Breast cancer is the most common non-cutaneous cancer in U.S. women, with an estimated 63,960 cases of in situ disease and 266,120 cases of invasive disease in 2018. Fewer than one of six women diagnosed with breast cancer die of the disease. By comparison, it is estimated that about 70,500 American women will die of lung cancer in 2018.
Widespread adoption of screening increases breast cancer detection in a given population and changes the characteristics of cancers detected, with increased incidence of lower-risk cancers, premalignant lesions, and ductal carcinoma in situ (DCIS). Population studies from the United States and the United Kingdom demonstrate an increase in DCIS and invasive breast cancer incidence since the 1970s, attributable to the widespread adoption of both postmenopausal hormone therapy and screening mammography. In the last decade, women have refrained from using postmenopausal hormones, and breast cancer incidence has declined, but not to the levels seen before the widespread use of screening mammography.
Increasing age is the most important risk factor for most cancers. Other risk factors for breast cancer include the following:
• Family health history
• Major inheritance susceptibility
• Germline mutation of the BRCA1 and BRCA2 genes and other breast cancer susceptibility genes
• Alcohol intake
• Breast tissue density (mammographic)
• Estrogen (endogenous)
• Menstrual history (early menarche/late menopause)
• Older age at first birth
• Hormone therapy history
• Combination estrogen plus progestin hormone replacement therapy
• Obesity (postmenopausal)
• Personal history of breast cancer
• Personal history of benign breast disease (BBD) (proliferative forms of BBD)
• Radiation exposure to breast/chest
Age-specific risk estimates are available to help counsel and design screening strategies for women with a family history of breast cancer.
Of all women with breast cancer, 5% to 10% may have a germline mutation of the genes BRCA1 and BRCA2. Specific mutations of BRCA1 and BRCA2 are more common in women of Jewish ancestry. The estimated lifetime risk of developing breast cancer for women with BRCA1 and BRCA2 mutations is 40% to 85%. Carriers with a history of breast cancer have an increased risk of contralateral disease that may be as high as 5% per year.
Mutations in either the BRCA1 or the BRCA2 gene also confer an increased risk of ovarian cancer or other primary cancers.
Clinical trials have established that screening asymptomatic women using mammography, with or without clinical breast examination, decreases breast cancer mortality.
When breast cancer is suspected, patient management generally includes the following:
• Confirmation of the diagnosis
• Evaluation of the stage of disease
• Selection of therapy
The following tests and procedures are used to diagnose breast cancer:
• Breast magnetic resonance imaging (MRI), if clinically indicated
Pathologically, breast cancer can be a multicentric and bilateral disease. Bilateral disease is somewhat more common in patients with infiltrating lobular carcinoma. At 10 years after diagnosis, the risk of a primary breast cancer in the contralateral breast ranges from 3% to 10%, although endocrine therapy decreases that risk. The development of a contralateral breast cancer is associated with an increased risk of distant recurrence. When BRCA1/BRCA2 mutation carriers have been diagnosed before the age of 40 years, the risk of a contralateral breast cancer reaches nearly 50% in the ensuing 25 years.
Patients who have breast cancer will undergo bilateral mammography at the time of diagnosis to rule out synchronous contralateral disease. To detect either recurrence in the ipsilateral breast in patients treated with breast-conserving surgery or a second primary cancer in the contralateral breast.
The role of MRI in screening the contralateral breast and monitoring women treated with breast-conserving therapy continues to evolve. Because an increased detection rate of mammographically occult disease has been demonstrated, the selective use of MRI for additional screening is applied more frequently despite the absence of randomized, controlled data. Because only 25% of MRI-positive findings represent malignancy, pathologic confirmation before treatment is recommended. Whether this increased detection rate will translate into improved treatment outcome is unknown.
Prognostic and Predictive Factors
Breast cancer is commonly treated by various combinations of surgery, radiation therapy, chemotherapy, and hormone therapy. Prognosis and selection of therapy may be influenced by the following clinical and pathological features (based on conventional histology and immunohistochemistry):
• Menopausal status of the patient
• Stage of the disease
• Grade of the primary tumor
• Estrogen receptor (ER) and progesterone receptor (PR) status of the tumor
• Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or amplification
Breast cancer is classified into a variety of histologic types, some of which have prognostic importance. Favorable histologic types include mucinous, medullary, and tubular carcinomas.
The use of molecular profiling in breast cancer includes the following:
• ER and PR status testing
• HER2/neu receptor status testing
• Gene profile testing by microarray assay or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX)
On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the following types:
• Hormone receptor positive
• HER2/neu positive
• Triple negative (ER, PR, and HER2/neu negative)
ER, PR, and HER2 status are important in determining prognosis and in predicting response to endocrine and HER2-directed therapy. The American Society of Clinical Oncology/College of American Pathologists consensus panel has published guidelines to help standardize the performance, interpretation, and reporting of assays used to assess the ER/PR status by immunohistochemistry and HER2 status by immunohistochemistry and in situ hybridization.
The National Surgical Adjuvant Breast and Bowel Project trial randomly assigned patients to receive tamoxifen or placebo; the results, favoring tamoxifen, changed clinical practice in the late 1980s. Formalin-fixed, paraffin-embedded tissue was available for 668 patients. The 10-year distant recurrence risk for patients treated with tamoxifen was 7% for those with a low RS, 14% for those with an intermediate RS, and 31% for those with high RS (P < .001).
The 10-year disease-free survival (DFS) improved from 60% to 88% by adding chemotherapy to tamoxifen in the high-risk group, while no benefit was observed in the low RS group.
Different types of treatment are available for patients with breast cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials.
Five types of standard treatment are used:
• Radiation therapy
• Hormone therapy
• Targeted therapy
Most patients with breast cancer have surgery to remove the cancer. Sentinel lymph node biopsy is the removal of the sentinel lymph node during surgery. The sentinel lymph node is the first lymph node to receive lymphatic drainage from a tumor. It is the first lymph node where the cancer is likely to spread.
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy).
The way the chemotherapy is given depends on the type and stage of the cancer being treated. Systemic chemotherapy is used in the treatment of breast cancer.
Hormone therapy is a cancer treatment that removes hormones or blocks their action and thereby stops cancer cells from growing. Hormones are substances made by glands in the body and circulated in the bloodstream. Some hormones can cause certain cancers to grow. If tests show that the cancer cells have places where hormones can attach (receptors), drugs, surgery, or radiation therapy are used to reduce the production of hormones or block them from working.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibodies, tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and PARP inhibitors are types of targeted therapies used in the treatment of breast cancer.
Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify and block substances on cancer cells or normal substances that may help cancer cells grow.
Cancer of the colon is a highly treatable and often curable disease when localized to the bowel. Surgery is the primary form of treatment and results in cure in approximately 50% of the patients. Recurrence following surgery is a major problem and is often the ultimate cause of death.
Incidence and Mortality
Estimated new cases and deaths from colon cancer in the United States in 2018:
• New cases: 97,220 (colon cancer only)
• Deaths: 50,630 (colon and rectal cancers combined)
• Gastrointestinal stromal tumors can occur in the colon
Increasing age is the most important risk factor for most cancers. Other risk factors for colorectal cancer include the following:
• Family history of colorectal cancer in a first-degree relative
• Personal history of colorectal adenomas, colorectal cancer, or ovarian cancer
• Hereditary conditions, including familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]
• Personal history of long-standing chronic ulcerative colitis or Crohn colitis.
• Excessive alcohol use
• Cigarette smoking
• Race/ethnicity: African American
Because of the frequency of the disease, ability to identify high-risk groups, slow growth of primary lesions, better survival of patients with early-stage lesions, and relative simplicity and accuracy of screening tests, screening for colon cancer should be a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer.
The prognosis of patients with colon cancer is clearly related to the following:
• The degree of penetration of the tumor through the bowel wall
• The presence or absence of nodal involvement
• The presence or absence of distant metastases
These three characteristics form the basis for all staging systems developed for this disease.
Other prognostic factors include the following:
• Bowel obstruction and bowel perforation are indicators of poor prognosis
• Elevated pretreatment serum levels of carcinoembryonic antigen (CEA) have a negative prognostic significance
Treatment decisions depend on factors such as physician and patient preferences and the stage of the disease, rather than the age of the patient.
Racial differences in overall survival (OS) after adjuvant therapy have been observed, without differences in disease-free survival, suggesting that comorbid conditions play a role in survival outcome in different patient populations.
Follow-up and Survival
Limited data and no level 1 evidence are available to guide patients and physicians in surveillance and management of patients after surgical resection and adjuvant therapy. The American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend specific surveillance and follow-up strategies.
Following treatment of colon cancer, periodic evaluations may lead to the earlier identification and management of recurrent disease The impact of such monitoring on overall mortality of patients with recurrent colon cancer, however, is limited by the relatively small proportion of patients in whom localized, potentially curable metastases are found. To date, no large-scale randomized trials have documented an OS benefit for standard, postoperative monitoring programs.
CEA is a serum glycoprotein frequently used in the management of patients with colon cancer. A review of the use of this tumor marker suggests the following:
• A CEA level is not a valuable screening test for colorectal cancer because of the large numbers of false-positive and false-negative reports
• Postoperative CEA testing should be restricted to patients who would be candidates for resection of liver or lung metastases
• Routine use of CEA levels alone for monitoring response to treatment should not be recommended
• Primary Surgical Therapy
• Adjuvant Chemotherapy
• Adjuvant Radiation Therapy
The optimal regimen and frequency of follow-up examinations are not well defined because the impact on patient survival is not clear and the quality of data is poor.
Standard treatment for patients with colon cancer has been open surgical resection of the primary and regional lymph nodes for localized disease.
The potential value of adjuvant chemotherapy for patients with stage II colon cancer is controversial. Pooled analyses and meta-analyses have suggested a 2% to 4% improvement in OS for patients treated with adjuvant fluorouracil (5-FU)–based therapy compared with observation.
While combined modality therapy with chemotherapy and radiation therapy has a significant role in the management of patients with rectal cancer, the role of adjuvant radiation therapy for patients with colon cancer (above the peritoneal reflection) is not well defined. Patterns-of-care analyses and single-institution retrospective reviews suggest a role for radiation therapy in certain high-risk subsets of colon cancer patients (e.g., T4, tumor location in immobile sites, local perforation, obstruction, and residual disease postresection).
It is difficult to separate epidemiological considerations of rectal cancer from those of colon cancer because epidemiological studies often consider colon and rectal cancer (i.e., colorectal cancer) together. Worldwide, colorectal cancer is the third most common form of cancer. In 2012, there were an estimated 1.36 million new cases of colorectal cancer and 694,000 deaths.
Colorectal cancer affects men and women almost equally. Among all racial groups in the United States, African Americans have the highest sporadic colorectal cancer incidence and mortality rates.
Evidence supports the value of screening for rectal cancer as a part of routine care for all adults aged 50 years and older, especially for those with first-degree relatives with colorectal cancer, for the following reasons:
• Ability to identify high-risk groups
• Slow growth of primary lesions
• Better survival of patients with early-stage lesions
• Relative simplicity and accuracy of screening tests
As with colon cancer, symptoms of rectal cancer may include the following:
• Rectal bleeding
• Change in bowel habits
• Abdominal pain
• Intestinal obstruction
• Change in appetite
• Weight loss
With the exception of obstructive symptoms, these symptoms do not necessarily correlate with the stage of disease or signify a particular diagnosis.
• Physical exam and history
• Digital rectal exam
• Carcinoembryonic antigen (CEA) assay
• Reverse-transcription polymerase chain reaction test
Physical examination may reveal a palpable mass and bright blood in the rectum. Adenopathy, hepatomegaly, or pulmonary signs may be present with metastatic disease. Laboratory examination may reveal iron-deficiency anemia and electrolyte and liver function abnormalities.
• Tumor adherence to or invasion of adjacent organs
• Presence or absence of tumor involvement in the lymph nodes and the number of positive lymph nodes
• Presence or absence of distant metastases
• Perforation or obstruction of the bowel
And also the presence or absence of high-risk pathologic features, including the following:
• Tumor positive surgical margins
• Lymphatic or vascular invasion
• Perineural invasion
• Poorly differentiated histology
Only disease stage (designated by tumor [T], nodal status [N], and distant metastasis [M]) has been validated as a prognostic factor in multi-institutional prospective studies. A major pooled analysis evaluating the impact of T and N stage and treatment on survival and relapse in patients with rectal cancer who are treated with adjuvant therapy has been published and confirms these findings.
The management of rectal cancer varies somewhat from that of colon cancer because of the increased risk of local recurrence and a poorer overall prognosis. Differences include surgical technique, the use of radiation therapy, and the method of chemotherapy administration. In addition to determining the intent of rectal cancer surgery (i.e., curative or palliative), it is important to consider therapeutic issues related to the maintenance or restoration of normal anal sphincter, genitourinary function, and sexual function.
The approach to the management of rectal cancer is multimodal and involves a multidisciplinary team of cancer specialists with expertise in gastroenterology, medical oncology, surgical oncology, radiation oncology, and radiology.
A large number of studies have evaluated other clinical, pathologic, and molecular parameters. As yet, none has been validated in multi-institutional prospective trials. For example, microsatellite instability–high, also associated with Lynch syndrome–related rectal cancer, was shown to be associated with improved survival independent of tumor stage in a population-based series of 607 patients with colorectal cancer who were 50 years old or younger at the time of diagnosis. In addition, gene expression profiling has been reported to be useful in predicting the response of rectal adenocarcinomas to preoperative chemoradiation therapy and in determining the prognosis of stages II and III rectal cancer after neoadjuvant 5-fluorouracil-based chemoradiation therapy.
Follow-up after Treatment
The primary goals of postoperative surveillance programs for rectal cancer are:
• To assess the efficacy of initial therapy
• To detect new or metachronous malignancies
• To detect potentially curable recurrent or metastatic cancers
Routine, periodic studies following treatment for rectal cancer may lead to earlier identification and management of recurrent disease. A statistically significant survival benefit has been demonstrated for more intensive follow-up protocols in two clinical trials.
Guidelines for surveillance after initial treatment with curative intent for colorectal cancer vary between leading U.S. and European oncology societies, and optimal surveillance strategies remain uncertain. Large, well-designed, prospective, multi-institutional, randomized studies are required to establish an evidence-based consensus for follow-up evaluation.
Non-Small Cell Lung Cancer (NSCLC)
NSCLC is any type of epithelial lung cancer other than small cell lung cancer (SCLC). The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, but there are several other types that occur less frequently, and all types can occur in unusual histologic variants. Although NSCLCs are associated with cigarette smoke, adenocarcinomas may be found in patients who have never smoked. As a class, NSCLCs are relatively insensitive to chemotherapy and radiation therapy compared with SCLC. Patients with resectable disease may be cured by surgery or surgery followed by chemotherapy. Local control can be achieved with radiation therapy in a large number of patients with unresectable disease, but cure is seen only in a small number of patients. Patients with locally advanced unresectable disease may achieve long-term survival with radiation therapy combined with chemotherapy. Patients with advanced metastatic disease may achieve improved survival and palliation of symptoms with chemotherapy, targeted agents, and other supportive measures.
Incidence and Mortality
Lung cancer is the leading cause of cancer-related mortality in the United States. The 5-year relative survival rate from 1995 to 2001 for patients with lung cancer was 15.7%. The 5-year relative survival rate for patients with local-stage (49%), regional-stage (16%), and distant-stage (2%) disease varies markedly, depending on the stage at diagnosis.
Smoking-related lung carcinogenesis is a multistep process. Squamous cell carcinoma and adenocarcinoma have defined premalignant precursor lesions. Before becoming invasive, lung epithelium may undergo morphological changes that include the following:
• Carcinoma in situ
Dysplasia and carcinoma in situ are considered the principal premalignant lesions because they are more likely to progress to invasive cancer and less likely to spontaneously regress. In addition, after resection of a lung cancer, there is a 1% to 2% risk per patient per year that a second lung cancer will occur.
NSCLC consists of a heterogeneous group of histologies. The most common histologies include the following:
• Epidermoid or squamous cell carcinoma
• Large cell carcinoma
These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar.
Increasing age is the most important risk factor for most cancers. Other risk factors for lung cancer include the following:
• History of or current tobacco use: cigarettes, pipes, and cigar
• Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents
• Radiation exposure
• Living in an area with air pollution
• Family history of lung cancer
• Human immunodeficiency virus infection
The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime nonsmokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the number of cigarettes, duration of smoking and starting age.
A significant number of patients cured of their smoking-related lung cancer may develop a second malignancy. In the Lung Cancer Study Group trial of 907 patients with stage T1, N0 resected tumors, the rate was 1.8% per year for non-pulmonary second cancers and 1.6% per year for new lung cancers. Other studies have reported even higher risks of second tumors in long-term survivors, including rates of 10% for second lung cancers and 20% for all second cancers.
Because of the persistent risk of developing second lung cancers in former smokers, various chemoprevention strategies have been evaluated in randomized control trials. None of the phase III trials using the agents beta carotene, retinol, 13-cis-retinoic acid, [alpha]-tocopherol, N-acetylcysteine, or acetylsalicylic acid has demonstrated beneficial, reproducible results. Chemoprevention of second primary cancers of the upper respiratory and digestive tract is undergoing clinical evaluation in patients with early-stage
In patients considered at high risk for developing lung cancer, the only screening modality for early detection that has been shown to alter mortality is low-dose helical CT scanning. Studies of lung cancer screening with chest radiography and sputum cytology have failed to demonstrate that screening lowers lung cancer mortality rates.
Lung cancer may present with symptoms or be found incidentally on chest imaging. Symptoms and signs may result from the location of the primary local invasion or compression of adjacent thoracic structures, distant metastases, or paraneoplastic phenomena. The most common symptoms at presentation are worsening cough or chest pain.
Investigations of patients with suspected NSCLC focus on confirming the diagnosis and determining the extent of the disease. Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient.
The procedures used to determine the presence of cancer include the following:
• Physical examination
• Routine laboratory evaluation
• Chest x-ray
• Chest CT scan with infusion of contrast material
Before a patient begins lung cancer treatment, an experienced lung cancer pathologist must review the pathologic material. This is critical because SCLC, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with NSCLC. Immunohistochemistry and electron microscopy are invaluable techniques for diagnosis and subclassification, but most lung tumors can be classified by light microscopic criteria.
The identification of mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, subsets of adenocarcinoma now can be defined by specific mutations in genes encoding components of the epidermal growth factor receptor (EGFR) and downstream mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3K) signaling pathways. These mutations may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors.
Other genetic abnormalities of potential relevance to treatment decisions include translocations involving the anaplastic lymphoma kinase (ALK)-tyrosine kinase receptor, which are sensitive to ALK inhibitors, and amplification of MET (mesenchymal epithelial transition factor), which encodes the hepatocyte growth factor receptor. MET amplification has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.
Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors. Factors that have correlated with adverse prognosis include the following:
• Presence of pulmonary symptoms.
• Large tumor size (>3 cm).
• Nonsquamous histology.
• Metastases to multiple lymph nodes within a TNM-defined nodal station
• Vascular invasion
In non-small cell lung cancer (NSCLC), results of standard treatment are poor except for the most localized cancers. All newly diagnosed patients with NSCLC are potential candidates for studies evaluating new forms of treatment.
Surgery is potentially the most curative therapeutic option for this disease. Postoperative chemotherapy may provide an additional benefit to patients with resected NSCLC. Radiation therapy combined with chemotherapy can produce a cure in a small number of patients and can provide palliation in most patients. Prophylactic cranial irradiation may reduce the incidence of brain metastases, but there is no evidence of a survival benefit and the effect of prophylactic cranial irradiation on quality of life is not known. In patients with advanced-stage disease, chemotherapy or epidermal growth factor receptor (EGFR) kinase inhibitors offer modest improvements in median survival, though overall survival is poor.
Chemotherapy has produced short-term improvement in disease-related symptoms in patients with advanced NSCLC. Several clinical trials have attempted to assess the impact of chemotherapy on tumor-related symptoms and quality of life. In total, these studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life; however, the impact of chemotherapy on quality of life requires more study. In general, medically fit elderly patients with good performance status obtain the same benefits from treatment as younger patients.
The identification of gene mutations in lung cancer has led to the development of molecularly targeted therapy to improve the survival of subsets of patients with metastatic disease. In particular, genetic abnormalities in EGFR, MAPK, and PI3K signaling pathways in subsets of NSCLC may define mechanisms of drug sensitivity and primary or acquired resistance to kinase inhibitors. EGFR mutations strongly predict the improved response rate and progression-free survival of inhibitors of EGFR. Fusions of ALK with EML4 and other genes form translocation products that occur in a range from 3% to 7% in unselected NSCLC and are responsive to pharmacological inhibition of ALK by agents such as crizotinib. The MET oncogene encodes hepatocyte growth factor receptor. Amplification of this gene has been associated with secondary resistance to EGFR tyrosine kinase inhibitors.
In addition to the standard treatment options, treatment options under clinical evaluation include the following:
• Combining local treatment (surgery)
• Regional treatment (radiation therapy)
• Systemic treatments (chemotherapy, immunotherapy, and targeted agents)
• Developing more effective systemic therapy
Small Cell Lung Cancer (SCLC)
SCLC accounts for approximately 15% of bronchogenic carcinomas. At the time of diagnosis, approximately 30% of patients with SCLC will have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited-stage disease (LD). Patients with tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease (ED).
SCLC is more responsive to chemotherapy and radiation therapy than other cell types of lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be widely disseminated by the time of diagnosis.
Treatment options for patients are determined by histology, stage, and general health and comorbidities of the patient. Investigations of patients with suspected SCLC focus on confirming the diagnosis and determining the extent of the disease.
The procedures used to determine the presence of cancer include the following:
• Physical examination
• Routine laboratory evaluations
• Chest x-ray
• Chest CT scan with infusion of contrast material
Prognosis and Survival
Regardless of stage, the current prognosis for patients with SCLC is unsatisfactory despite improvements in diagnosis and therapy made during the past 25 years. Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. About 10% of the total population of SCLC patients remains free of disease during the 2 years from the start of therapy, which is the time period during which most relapses occur. Even these patients, however, are at risk of dying from lung cancer (both small and non-small cell types). The overall survival at 5 years is 5% to 10%.
An important prognostic factor for SCLC is the extent of disease. Patients with LD have a better prognosis than patients with ED. For patients with LD, median survival of 16 to 24 months and 5-year survivals of 14% with current forms of treatment have been reported.
Chemotherapy and radiation therapy have been shown to improve survival for patients with small cell lung cancer (SCLC).
Chemotherapy improves the survival of patients with limited-stage disease (LD) or extensive-stage disease (ED), but it is curative in only a minority of patients. Because patients with SCLC tend to develop distant metastases, localized forms of treatment, such as surgical resection or radiation therapy, rarely produce long-term survival. With incorporation of current chemotherapy regimens into the treatment program, however, survival is prolonged, with at least a fourfold to fivefold improvement in median survival compared with patients who are given no therapy.
The combination of platinum and etoposide is the most widely used standard chemotherapeutic regimen. No consistent survival benefit has resulted from platinum versus nonplatinum combinations, increased dose intensity or dose density, altered mode of administration (e.g., alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy.
SCLC is highly radiosensitive and thoracic radiation therapy improves survival of patients with LD and ED tumors. Prophylactic cranial irradiation (PCI) prevents central nervous system recurrence and may improve the long-term survival of patients with good performance status who have responded to chemoradiation therapy and offers palliation of symptomatic metastatic disease.
Despite treatment advances, most patients with SCLC die of their tumor even with the best available therapy. Most of the improvements in the survival of patients with SCLC are attributable to clinical trials that have attempted to improve on the best available and most accepted therapy. Patient entry into such studies is highly desirable.
Liver cancer includes two major types: hepatocellular carcinoma (HCC) and intrahepatic bile duct cancer. HCC is relatively uncommon in the United States, although its incidence is rising, principally in relation to the spread of hepatitis C virus (HCV) infection. Worldwide, HCC is the sixth most prevalent cancer and the third leading cause of cancer-related deaths.
The etiology of HCC is likely multifactorial. The following factors may increase the risk of HCC:
Hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection: HBV and HCV infections appear to be the most significant causes of HCC worldwide. The annual incidence of HCC in HBV carriers is 0.5% to 1% per year in patients without cirrhosis and 2.5% per year in patients with cirrhosis. The relative risk of HCC is 100 (i.e., carriers of HBV are 100 times more likely to develop HCC than uninfected persons).
Alcoholic cirrhosis: Several reports suggest that alcoholic cirrhosis is a risk factor for HCC. However, the true incidence of HCC in alcoholic cirrhosis is unknown because most epidemiology reports on this subject were published before the identification of HCV.
Metabolic syndrome: The risk factors associated with metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and obesity, have been recognized as potential causes of nonalcoholic hepatosteatosis, cirrhosis, and HCC. However, no study to date has followed a sufficiently large group of these patients for long enough to describe the incidence of HCC caused by metabolic syndrome.
Biliary cirrhosis: The incidence of HCC in stage IV primary biliary cirrhosis is approximately the same as in cirrhosis resulting from hepatitis C.
Chronic liver injury: Chronic liver injury probably increases the risk of HCC, especially in patients who develop cirrhosis.
Hemochromatosis: Hemochromatosis is a significant risk factor for HCC and has a relative risk twenty times that of the normal population.
All patients with liver cirrhosis need close surveillance, as well as some patients with no cirrhosis but with HBV and HCV infections. Every 6 months, an ultrasound of the liver should be performed, in order to screen for any new nodule, cyst or lump that could turn into cancer.
For lesions that are smaller than 1 cm and are detected during screening in patients at high risk for HCC, further diagnostic evaluation is not required because most of these lesions will be cirrhotic lesions rather than HCC. Close follow-up at 3-month intervals is a common surveillance strategy, using the same technique that first documented the presence of the lesions. For patients with liver lesions larger than 1 cm who are at risk for HCC, a diagnosis should be established. The tests required to diagnose HCC may include imaging, biopsy, or both.
In patients with cirrhosis, liver disease, or other risk factors for HCC, and with lesions greater than 1 cm, triple-phase, contrast-enhanced studies (dynamic computed tomography [CT]-scan or magnetic resonance imaging [MRI]) can be used to establish a diagnosis of HCC. A triple-phase CT or MRI assesses the entire liver in distinct phases of perfusion. Following the controlled administration of intravenous contrast media, the arterial and venous phases of perfusion are imaged.
A liver biopsy may be performed when a diagnosis of HCC is not established by a dynamic imaging modality (three-phase CT or MRI) for liver lesions 1 cm or larger in high-risk patients.
Alpha-fetoprotein levels (AFP) is insufficiently sensitive or specific for use as a diagnostic assay. AFP can be elevated in intrahepatic cholangiocarcinoma and in some cases in which there are metastases from colon cancer. Finding a mass in the liver of a patient with an elevated AFP does not automatically indicate HCC. If a higher than normal level is found in the blood of adults, it suggests they may have liver cancer. AFP blood tests may be used to look for early tumors in people suffering from cirrhosis.
One combination system for staging liver cancer is known as the Barcelona Clinic Liver Cancer (BCLC) staging system. The BCLC staging system consists of five stages. These are:
stage 0 – the tumor is less than 2cm (20mm) in diameter and the person is very well and has normal liver function
stage A – a single tumor has grown but is less than 5cm (50mm) in diameter, or there are three or fewer smaller tumors less than 3cm (30mm) in diameter and the person is very well with normal liver function
stage B – there are multiple tumors in the liver, but the person is well and their liver function is unaffected
stage C – any of the above circumstances, but the person is not so well and their liver function is not so good, or where the cancer has started to spread into the main blood vessel of the liver, nearby lymph nodes or other parts of the body
stage D – where the liver has lost most of its functioning abilities and the person begins to have symptoms of end-stage liver disease, such as a build-up of fluid inside their abdomen
There is no agreement on a single treatment strategy for patients with HCC. Selection of treatment is complex due to several factors, including:
• Underlying liver function.
• Extent and location of the tumor.
• General condition of the patient.
Several treatments for HCC are associated with long-term survival, including surgical resection, liver transplantation, and ablation. There are no large, robust, randomized studies that compare treatments considered effective for early-stage disease, nor are there studies comparing these treatments with best supportive care. Often, patients with HCC are evaluated by a multidisciplinary team including hepatologists, radiologists, interventional radiologists, radiation oncologists, transplant surgeons, surgical oncologists, pathologists, and medical oncologists.
Best survivals are achieved when the HCC can be removed either by surgical resection or liver transplantation. Surgical resection is usually performed in patients with localized HCC and sufficient functional hepatic reserve.
For patients with decompensated cirrhosis and a solitary lesion (<5 cm) or early multifocal disease (≤3 lesions, ≤3 cm in diameter), the best option is liver transplantation, but the limited availability of liver donors restricts the use of this approach.
Among noncurative treatments for HCC, transarterial chemoembolization and sorafenib have been shown to improve survival.
For treatment, HCC can be divided into the following two broad categories:
• Tumors for which potentially curative treatments are available (BCLC stages 0, A, and B).
• Tumors for which curative options are not available (BCLC stages C and D).
Stages 0, A, and B
• Surgical resection
• Liver transplantation
Stages C and D
• Transarterial embolization and transcatheter arterial chemoembolization
• Targeted therapy
• Radiation therapy
• Liver Transplantation
• Surgical Resection
The median age at diagnosis of carcinoma of the prostate is 66 years. Prostate cancer may be cured when localized, and it frequently responds to treatment when widespread. The rate of tumor growth varies from very slow to moderately rapid, and some patients may have prolonged survival even after the cancer has metastasized to distant sites, such as bone. The 5-year relative survival rate for men diagnosed in the United States from 2001 to 2007 with local or regional disease was 100%, and the rate for distant disease was 28.7%; a 99% survival rate was observed for all stages combined. The approach to treatment is influenced by age and coexisting medical problems. Side effects of various forms of treatment should be considered in selecting appropriate management.
Many patients—especially those with localized tumors—may die of other illnesses without ever having suffered disability from the cancer, even if managed conservatively without an attempt at curative therapy. In part, these favorable outcomes are likely the result of widespread screening with the prostate-specific antigen (PSA) test, which can identify patients with asymptomatic tumors that have little or no lethal potential.
More than 95% of primary prostate cancers are adenocarcinomas. Prostate adenocarcinomas are frequently multifocal and heterogeneous in patterns of differentiation. Prostatic intraepithelial neoplasia ([PIN] noninvasive atypical epithelial cells within benign appearing acini) is often present in association with prostatic adenocarcinoma. PIN is subdivided into low grade and high grade. The high-grade form may be a precursor for adenocarcinoma.
The histologic grade of prostate adenocarcinomas is usually reported according to one of the variations of the Gleason scoring system, which provides a useful, albeit crude, adjunct to tumor staging in determining prognosis. The Gleason score is calculated based on the dominant histologic grades, from grade 1 (well differentiated) to grade 5 (very poorly differentiated). The classical score is derived by adding the two most prevalent pattern grades, yielding a score ranging from 2 to 10.
Needle biopsy is the most common method used to diagnose prostate cancer. Most urologists now perform a transrectal biopsy using a bioptic gun with ultrasound guidance. Over the years, there has been a trend toward taking eight to ten or more biopsy samples from several areas of the prostate with a consequent increased yield of cancer detection after an elevated PSA blood test.
Local treatment modalities are associated with prolonged disease-free survival (DFS) for many patients with localized prostate cancer but are rarely curative in patients with locally extensive tumors. Because of clinical understaging using current diagnostic techniques, even when the cancer appears clinically localized to the prostate gland, some patients develop disseminated tumors after local therapy with surgery or radiation.
Depending on each case, treatment options for men with prostate cancer might include:
• Watchful waiting or active surveillance
• Radiation therapy
• Cryotherapy (cryosurgery)
• Hormone therapy
• Vaccine treatment
• Bone-directed treatment
Whole-gland cryotherapy is also used, but its adverse effects are considerable and survival benefit compared with active surveillance has not been shown. Newer therapies, such as proton-beam radiation and high-intensity focused ultrasound are being used, but long-term survival and complication rates have not been presented in well-done studies.
For locally advanced prostate cancer, radiation therapy along with androgen ablation is generally recommended, although radical prostatectomy may be an appropriate alternative to radiation therapy in some cases. A combination of external radiation, brachytherapy, and hormone therapy is also being used, but it is unclear whether it offers advantages over hormone therapy and external radiation alone, and it does increase complications.
Metastatic prostate cancer is rarely curable. Management of these cases typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) and attempts to slow further progression of disease.
Cancer of the endometrium is the most common gynecologic malignancy in the United States and accounts for 6% of all cancers in women. The majority of cases are diagnosed at an early stage and are amenable to treatment with surgery alone. However, patients with pathologic features predictive of a high rate of relapse and patients with extrauterine spread at diagnosis have a high rate of relapse despite adjuvant therapy.
Endometrial cancer is usually diagnosed and treated at an early stage. Cardiovascular disease is the most common cause of death in patients with endometrial cancer because of the related metabolic risk factors.
Increasing age is the most important risk factor for most cancers. Other risk factors for endometrial cancer include the following:
• Hormone therapy
• Postmenopausal estrogen therapy
• Selective estrogen receptor modifiers
• Tamoxifen therapy
• Metabolic syndrome
• Reproductive factors
• Early menarche/late menopause
• Polycystic ovarian syndrome
• Family history/genetic predisposition
• Mother, sister, or daughter with uterine cancer
• Certain genetic syndromes, such as Lynch syndrome
• Endometrial hyperplasia
Tamoxifen, which is used for both the treatment and prevention of breast cancer (NSABP-B-14), is associated with an increased risk of endometrial cancer related to the estrogenic effect of tamoxifen on the endometrium. It is important that patients who are receiving tamoxifen and experiencing abnormal uterine bleeding have follow-up examinations and biopsy of the endometrial lining. The U.S. Food and Drug Administration released a black box warning that includes data about the increase in uterine malignancies associated with tamoxifen use.
Irregular vaginal bleeding is the most common presenting sign of endometrial cancer. It generally occurs early in the disease process, and is the reason why most patients are diagnosed with highly curable stage I endometrial cancer.
The following procedures may be used to detect endometrial cancer:
• Transvaginal ultrasound
• Endometrial biopsy
• Pelvic exam
• Dilatation and curettage (D&C)
To definitively diagnose endometrial cancer, a procedure that directly samples the endometrial tissue is necessary.
The Pap smear is not a reliable screening procedure for the detection of endometrial cancer, even though a retrospective study found a strong correlation between positive cervical cytology and high-risk endometrial disease (i.e., high-grade tumor and deep myometrial invasion). A prospective study found a statistically significant association between malignant cytology and increased risk of nodal disease.
Once cancer has been diagnosed, the doctor works to determine the extent (stage) of the cancer. Tests used to determine the cancer’s stage may include a chest X-ray, a computerized tomography (CT) scan, positron emission tomography (PET) scan and blood tests. The final determination of the cancer’s stage may not be made until after undergoing surgery to treat the cancer.
Stages of endometrial cancer include:
Stage I cancer is found only in the uterus.
Stage II cancer is present in both the uterus and cervix.
Stage III cancer has spread beyond the uterus, but hasn’t reached the rectum and bladder. The pelvic area lymph nodes may be involved.
Stage IV cancer has spread past the pelvic region and can affect the bladder, rectum and more-distant parts of the body.
Treatment of the endometrial cancer will depend on the stage, patient general health and preferences.
Surgery to remove the uterus is recommended for most women with endometrial cancer. Most women with endometrial cancer undergo a procedure to remove the uterus (hysterectomy), as well as to remove the fallopian tubes and ovaries (salpingo-oophorectomy).
In certain situations, radiation therapy may also be recommended before surgery, to shrink a tumor and make it easier to remove. In women with advanced endometrial cancer, radiation therapy may help control cancer-related pain.
Hormone therapy may be an option for the advanced endometrial cancer that has spread beyond the uterus.
Chemotherapy may be recommended for women with advanced or recurrent endometrial cancer that has spread beyond the uterus.
Supportive (palliative) care
Palliative care can be used while undergoing other aggressive treatments, such as surgery, chemotherapy or radiation therapy. When palliative care is used along with all of the other appropriate treatments, people with cancer may feel better and live longer.
- National Institute of Health (NIH) – National Cancer Institute. Breast Cancer, 2018. Available at: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq
- National Institute of Health (NIH) – National Cancer Institute. Colorectal Cancer, 2018. Available at: https://www.cancer.gov/types/colorectal/hp/colon-treatment-pdq
- National Institute of Health (NIH) – National Cancer Institute. Lung Cancer – Non-Small Cell Lung Cancer, 2018. Available at: https://www.cancer.gov/types/lung/hp/non-small-cell-lung-treatment-pdq
- National Institute of Health (NIH) – National Cancer Institute. Lung Cancer – Small Cell Lung Cancer, 2018. Available at: https://www.cancer.gov/types/lung/hp/small-cell-lung-treatment-pdq
- National Institute of Health (NIH) – National Cancer Institute. Liver Cancer, 2018. Available at: https://www.cancer.gov/types/liver/hp/adult-liver-treatment-pdq
- ESMO/ACF Patient Guide Series. Liver Cancer: a guide for patients – Information based on ESMO Clinical Practice Guidelines – v.2014.1
- National Health System (NHS) – UK. Liver Cancer. Available at: https://www.nhs.uk/conditions/liver-cancer/diagnosis/
- National Institute of Health (NIH) – National Cancer Institute. Prostate Cancer, 2018. Available at: https://www.cancer.gov/types/prostate/hp/prostate-treatment-pdq
- American Cancer Society. Prostate cancer |Therapy. Available at : https://www.cancer.org/cancer/prostate-cancer/treating.html
- Mayo Clinic. Endometrial Cancer, 2018. Available at: https://www.mayoclinic.org/diseases-conditions/endometrial-cancer/diagnosis-treatment/drc-20352466