, X. Zheng, N. Keum, X. Zong, X. Li, K. Wu, C.S. Fuchs, S. Ogino, K.Ng, W.C. Willett, A.T. Chan, E.L. Giovannucci, and Y. Cao. 2018. Sedentary behaviors, TV viewing time, and risk of young-onset colorectal cancer. JNCI Cancer Spectrum 2(4):pky073.

NLM (National Library of Medicine). 2020. Head and neck squamous cell carcinoma. https://ghr.nlm.nih.gov/condition/head-and-neck-squamous-cell-carcinoma (accessed August 3, 2020).

PDQ® Adult Treatment Editorial Board. 2020a. Pancreatic neuroendocrine tumors (islet cell tumors) treatment (PDQ®): Health professional version. Bethesda, MD: National Cancer Institute. https://www.cancer.gov/types/pancreatic/hp/pnet-treatment-pdq (accessed October 15, 2020).

PDQ® Adult Treatment Editorial Board. 2020b. Adult Hodgkin lymphoma treatment (PDQ®): Health Professional Version. Bethesda, MD: National Cancer Institute. https://www.ncbi.nlm.nih.gov/books/NBK66038 (accessed December 30, 2020).

Pulte, D., and H. Brenner. 2010. Changes in survival in head and neck cancers in the late 20th and early 21st century: A period analysis. The Oncologist 15(9):994–1001.

Rahman, R., C. Schmaltz, C.S. Jackson, E.J. Simoes, J. Jackson-Thompson, and J.A. Ibdah. 2015. Increased risk for colorectal cancer under age 50 in racial and ethnic minorities living in the United States. Cancer Medicine 4(12):1863–1870.

Robert, C., G.V. Long, J. Schachter, A. Arance, J.J. Grob, L. Mortier, A. Daud, M.S. Carlino, C.M. McNeil, M. Lotem, J.M.G. Larkin, P. Lorigan, B. Neyns, C.U. Blank, T.M. Petrella, O. Hamid, H. Zhou, B.H. Moreno, N. Ibrahim, and A. Ribas. 2017. Long-term outcomes in patients (pts) with ipilimumab (ipi)-naive advanced melanoma in the phase 3 KEYNOTE-006 study who completed pembrolizumab (pembro) treatment. Journal of Clinical Oncology 35(15_suppl):9504.

Robert, C., J.J. Grob, D. Stroyakovskiy, B. Karaszewska, A. Hauschild, E. Levchenko, V. Chiarion Sileni, J. Schachter, C. Garbe, I. Bondarenko, H. Gogas, M. Mandalá, J.B.A.G. Haanen, C. Lebbé, A. Mackiewicz, P. Rutkowski, P.D. Nathan, A. Ribas, M.A. Davies, K.T. Flaherty, P. Burgess, M. Tan, E. Gasal, M. Voi, D. Schadendorf, and G.V. Long. 2019. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. New England Journal of Medicine 381(7):626–636.

Salvatore, T., R. Marfella, M.R. Rizzo, and F.C. Sasso. 2015. Pancreatic cancer and diabetes: A two-way relationship in the perspective of diabetologist. International Journal of Surgery 21:S72–S77.

Saraiya, M., E.R. Unger, T.D. Thompson, C.F. Lynch, B.Y. Hernandez, C.W. Lyu, M. Steinau, M. Watson, E.J. Wilkinson, C. Hopenhayn, G. Copeland, W. Cozen, E.S. Peters, Y. Huang, M.S. Saber, S. Altekruse, M. T. Goodman, and HPV Typing of Cancers Workgroup. 2015. U.S. assessment of HPV types in cancers: Implications for current and 9-valent HPV vaccines. Journal of the National Cancer Institute 107(6):djv086.

Schadendorf, D., F.S. Hodi, C. Robert, J.S. Weber, K. Margolin, O. Hamid, D. Patt, T.T. Chen, D.M. Berman, and J.D. Wolchok. 2015. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. Journal of Clinical Oncology 33(17):1889–1894.

Schmitz, N., B. Pfistner, M. Sextro, M. Sieber, A.M. Carella, M. Haenel, F. Boissevain, R. Zschaber, P. Müller, H. Kirchner, A. Lohri, S. Decker, B. Koch, D. Hasenclever, A.H. Goldstone, and V. Diehl. 2002. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: A randomised trial. The Lancet 359(9323):2065–2071.

SEER (Surveillance, Epidemiology, and End Results Programs). n.d.-a. Cancer stat facts: Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/hodg.html (accessed September 14, 2020).

SEER. n.d.-b. Cancer stat facts: Leukemia. https://seer.cancer.gov/statfacts/html/leuks.html (accessed September 21, 2020).

SEER. n.d.-c. Cancer stat facts: Leukemia—acute lymphocytic leukemia (ALL). https://seer.cancer.gov/statfacts/html/alyl.html (accessed September 14, 2020).

SEER. n.d.-d. Cancer stat facts: Leukemia—acute myeloid leukemia (AML). https://seer.cancer.gov/statfacts/html/amyl.html (accessed September 14, 2020).

SEER. n.d.-e. Cancer stat facts: Leukemia—chronic lymphocytic leukemia (CLL). https://seer.cancer.gov/statfacts/html/clyl.html (accessed September 21, 2020).

SEER. n.d.-f. Cancer stat facts: Leukemia—chronic myeloid leukemia (CML). https://seer.cancer.gov/statfacts/html/cmyl.html (accessed September 21, 2020).

SEER. n.d.-g. Cancer stat facts: Liver and intrahepatic bile duct cancer. https://seer.cancer.gov/statfacts/html/livibd.html (accessed September 14, 2020).

SEER. n.d.-h. Cancer stat facts: Melanoma of the skin. https://seer.cancer.gov/statfacts/html/melan.html (accessed September 14, 2020).

SEER. n.d.-i. Cancer stat facts: Non-Hodgkin lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html (accessed September, 2020).

SEER. n.d.-j. Cancer stat facts: Oral cavity and pharynx cancer. https://seer.cancer.gov/statfacts/html/oralcav.html (accessed September 21, 2020).

SEER. n.d.-k. Cancer stat facts: Ovarian cancer. https://seer.cancer.gov/statfacts/html/ovary.html (accessed September 21, 2020).

SEER. n.d.-l. Cancer stat facts: Pancreatic cancer. https://seer.cancer.gov/statfacts/html/pancreas.html (accessed September 21, 2020).

SEER. n.d.-m. Melanoma of the skin. Recent trends in SEER age-adjusted incidence rates, 2000-2017, by stage at diagnosis, both sexes, all races (includes Hispanic), all ages, observed rates. https://seer.cancer.gov/explorer/application.html?site=53&data_type=1&graph_type=2&compareBy=stage&chk_stage_104=104&chk_stage_105=105&chk_stage_106=106&chk_stage_107=107&sex=1&race=1&age_range=1&hdn_rate_type=1&advopt_precision=1&advopt_display=2 (accessed September 14, 2020).

Shanbhag, S., and R.F. Ambinder. 2018. Hodgkin lymphoma: A review and update on recent progress. CA: A Cancer Journal for Clinicians 68(2):116–132.

Siegel, R.L., K.D. Miller, S.A. Fedewa, D.J. Ahnen, R.G.S. Meester, A. Barzi, and A. Jemal. 2017. Colorectal cancer statistics, 2017. CA: A Cancer Journal for Clinicians 67(3):177–193.

Siegel, R.L., K.D. Miller, and A. Jemal. 2020. Cancer statistics, 2020. CA: A Cancer Journal for Clinicians 70(1):7–30.

Smith, J.J., P. Strombom, O.S. Chow, C.S. Roxburgh, P. Lynn, A. Eaton, M. Widmar, K. Ganesh, R. Yaeger, A. Cercek, M.R. Weiser, G.M. Nash, J.G. Guillem, L.K.F. Temple, S.B. Chalasani, J.L. Fuqua, I. Petkovska, A.J. Wu, M. Reyngold, E. Vakiani, J. Shia, N.H. Segal, J.D. Smith, C. Crane, M.J. Gollub, M. Gonen, L.B. Saltz, J. Garcia-Aguilar, and P.B. Paty. 2019. Assessment of a watch-and-wait strategy for rectal cancer in patients with a complete response after neoadjuvant therapy. JAMA Oncology 5(4):e185896.

SSA (U.S. Social Security Administration). 2015. 13.00 cancer—Adult. https://www.ssa.gov/disability/professionals/bluebook/13.00-NeoplasticDiseases-Malignant-Adult.htm (accessed January 16, 2020).

Stein, A.P., S. Saha, J.L. Kraninger, A.D. Swick, M. Yu, P.F. Lambert, and R.J. Kimple. 2015. Prevalence of human papillomavirus in oropharyngeal cancer: A systematic review. Cancer Journal 21(3):138–146.

Stock, W., S.M. Luger, A.S. Advani, J. Yin, R.C. Harvey, C.G. Mullighan, C.L. Willman, N. Fulton, K.M. Laumann, G. Malnassy, E. Paietta, E. Parker, S. Geyer, K. Mrózek, C.D. Bloomfield, B. Sanford, G. Marcucci, M. Liedtke, D.F. Claxton, M.C. Foster, J.A. Bogart, J.C. Grecula, F.R. Appelbaum, H. Erba, M.R. Litzow, M.S. Tallman, R.M. Stone, and R.A. Larson. 2019. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: Results of CALGB 10403. Blood 133(14):1548–1559.

Sung, H., R.L. Siegel, P.S. Rosenberg, and A. Jemal. 2019. Emerging cancer trends among young adults in the USA: Analysis of a population-based cancer registry. The Lancet Public Health 4(3):e137–e147.

Tempero, M.A., M.P. Malafa, M. Al-Hawary, H. Asbun, A. Bain, S.W. Behrman, A.B. Benson, 3rd, E. Binder, D.B. Cardin, C. Cha, E.G. Chiorean, V. Chung, B. Czito, M. Dillhoff, E. Dotan, C.R. Ferrone, J. Hardacre, W.G. Hawkins, J. Herman, A.H. Ko, S. Komanduri, A. Koong, N. LoConte, A.M. Lowy, C. Moravek, E.K. Nakakura, E.M. O’Reilly, J. Obando, S. Reddy, C. Scaife, S. Thayer, C.D. Weekes, R.A. Wolff, B.M. Wolpin, J. Burns, and S. Darlow. 2017. Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology. Journal of the National Comprehensive Cancer Network 15(8):1028–1061.

Tewari, K.S., J.J. Java, R.N. Eskander, B.J. Monk, and R.A. Burger. 2016. Early initiation of chemotherapy following complete resection of advanced ovarian cancer associated with improved survival: NRG Oncology/Gynecologic Oncology Group study. Annals of Oncology 27(1):114–121.

Thrall, M.M., H.J. Gray, R.G. Symons, N.S. Weiss, D.R. Flum, and B.A. Goff. 2011. Trends in treatment of advanced epithelial ovarian cancer in the Medicare population. Gynecologic Oncology 122(1):100–106.

Valle, J., H. Wasan, D.H. Palmer, D. Cunningham, A. Anthoney, A. Maraveyas, S. Madhusudan, T. Iveson, S. Hughes, S.P. Pereira, M. Roughton, and J. Bridgewater. 2010. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. New England Journal of Medicine 362(14):1273–1281.

Venook, A.P., D. Niedzwiecki, H.J. Lenz, F. Innocenti, B. Fruth, J.A. Meyerhardt, D. Schrag, C. Greene, B.H. O’Neil, J.N. Atkins, S. Berry, B.N. Polite, E.M. O’Reilly, R.M. Goldberg, H.S. Hochster, R.L. Schilsky, M.M. Bertagnolli, A.B. El-Khoueiry, P. Watson, A.B. Benson, 3rd, D.L. Mulkerin, R.J. Mayer, and C. Blanke. 2017. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA 317(23):2392–2401.

Viveiros, P., A. Riaz, R.J. Lewandowski, and D. Mahalingam. 2019. Current state of liver-directed therapies and combinatory approaches with systemic therapy in hepatocellular carcinoma (HCC). Cancers 11(8):1085.

Von Hoff, D.D., T. Ervin, F.P. Arena, E.G. Chiorean, J. Infante, M. Moore, T. Seay, S.A. Tjulandin, W.W. Ma, M.N. Saleh, M. Harris, M. Reni, S. Dowden, D. Laheru, N. Bahary, R.K. Ramanathan, J. Tabernero, M. Hidalgo, D. Goldstein, E. Van Cutsem, X. Wei, J. Iglesias, and M.F. Renschler. 2013. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. New England Journal of Medicine 369(18):1691–1703.

Wang, Q., H. Peng, X. Qi, M. Wu, and X. Zhao. 2020. Targeted therapies in gynecological cancers: A comprehensive review of clinical evidence. Signal Transduction and Targeted Therapy 5(1):137.

Waxman, A.J., P.J. Mink, S.S. Devesa, W.F. Anderson, B.M. Weiss, S.Y. Kristinsson, K.A. McGlynn, and O. Landgren. 2010. Racial disparities in incidence and outcome in multiple myeloma: A population-based study. Blood 116(25):5501–5506.

Yamamoto, J.F., and M.T. Goodman. 2008. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997–2002. Cancer Causes & Control 19(4):379–390.

Yang, B., J.B. Liu, S.K. So, S.S. Han, S.S. Wang, A. Hertz, S. Shariff-Marco, S. Lin Gomez, P.S. Rosenberg, M.H. Nguyen, and A.W. Hsing. 2018. Disparities in hepatocellular carcinoma incidence by race/ethnicity and geographic area in California: Implications for prevention. Cancer 124(17):3551–3559.

Yang, L., B. Zhang, G. Xing, J. Du, B. Yang, Q. Yuan, and Y. Yang. 2017. Neoadjuvant chemotherapy versus primary debulking surgery in advanced epithelial ovarian cancer: A meta-analysis of peri-operative outcome. PLOS ONE 12(10):e0186725.