Cancer Patricia A. Cornett, MD Tiffany O. Dea, PharmD
The major features of this chapter are the clinical aspects of cancer, including etiology and prevention; staging; diagnosis and treatment of common cancers; and recognition and management of complications from cancer. Additional information may be obtained from the National Cancer Institute (NCI) website at www.cancer.gov/cancer topics, the American Society of Clinical Oncology website at www. asco.org, and the National Comprehensive Cancer Network (NCCN) website at www.nccn.org. The NCCN website provides detailed, evidence-based recommendations for management of specific cancers as well as guidelines for cancer screening and for supportive care. General reviews in oncology can be obtained from Medscape Hematology/ Oncology (www.medscape.com).
``Etiology Cancer is the second most common cause of death in the United States. In 2011 an estimated 1,596,670 cases of cancer were diagnosed, and 571,950 persons died as a result of cancer. Based on cancer rates determined in 2003–2005, more than 40% of people born today will have cancer diagnosed at some point in their lifetime. Table 39–1 lists the 10 leading cancer types in men and women by site. However, the incidence of cancer in both men and women is decreasing. In 2008, the American Cancer Society, NCI, and the Centers for Disease Control and Prevention reported that the incidence of all cancers for both sexes decreased 0.8% per year from 1999 through 2005. As the incidence of cancer is decreasing, the survival rate is increasing. In 2010, using information from the Surveillance Epidemiology and End Results (SEER) database, the NCI reported a survival rate of 68% for individuals in whom cancer was diagnosed between 1999 and 2006 compared to 50% for those in whom cancer was diagnosed between 1975 and 1977. Reductions in cancer incidence and mortality reflect a successful implementation of a broad strategy of prevention, detection, and treatment.
``Modifiable Risk Factors Tobacco is the most common preventable cause of cancer death; it is estimated that at least 30% of all cancer deaths
in the United States are directly linked to tobacco. A total of 171,000 cancer deaths in the United States and 1.42 million cancer deaths worldwide can be directly attributed to tobacco abuse. Clear evidence links at least 15 cancers to tobacco use. The most dramatic link is with lung cancer, the most common non-dermatologic malignancy; 87% of lung cancer cases occur in smokers. Any strategy for cancer control must include the goal of markedly reducing if not eliminating tobacco use. Strategies for tobacco control should involve a focus on the individual as well as society as a whole. Tobacco cessation directed toward the individual should start with the clinician providing counseling. Simple, concise advice from a clinician can yield cessation rates of 10–20%. Additive strategies include more intensive counseling; nicotine replacement therapy with patches, gum, or lozenges; and prescription medication with bupropion or varenicline. Perhaps a more intriguing phenomenon, with potential for significant impact on cessation rates, is the influence of social contact behavior on an individual smoker’s abstinence decision. For instance, analysis of the Framingham Heart Study demonstrated that smoking cessation by a spouse resulted in a 67% decrease in the subject’s likelihood of continuing to smoke, and smoking cessation by a friend resulted in a 36% decrease in the subject’s likelihood of smoking. On a societal level, many initiatives have been put into place to actively discourage tobacco use. State or local laws regulating tobacco use in restaurants, the workplace, and other public places have resulted in declines in tobacco use. Countermarketing with aggressive anti-tobacco advertisements has also contributed to tobacco cessation and abstinence. The key recipients of these messages are children; 80% of smokers will start by age 18. Preventing the start of addiction in this vulnerable population should be a top priority (see Chapter 1). There are encouraging signs of success with tobacco control. The prevalence of smoking for United States adults based on the 2011 National Health Interview Survey is 19.4%, which is a remarkable reduction from the 1955 peak of 57% for males and the 1965 peak of 34% for females but still falls short of the Healthy People 2010 goal of < 12%. See Chapter 1 for additional material on smoking cessation techniques.
Table 39–1. Estimated 10 most common cancer cases in the United States in males and females (all races).
Total Cases = 822,300 (percent)
Total Cases = 774,370 (percent)
Lung and bronchus (14)
Lung and bronchus (14)
Colon and rectum (9)
Colon and rectum (9)
Urinary bladder (6)
Uterine corpus (6)
Kidney and renal pelvis (5)
Oral cavity and pharynx (3)
Kidney and renal pelvis (3)
Other sites (18)
Other sites (19)
Data from the American Cancer Society, 2011.
For those Americans who do not use tobacco, the most modifiable risk factors would be nutrition and physical activity. Epidemiologic studies suggest that fruit- and vegetable-rich diets lower risks of several gastrointestinal malignancies, including esophageal, stomach, and colon cancers. Excessive consumption of alcohol is linked to increased risks of head and neck cancers as well as cancers of the esophagus and liver. Lastly, being overweight is linked to several malignancies, including breast and uterine cancers in women and colorectal, esophageal, and kidney cancers in both men and women. More importantly, weight reduction can decrease the risks of these cancers. Another modifiable risk factor is radiation from radiographic studies. A 2009 study reported that the use of computed tomography (CT) in diagnostic algorithms exposes individuals to significant radiation doses that may increase the lifetime risk of developing cancer. Both standardization of CT radiation doses and limiting testing will be important steps in minimizing this risk. Smith-Bindman R et al. Radiation dose associated with common computed tomography examinations and the associated lifetime attributable risk of cancer. Arch Intern Med. 2009 Dec 14;169(22):2078–86. [PMID: 20008690]
``Staging The most commonly used staging system at the time of diagnosis is the TNM (Tumor, Nodes, Metastasis) system (see www.cancerstaging.org). Rules for staging for individual cancers are established and published by the American
Joint Committee on Cancer (AJCC). Elements used for staging include tumor location, size and level of tumor invasion (T), absence or presence and extent of nodal metastases (N), and presence or absence of systemic metastases (M). Once the TNM designations have been determined, an overall stage is assigned, stage I, II, III, or IV. Clinical staging utilizes physical examination, laboratory and imaging tests as well as results from biopsies; pathologic staging relies on the results from surgery. In some instances, other classifications may be used for certain cancers such as the Ann Arbor staging system for lymphomas. Other characteristics of cancers, not reflected in the TNM stage, may be used as another indicator of prognosis. Pathologic features seen on routine histologic examination for some cancers are very important; examples include the Gleason score for prostate cancer and the grade of sarcomas. Cancer specimens may also be sent for targeted molecular diagnostic testing; results are used to determine prognosis as well as treatment. Examples include testing for HER-2/neu in breast and gastric cancers, KRAS and BRAF mutations in colorectal cancers, and EGFR and KRAS mutations in lung cancer. In the future, as the pathways for oncogenesis and relationships of mutations to treatment and prognosis are better delineated, analysis for detection of chromosomal alterations and oncogene products will continue to be increasingly incorporated into routine practice.
THE PARANEOPLASTIC SYNDROMES The clinical manifestations of cancer are usually due to pressure effects of local tumor growth, infiltration or metastatic deposition of tumor cells in a variety of organs in the body, or certain systemic symptoms. General problems observed in many patients with advanced or widespread metastatic cancer include anorexia, malaise, weight loss, and sometimes fever. These characteristics must be considered when evaluating a patient with an undiagnosed illness. Except in the case of functioning tumors such as those of the endocrine glands, systemic symptoms of cancer usually are not specific, often consisting of weakness, anorexia, and weight loss. The term “paraneoplastic” refers to features of disease considered to be due to the remote effects of a cancer. These features cannot be attributed either to a cancer’s direct invasive or metastatic properties and are often considered to be due to aberrant hormonal or metabolic effects not observed in a cancer’s normal tissue equivalent. In the paraneoplastic syndromes, clinical findings may resemble those of primary endocrine, metabolic, hematologic, or neuromuscular disorders. At present, the mechanisms for such remote effects can be classified into three groups: (1) effects initiated by a tumor product (eg, carcinoid syndrome, ectopic hormone production), (2) effects of destruction of normal tissues by tumor (eg, hypercalcemia with osteolytic skeletal metastases), and (3) effects due to unknown mechanisms. In paraneoplastic syndromes associated with ectopic hormone production, tumor tissue itself secretes the hormone that produces the syndrome. Ectopic hormones secreted by neoplasms are often pro-hormones of higher molecular weight than those
Cancer secreted by the more differentiated normal endocrine cell. Such ectopic hormone production by cancer cells is believed to result from activation of genes in the malignant cells that are suppressed in the normal tissue equivalent and in most somatic cells. Autocrine growth factors secreted by neoplastic cells may also result in paraneoplastic syndromes. Small cell lung cancer is the one type of cancer most likely to be associated with paraneoplastic syndromes. The paraneoplastic syndromes are clinically important for the following reasons: (1) They sometimes accompany relatively limited neoplastic growth and may provide the clinician with an early clue to the presence of certain types of cancer. (2) The metabolic or toxic effects of the syndrome may constitute a more urgent hazard to the patient’s life than the underlying cancer (eg, hypercalcemia, hyponatremia). (3) Effective treatment of the tumor should be accompanied by resolution of the paraneoplastic syndrome and, conversely, recurrence of the cancer may be heralded by return of the systemic symptoms. In some instances, rapid response to cytotoxic chemotherapy may briefly increase the severity of the paraneoplastic syndrome in association with tumor lysis (eg, hyponatremia with inappropriate antidiuretic hormone excretion). In some instances the identical symptom complex (eg, hypercalcemia) may be induced by entirely different mechanisms. A single syndrome such as hypercalcemia may be due to any one of a variety of humoral factors, such as secretion of parathyroid hormone precursors or homologs or 1,25 dihydroxyvitamin D. Effective antitumor treatment usually results in return of serum calcium to normal. Common paraneoplastic syndromes and endocrine secretions associated with functional cancers are summarized in Table 39–2. cc
TYPES OF CANCER
LUNG CANCER Sunny Wang, MD
E ssent i a l s o f d i a g nos i s
New cough, or change in chronic cough. Dyspnea, hemoptysis, anorexia, weight loss. Enlarging nodule or mass; persistent opacity, atelectasis, or pleural effusion on chest radiograph or CT scan. Cytologic or histologic findings of lung cancer in sputum, pleural fluid, or biopsy specimen.
`` `` ``
``General Considerations Lung cancer is the leading cause of cancer deaths in both men and women. The American Cancer Society estimates
226,160 new diagnoses and 160,340 deaths from lung cancer in the United States in 2012, accounting for approximately 14% of new cancer diagnoses and 28% of all cancer deaths. More Americans die of lung cancer than of colorectal, breast, and prostate cancers combined. Cigarette smoking causes 85–90% of cases of lung cancer. Lung cancer was a previously reportable disease until the widespread use of manufactured cigarettes in the 20th century. The causal connection between cigarettes and lung cancer is established not only epidemiologically but also through identification of carcinogens in tobacco smoke and analysis of the effect of these carcinogens on specific oncogenes expressed in lung cancer. Since the early 1990s, mortality from lung cancer fell among men while it increased among women and is only now peaking among women, reflecting changing patterns of tobacco use over the past 30 years (see Chapter 1). Other environmental risk factors for the development of lung cancer include exposure to environmental tobacco smoke, radon gas (among uranium miners and in areas where radium in the soil causes significant indoor air contamination), asbestos (60- to 100-fold increased risk in smokers with asbestos exposure), metals (arsenic, chromium, nickel, iron oxide), and industrial carcinogens (bis-chloromethyl ether). A familial predisposition to lung cancer is recognized. Certain diseases are associated with an increased risk of lung cancer, including pulmonary fibrosis, chronic obstructive pulmonary disease, and sarcoidosis. Second primary lung cancers are more frequent in patients who survive their initial lung cancer. The median age at diagnosis of lung cancer in the United States is 71; it is unusual under the age of 40. After the diagnosis of lung cancer is made, approximately 41% of patients survive 1 year. The combined relative 5-year survival rate for all stages of lung cancer is currently 16%, slightly improved from 13% for lung cancers diagnosed in the 1970-80s. Five histologic categories of bronchogenic carcinoma account for more than 90% of cases of primary lung cancer. Squamous cell carcinoma (20% of cases) arises from the bronchial epithelium, typically as a centrally located, intraluminal sessile or polypoid mass. Squamous cell tumors are more likely to present with hemoptysis and more frequently diagnosed by sputum cytology. They spread locally and may be associated with hilar adenopathy and mediastinal widening on chest radiography. Adenocarcinoma (35–40% of cases) arises from mucus glands or, in the case of bronchioloalveolar cell carcinoma (2% of cases), from any epithelial cell within or distal to the terminal bronchioles. Adenocarcinomas usually present as peripheral nodules or masses. Bronchioloalveolar cell carcinoma, now known as adenocarcinoma in situ, spreads along preexisting alveolar structures (lepidic growth) without evidence of invasion. Large cell carcinoma (3–5% of cases) is a heterogeneous group of relatively undifferentiated tumors that share large cells and do not fit into other categories. Large cell carcinomas typically have rapid doubling times and an aggressive clinical course. They present as central or peripheral masses. Tumors that are not better differentiated on pathologic review other than carcinoma
Hormone Excess or Syndrome
Non– Small Cell Lung Cancer
Small Cell Lung Cancer
Renal Cell Carcinoma
Table 39–2. Paraneoplastic syndromes associated with cancer.
Germ Cell Cancers
Hypoglycemia Gonadotropin secretion
Pure red cell aplasia
Subacute cerebellar syndrome
Sensory motor peripheral neuropathy
Neurologic Lambert-Eaton myasthenia syndromes
Stiff man syndrome Dermatologic Dermatomyositis
Fever Hypertrophic osteoarthropathy
+, reported associated; + +, strong association. SIADH, syndrome of inappropriate antidiuretic hormone.
+ + ++
Cancer unspecified make up about 20–25% of cases. Small cell carcinoma (10–15% of cases) is a tumor of bronchial origin that typically begins centrally, infiltrating submucosally to cause narrowing or obstruction of the bronchus without a discrete luminal mass. Hilar and mediastinal abnormalities are common on chest radiography. For purposes of staging and treatment, bronchogenic carcinoma is divided into small cell lung cancer (SCLC) and the other four types, conveniently labeled non–small cell lung cancer (NSCLC). This practical classification reflects different natural histories and different treatment. SCLC is prone to early hematogenous spread. It is rarely amenable to surgical resection and has a very aggressive course with a median survival (untreated) of 6–18 weeks. The four histologic categories comprising NSCLC spread more slowly. They may be cured in the early stages following resection, and for advanced disease, chemotherapy is tailored to specific histologies and molecular mutations found within NSCLC.
``Clinical Findings Lung cancer is symptomatic at diagnosis in 75–90% of patients. The clinical presentation depends on the type and location of the primary tumor, the extent of local spread, and the presence of distant metastases and any paraneoplastic syndromes.
A. Symptoms and Signs Anorexia, weight loss, or asthenia occurs in 55–90% of patients presenting with a new diagnosis of lung cancer. Up to 60% of patients have a new cough or a change in a chronic cough; 6–31% have hemoptysis; and 25–40% complain of pain, either nonspecific chest pain or pain from bony metastases to the vertebrae, ribs, or pelvis. Local spread may cause endobronchial obstruction with atelectasis and postobstructive pneumonia, pleural effusion (12–33%), change in voice (compromise of the recurrent laryngeal nerve), superior vena cava syndrome (obstruction of the superior vena cava with supraclavicular venous engorgement), and Horner syndrome (ipsilateral ptosis, miosis, and anhidrosis from involvement of the inferior cervical ganglion and the paravertebral sympathetic chain). Distant metastases to the liver are associated with asthenia and weight loss. Brain metastases (10% in NSCLC, more common in adenocarcinoma, and 20–30% in SCLC) may present with headache, nausea, vomiting, seizures, dizziness, or altered mental status. Paraneoplastic syndromes are incompletely understood patterns of organ dysfunction related to immunemediated or secretory effects of neoplasms. These syndromes occur in 10–20% of lung cancer patients. They may precede, accompany, or follow the diagnosis of lung cancer and do not necessarily indicate metastatic disease. In patients with small cell carcinoma, the syndrome of inappropriate antidiuretic hormone (SIADH) can develop in 10–15%; in those with squamous cell carcinoma, hypercalcemia can develop in 10% (Table 39–2). Digital clubbing is seen in up to 20% of patients at diagnosis (see Figure 6–41). Other common paraneoplastic syndromes include
increased ACTH production, anemia, hypercoagulability, peripheral neuropathy, and the Eaton-Lambert myasthenia syndrome. Their recognition is important because treatment of the primary tumor may improve or resolve symptoms even when the cancer is not curable.
B. Laboratory Findings The diagnosis of lung cancer rests on examination of a tissue or cytology specimen. Sputum cytology is highly specific but insensitive; the yield is highest when there are lesions in the central airways. Thoracentesis (sensitivity 50–65%) can be used to establish a diagnosis of lung cancer in patients with malignant pleural effusions. If cytologic examination of an adequate sample (50–100 mL) of pleural fluid is nondiagnostic, the procedure should be repeated; approximately 30% of second samples are positive when the first sample is negative. If results remain negative, thoracoscopy is preferred to blind pleural biopsy. Fine-needle aspiration (FNA) of palpable supraclavicular or cervical lymph nodes is frequently diagnostic. Serum tumor markers are neither sensitive nor specific enough to aid in diagnosis. Fiberoptic bronchoscopy allows visualization of the major airways, cytology brushing of visible lesions or lavage of lung segments with cytologic evaluation of specimens, direct biopsy of endobronchial abnormalities, blind transbronchial biopsy of the pulmonary parenchyma or peripheral nodules, and FNA biopsy of mediastinal lymph nodes. Diagnostic yield varies widely (10–90%) depending on the size of the lesion and its location. The use of fluorescence bronchoscopy improves the ability to identify early endobronchial lesions, while endobronchial and transesophageal endoscopic ultrasound enhance the direction and yield of FNA of mediastinal nodes. Transthoracic needle aspiration (TTNA) has a sensitivity between 50% and 97%. Mediastinoscopy, video-assisted thoracoscopic surgery (VATS), and thoracotomy are necessary in cases where less invasive techniques fail to yield a diagnosis.
C. Imaging Nearly all patients with lung cancer have abnormal findings on chest radiography or CT scan. These findings are rarely specific for a particular diagnosis. Interpretation of characteristic findings in isolated nodules is described in Chapter 9.
D. Special Examinations 1. Staging—Accurate staging is crucial (1) to provide the clinician with information to guide treatment, (2) to provide the patient with accurate information regarding prognosis, and (3) to standardize entry criteria for clinical trials to allow interpretation of results. There are two essential principles of staging NSCLC. First, the more extensive the disease, the worse the prognosis; second, surgical resection offers the best chance for cure. Staging of NSCLC uses two integrated systems. The TNM international staging system attempts a physical description of the neoplasm: T describes the size and location of the primary tumor; N describes the presence and location of nodal metastases; and M refers to the presence
Table 39–3. Approximate survival rates following treatment for lung cancer. Non–Small Cell Lung Cancer: Mean 5-Year Survival Following Resection Stage
IIB (T2N1M0, T3N0M0)
Small Cell Lung Cancer: Survival Following Chemotherapy Stage
Mean 2-Year Survival
1 Independent of therapy, generally not surgical patients. Data from multiple sources. Modified and reproduced, with permission, from Reif MS et al. Evidence-based medicine in the treatment of non-small cell cancer. Clin Chest Med. 2000;21:107.
or absence of distant metastases. These TNM stages are grouped into prognostic categories (stages I–IV) using the results of clinical trials. This classification is used to guide therapy. Many patients with stage I and stage II disease are cured through surgery. Patients with stage IIIB and stage IV disease do not benefit from surgery (Table 39–3). Patients with stage IIIA disease have locally invasive disease that may benefit from surgery in certain circumstances. SCLC is not staged using the TNM system because micrometastases are assumed to be present on diagnosis. SCLC is divided into two categories: limited disease (30%), when the tumor is limited to the unilateral hemithorax (including contralateral mediastinal nodes); or extensive disease (70%), when the tumor extends beyond the hemithorax (including pleural effusion). For both SCLC and NSCLC, staging begins with a thorough history and physical examination. A complete examination is essential to exclude obvious metastatic disease to lymph nodes, skin, and bone. A detailed history is essential because the patient’s performance status is a powerful predictor of disease course. All patients should have measurement of a complete blood count, electrolytes including calcium, creatinine, liver tests, lactate dehydrogenase, albumin, and a chest radiograph. Further evaluation will follow the results of these tests. NSCLC patients being considered for surgery require meticulous evaluation to identify those with resectable disease. CT imaging is the most important modality for staging candidates for resection. A chest CT scan precisely defines the size of parenchymal lesions and identifies atelectatic lung or pleural effusions. However, CT imaging is less accurate at determining invasion of the chest wall
(sensitivity 62%) or mediastinum (sensitivity 60–75%). The sensitivity and specificity of CT imaging for identifying lung cancer metastatic to the mediastinal lymph nodes are 57% (49–66%) and 82% (77–86%), respectively. Therefore, chest CT imaging does not provide definitive information on staging. CT imaging does help in making the decision about whether to proceed to resection of the primary tumor and sample the mediastinum at thoracotomy (common if there are no lymph nodes > 1 cm) or to use TTNA, mediastinoscopy, esophageal ultrasound with transesophageal needle aspiration, or limited thoracotomy to biopsy suspected metastatic disease (common where there are lymph nodes > 1–2 cm). Positron emission tomography (PET) using 2-[18F] fluoro-2-deoxyglucose (FDG) is an important modality for identifying metastatic foci in the mediastinum or distant sites. The sensitivity and specificity of PET for detecting mediastinal spread of primary lung cancer depend on the size of mediastinal nodes or masses. When only normalsized (< 1 cm) mediastinal lymph nodes are present, the sensitivity and specificity of PET for tumor involvement of nodes are 74% and 96%, respectively. When CT shows enlarged (> 1 cm) lymph nodes, the sensitivity and specificity are 95% and 76%, respectively. The combined modalities of PET and CT imaging have improved preoperative staging compared with CT or PET alone. Many lung cancer specialists find whole body fusion PET-CT imaging most useful to confirm lack of metastatic disease in NSCLC patients who are candidates for surgical resection. There is evidence that PET-CT imaging reduces futile thoracotomies by identifying mediastinal and distant metastases in patients with NSCLC. Disadvantages of PET imaging include limited resolution below 1 cm; the expense of FDG; limited availability; and false-positive scans due to sarcoidosis, tuberculosis, or fungal infections. PET-CT scans are also inadequate for evaluating brain metastases due to the high FDG uptake there. Obtaining an MRI of the brain is important to rule out brain metastases in patients with at least stage II disease. 2. Preoperative assessment—See Chapter 3. 3. Pulmonary function testing—Many patients with NSCLC have moderate to severe chronic lung disease that increases the risk of perioperative complications as well as long-term pulmonary insufficiency following lung resection. All patients considered for surgery require spirometry. In the absence of other comorbidities, patients with good lung function (preoperative FEV1 ≥ 2 L) are at low risk for complications from lobectomy or pneumonectomy. If the FEV1 is < 2 L, then an estimated postoperative FEV1 should be calculated. The postresection FEV1 may be estimated from considering preoperative spirometry and the amount of lung to be resected; in severe obstructive disease, a quantitative lung perfusion scan may improve the estimate. A predicted post-lung resection FEV1 > 800 mL (or > 40% of predicted FEV1) is associated with a low incidence of perioperative complications. High-risk patients include those with a predicted postoperative FEV1< 700 mL (or < 40% of predicted FEV1). In these patients and in those with borderline spirometry, cardiopulmonary
Cancer exercise testing may be helpful. A maximal oxygen uptake · (Vo2) of > 15 mL/kg/min identifies patients with an acceptable incidence of complications and mortality. Patients · with a Vo2 of < 10 mL/kg/min have a very high mortality rate at thoracotomy. Hypoxemia and hypercapnia are not independent predictors of outcome. 4. Screening—Prior data showed that chest radiographs and analysis of expectorated sputum as lung cancer screening modalities did not improve survival. The National Lung Screening Trial, a multicenter randomized national trial involving over 53,000 current and former heavy smokers, published results showing a 20% reduction in lung cancer deaths. It compared low-dose helical CT with standard chest radiographs as screening modalities for lung cancer. Given these findings, clinical guidelines and policy recommendations on lung cancer screening are currently being discussed. Risk-benefit and cost-effective analyses are underway. The implications of widespread screening of smokers raise issues of false positives (96% in this study), surgical and medical complications from additional testing, risks of cumulative exposure to radiation, and risks of increasing patient anxiety and stress on an already limited pool of resources.
``Treatment A. Non–Small Cell Carcinoma Cure of NSCLC is unlikely without resection. Therefore, the initial approach to the patient is determined by the answers to two questions: (1) Is complete surgical resection technically feasible? (2) If yes, is the patient able to tolerate the surgery with acceptable morbidity and mortality? Clinical features that preclude complete resection include extrathoracic metastases or a malignant pleural effusion; or tumor involving the heart, pericardium, great vessels, esophagus, recurrent laryngeal or phrenic nerves, trachea, main carina, or contralateral mediastinal lymph nodes. Accordingly, stage I and stage II patients are treated with surgical resection where possible. Stage II, and possibly a subset of stage IB, are additionally recommended to receive adjuvant chemotherapy. Stage IIIA patients have poor outcomes when treated with resection alone. They should be referred to multimodality protocols, including chemotherapy or radiotherapy, or both. Stage IIIB patients treated with concurrent chemotherapy and radiation therapy have improved survival. Stage IV patients are treated with chemotherapy or symptom-based palliative therapy, or both (see below). Surgical approach affects outcome. The North American Lung Cancer Study Group conducted a prospective trial of stage IA patients randomized to lobectomy versus limited resection. They reported a threefold increased rate of local recurrence in the limited resection group (P = 0.008) and a trend toward an increase in overall death rate (increase of 30%, P = 0.08) and increase in death rate due to cancer (increase of 50%, P = 0.09), compared with patients receiving lobectomy. There are inadequate outcome data on which to base a comparison of VATS with standard thoracotomy. Radiation therapy following surgery improves local control but does not improve survival.
Patients with small early-stage primary lung cancers who are not candidates for surgery because of significant comorbidity or other surgical contraindication may be candidates for stereotactic body radiotherapy. Stereotactic body radiotherapy (cyberknife), which is composed of multiple non-parallel radiation beams that converge, allows the delivery of a relatively large dose of radiation to a small, well-defined target. For small, early-stage cancers, 3-year local control rates with cyberknife exceed 90%, and 3-year survival is estimated at over 55%. Patients with locally advanced disease (stages IIIA and IIIB) who are not surgical candidates have improved survival when treated with concurrent chemotherapy and radiation therapy compared with no therapy, radiation alone, or even sequential chemotherapy and radiation. Neoadjuvant chemotherapy consists of giving anti neoplastic drugs in advance of surgery or radiation therapy. There is no consensus on the impact of neoadjuvant therapy on survival in stage I and stage II NSCLC. Such therapy is not recommended outside of ongoing clinical trials. Neoadjuvant therapy is more widely used in selected patients with stage IIIA or stage IIIB disease. Some studies suggest a survival advantage. This remains an area of active research. Adjuvant chemotherapy consists of administering antineoplastic drugs following surgery or radiation therapy. Cisplatin-containing regimens have been shown to confer an overall survival benefit in at least stage II disease and possibly a subset of stage IB disease. The Lung Adjuvant Cisplatin Evaluation Collaborative Group published a meta-analysis of the five largest cisplatin-based adjuvant trials. They reported a 5% absolute benefit in 5-year overall survival with a cisplatin-containing doublet regimen following surgery (P = 0.005) in patients with at least stage II disease. For patients with poor performance status (Eastern Cooperative Oncology Group Score ≤ 2), there is no evidence of survival benefit for adjuvant chemotherapy; rather, it may be detrimental. Novel targeted agents with less toxicity are in clinical trials, and gene expression profiling has shown promise in defining a subset of patients who may benefit from adjuvant therapy. Although not curative, chemotherapy has been shown in multiple clinical trials to provide a modest increase in overall survival and performance status in patients with stage IIIB and stage IV NSCLC compared with supportive care alone, with median survival increased from 5 months to a range of 7–11 months. Palliative chemotherapy also leads to improved quality of life and symptom control, with first-line therapy involving a platinum-based regimen. Platinum-based doublet regimens consist of cisplatin or carboplatin (agents that bind DNA to form adducts that inhibit their synthesis and function) combined with another agent, such as gemcitabine, taxane, vinorelbine, or pemetrexed. When compared in phase III trials for advanced NSCLC, these doublet regimens have shown comparable efficacy with varying toxicity profiles. Investigators have shown that the choice of chemotherapeutic agent can be tailored to histologic subtype in NSCLC. For nonsquamous histologies, patients have modestly improved overall survival when treated with a platinum agent plus pemetrexed
(an inhibitor of folate-dependent enzymes important in purine and pyrimidine synthesis). Patients with squamous cell lung carcinomas have modestly improved overall survival when a platinum agent is combined with gemcitabine (a deoxycytidine analog that inhibits DNA synthesis). For good performance status patients with nonsquamous histologies, bevacizumab (a monoclonal antibody to vascular endothelial growth factor [VEGF]) can be added to a traditional platinum doublet regimen with further modest increase in survival benefit. Cetuximab (a monoclonal antibody to the epidermal growth factor receptor [EGFR]) added to a platinum doublet regimen for all histologies of NSCLC has also shown a small survival benefit. With the advent of molecular profiling, targeted therapy has played a significant role in NSCLC. For the subgroup of patients with EGFR mutations, an EGFR inhibitor (erlotinib and gefitinib) rather than platinum-based chemotherapy is the first-line treatment. Response rates with EGFR inhibitors in patients with EGFR mutation are at least 60%, and median overall survival is estimated at 27–30 months. EGFR mutations are found in approximated 10–15% of the white population and 30–40% in the Asian population and are usually found among nonsmokers to light-smokers, females, and adenocarcinoma histology. Approximately 5% of all patients with NSCLC carry a different mutation, the EML4-ALK fusion gene product. This is found in a comparatively younger population, with adenocarcinoma histology, and nonsmoking to lightsmoking history. Based on early single-arm trials showing 60% response rates, crizotinib, an ALK and MET inhibitor, was approved by the US Food and Drug Administration (FDA) to treat EML4-ALK–positive NSCLCs. Finally, KRAS mutations are found among 25% of patients with adenocarcinomas, are associated with smoking, indicate a poor prognosis, and typically do not respond to EGFR inhibition. These three mutations are mutually exclusive. Ongoing research seeks to define the role of these targeted agents in early stage and locally advanced lung cancers, and identification of new novel mutations.
B. Small Cell Carcinoma Response rates of SCLC to cisplatin and etoposide are excellent with 80–90% response in limited-stage disease (50–60% complete response), and 60–80% response in extensive stage disease (15–20% complete response). However, remissions tend to be short-lived with a median duration of 6–8 months. Once the disease has recurred, median survival is 3–4 months. Overall 2-year survival is 20–40% in limitedstage disease and < 5% in extensive-stage disease. Thoracic radiation therapy improves survival in patients with limited SCLC and is given concurrently with chemotherapy. Thoracic radiation therapy is not beneficial for patients with extensive disease, and they should receive chemotherapy alone. There is a high rate of brain metastasis in patients with SCLC, even following a good response to chemo therapy, because chemotherapy does not adequately penetrate the blood-brain barrier. Prophylactic cranial irradiation has been shown to decrease the incidence of central nervous system disease and improve survival in patients with limited stage disease who respond to chemotherapy and a subset of
patients with extensive stage disease who have had an excellent response to chemotherapy. Occasionally, a patient may have a peripheral nodule resected that turns out to be SCLC. Five-year survival following resection of the equivalent of stage I and stage II SCLC is higher than in patients treated with chemotherapy.
C. Palliative Therapy Photoresection with the Nd:YAG laser is sometimes performed on central tumors to relieve endobronchial obstruction, improve dyspnea, and control hemoptysis. External beam radiation therapy is also used to control dyspnea, hemoptysis, endobronchial obstruction, pain from bony metastases, obstruction from superior vena cava syndrome, and symptomatic brain metastases. Resection of a solitary brain metastasis improves quality of life when combined with radiation therapy, and if there is no evidence of other metastatic disease, it may improve survival. Intraluminal radiation (brachytherapy) is an alternative approach to endobronchial disease. Pain syndromes are very common in advanced disease. As patients approach the end of life, meticulous efforts at pain control are essential (see Chapter 5). In addition to standard oncologic care, early consultation with—or referral to—a palliative care specialist is recommended in advanced disease to aid in symptom management; it may even modestly improve survival.
``Prognosis The overall 5-year survival rate for lung cancer is approximately 15%. Predictors of survival include the type of tumor (SCLC versus NSCLC), molecular typing, the stage of the tumor, the patient’s performance status, and weight loss in the past 6 months. Patients with EGFR mutation have better overall survival when compared with those without EGFR mutation, even when receiving similar cytotoxic chemotherapy. Anantham D et al. Endobronchial ultrasound. Respir Med. 2009 Oct;103(10):1406–14. [PMID: 19447014] Fischer B et al. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med. 2009 July 2;361(1):32–39. [PMID: 19571281] Goldstraw P et al. Non-small-cell lung cancer. Lancet. 2011 Nov 12;378(9804):1727–40. [PMID: 21565398] Kwak EK et al. Anaplastic lymphoma kinase inhibition in nonsmall cell lung cancer. N Engl J Med. 2010 Oct 28;363(18): 1693–703. [PMID: 20979469] Maemondo M et al; North-East Japan Study Group. Gefitinib or chemotherapy for non-small cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24;362(25):2380–8. [PMID: 20573926] Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sept 3;361(10):947–57. [PMID: 19692680] National Lung Screening Trial Research Team; Aberle DR et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011 Aug 4;365(5): 395–409. [PMID: 21714641] Ries LAG et al (eds). SEER Cancer Statistics Review, 1975–2005, National Cancer Institute. Bethesda, MD, http://seer.cancer. gov/csr/1975_2005/, based on November 2007 SEER data submission, posted to the SEER web site, 2008.
Sangha R et al. Adjuvant therapy in non-small cell lung cancer: current and future directions. Oncologist. 2010;15(8):862–72. [PMID: 20682608] Siegel R et al. Cancer Statistics, 2012. CA Cancer J Clin. 2012 Jan–Feb;62(1):10–29. [PMID: 22237781] Silvestri GA. Screening for lung cancer: it works, but does it really work? Ann Intern Med. 2011 Oct 18;155(8):537–9. [PMID: 21893614] Temel JS et al. Early palliative care for patients with metastatic non-small cell lung cancer. N Engl J Med. 2010 Aug 19; 363(8):733–42. [PMID: 20818875] Timmerman R et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010 Mar 17;303(11): 1070–6. [PMID: 20233825]
Pulmonary Metastases Pulmonary metastasis results from the spread of an extrapulmonary malignant tumor through vascular or lymphatic channels or by direct extension. Almost any cancer can metastasize to the lung, including primary lung carcinomas. Metastases usually occur via the pulmonary artery and typically present as multiple nodules or masses on chest radiography. The radiographic differential diagnosis of multiple pulmonary nodules also includes pulmonary arteriovenous malformation, pulmonary abscesses, granulomatous infection, sarcoidosis, rheumatoid nodules, and granulomatosis with polyangiitis (formerly Wegener granulomatosis). Metastases to the lungs are found in 20–55% of patients dying of various malignancies. Most are intraparenchymal. Endobronchial metastases occur in < 5% of patients dying of nonpulmonary cancer. Carcinoma of the kidney, breast, rectum, colon, and cervix and malignant melanoma are the most likely primary tumors. Head and neck cancers with extensive or lower cervical nodal involvement have a 30% risk for distant metastasis; half of these metastases present in the lungs. Lymphangitic carcinomatosis denotes diffuse involvement of the pulmonary lymphatic network by primary or metastatic lung cancer, probably a result of extension of tumor from lung capillaries to the lymphatics. Tumor embolization from extrapulmonary cancer (renal cell carcinoma, hepatocellular carcinoma, choriocarcinoma) is an uncommon route for tumor spread to the lungs. Metastatic cancer may also present as a malignant pleural effusion.
``Clinical Findings A. Symptoms and Signs Symptoms are uncommon but include cough, hemoptysis and, in advanced cases, dyspnea and hypoxemia. Symptoms are more often referable to the site of the primary tumor.
B. Laboratory Findings The diagnosis of metastatic cancer involving the lungs is usually established by identifying a primary tumor. Appropriate studies should be ordered if there is a suspicion of any primary cancer, such as breast, thyroid, testis, colorectal, or prostate, for which specific treatment is available.
For example, an elevated prostate-specific antigen (PSA) may indicate prostate cancer, carcinoembryonic antigen (CEA) tests for colorectal cancer, and β-human chorionic gonadotropin (βHCG) and α-fetoprotein test for germ cell tumors. Based on the clinical setting, imaging studies should be ordered (see below). If the history, physical examination, and initial studies fail to reveal the site of the primary tumor, attention is better focused on the lung, where tissue samples obtained by bronchoscopy, percutaneous needle biopsy, VATS, or thoracotomy may establish the histologic diagnosis and suggest the most likely primary cancer. Occasionally, cytologic studies of pleural fluid or pleural biopsy reveal the diagnosis. Sputum cytology is rarely helpful. If the initial histologic review does not reveal a primary diagnosis, immunohistochemical staining should be done on the biopsy specimen. For example, PSA and thyroglobulin staining are highly specific for prostate and thyroid cancer, respectively. Thyroid transcription factor-1 (TTF-1) is relatively specific for primary lung adenocarcinoma, while also positive for SCLC and thyroid carcinoma. An adenocarcinoma that demonstrates negative TTF-1 staining strongly suggests a nonpulmonary primary cancer. Positive estrogen receptor (ER) and progesterone receptor (PR) stains suggest primary breast cancer.
C. Imaging Chest radiographs usually show multiple spherical densities with sharp margins. The size of metastatic lesions varies from a few millimeters (miliary densities) to large masses. Nearly all are < 5 cm in diameter. The lesions are usually bilateral, pleural or subpleural in location, and more common in lower lung zones. Cavitation suggests squamous cell tumor; calcification suggests osteosarcoma. Lymphangitic spread and solitary pulmonary nodule are less common radiographic presentations of pulmonary metastasis. Conventional chest radiography is less sensitive than CT scan in detecting pulmonary metastases. Mammography should be considered in women to search for possible primary breast cancer. CT imaging of the chest, abdomen, and pelvis may reveal the site of a primary tumor and will help determine feasibility of surgical resection of the metastatic lung tumors. PET-CT scan may also help in identifying the site of a primary cancer or identifying other areas of extrathoracic metastasis.
``Treatment Once the diagnosis has been established, management consists of treatment of the primary neoplasm and any pulmonary complications. Surgical resection of a solitary pulmonary nodule is often prudent in the patient with known current or previous extrapulmonary cancer. Local resection of one or more pulmonary metastases is feasible in a few carefully selected patients with various sarcomas and carcinomas (breast, testis, colon, and kidney). Surgical resection should be considered only if the primary tumor is under control, if the patient is a good surgical risk, if all of the metastatic tumor can be resected, if effective nonsurgical approaches are not available, and if there are no
metastases elsewhere in the body. Relative contraindications to resection of pulmonary metastases include (1) malignant melanoma primary, (2) requirement for pneumonectomy, and (3) pleural involvement. Data from the International Registry of Lung Metastases report an overall 5-year survival rate of 36% and 10-year survival rate of 26% after complete resection of pulmonary metastases. Patients who are not surgical candidates but have solitary or limited metastatic disease to the lungs may be candidates for stereotactic radiosurgery, radioablation, or cryotherapy. For patients with progressive disease, diligent attention to palliative care is essential (see Chapter 5).
a history of asbestos exposure. The latent period between exposure and onset of symptoms ranges from 20 to 40 years. The clinician should inquire about asbestos exposure through mining, milling, manufacturing, shipyard work, insulation, brake linings, building construction and demolition, roofing materials, and a variety of asbestos products (pipe, textiles, paint, tile, gaskets, panels). Although cigarette smoking significantly increases the risk of bronchogenic carcinoma in asbestos workers and aggravates asbestosis, there is no association between smoking and mesothelioma.
``Clinical Findings Kaifi JT et al. Indications and approach to surgical resection of lung metastases. J Surg Oncol. 2010 Aug 1;102(2):187–95. [PMID: 20648593] Mitry E et al. Epidemiology, management and prognosis of colorectal cancer with lung metastases: a 30-year population-based study. Gut. 2010 Oct;59(10):1383–8. [PMID: 20732912] Oliaro A et al. Pulmonary metastasectomy for melanoma. J Thorac Oncol. 2010. Jun;5(6 Suppl 2):S187–91. [PMID: 20502260] Pfannschmidt J. Reported outcome factors for pulmonary resection of metastatic colorectal cancer. J Thorac Oncol. 2010 Jun;5(6 Suppl 2):S172–8. [PMID: 20502257] Pfannschmidt J. Thoracic metastasectomy for non-seminomatous germ cell tumors. J Thorac Oncol. 2010 Jun;5(6 Suppl 2): S182–6. [PMID: 20502259] Rusch VW. Pulmonary metastasectomy: a moving target. J Thorac Oncol.2010 Jun;5(6 Suppl 2):S130–1. [PMID: 20502246] Treasure T et al. Pulmonary metastasectomy in colorectal cancer: the PulMiCC Trial. J Thor Oncol.2010 Jun;5(6 Suppl 2): S203–6. [PMID: 20502265]
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Unilateral, nonpleuritic chest pain and dyspnea. Distant (> 20 years earlier) history of exposure to asbestos. Pleural effusion or pleural thickening or both on chest radiographs. Malignant cells in pleural fluid or tissue biopsy.
``General Considerations Mesotheliomas are primary tumors arising from the surface lining of the pleura (80% of cases) or peritoneum (20% of cases). About three-fourths of pleural mesotheliomas are diffuse (usually malignant) tumors, and the remaining one-fourth are localized (usually benign). Men outnumber women by a 3:1 ratio. Numerous studies have confirmed the association of malignant pleural mesothelioma with exposure to asbestos (particularly the crocidolite form). The lifetime risk to asbestos workers of developing malignant pleural mesothelioma is as high as 10%. Sixty to 80 percent of patients with malignant mesothelioma report
A. Symptoms and Signs The average interval between onset of symptoms and diagnosis is 2–3 months; the median age at diagnosis is 69 years in Western countries. Symptoms include the insidious onset of shortness of breath, nonpleuritic chest pain, and weight loss. Physical findings include dullness to percussion, diminished breath sounds and, in some cases, digital clubbing.
B. Laboratory Findings Pleural fluid is exudative and often hemorrhagic. Cytologic tests of pleural fluid are often negative. VATS biopsy is usually necessary to obtain an adequate specimen for histologic diagnosis. The histologic variants of malignant pleural mesothelioma are epithelial (50–60%), sarcomatoid (10%), and biphasic (30–40%). Since distinction from benign inflammatory conditions and metastatic adenocarcinoma may be difficult, immunohistochemical stains are important to confirm the diagnosis. Epithelial mesothelioma stains are positive for pankeratin, calretinin, keratin 5/6, and WT1 and are negative for epithelial markers, such as CEA, MOC-31, TTF-1, CD15, and B72.3 (usually three needed). Soluble mesothelin-related peptide also may be found in serum or pleural fluid (or both) of patients with mesothelioma, epithelioid type.
C. Imaging Radiographic abnormalities consist of nodular, irregular, unilateral pleural thickening and varying degrees of unilateral pleural effusion. Sixty percent of patients have right-sided disease, while only 5% have bilateral involvement. CT scans demonstrate the extent of pleural involvement. PET-CT is increasingly used to help differentiate benign from malignant pleural disease, improve staging accuracy, and identify candidates for aggressive surgical approaches.
``Complications Malignant pleural mesothelioma progresses rapidly as the tumor spreads along the pleural surface to involve the pericardium, mediastinum, and contralateral pleura. The tumor may eventually extend beyond the thorax to involve abdominal lymph nodes and organs. Progressive pain and dyspnea are characteristic. Local invasion of thoracic
Cancer structures may cause superior vena cava syndrome, hoarseness, Horner syndrome, arrhythmias, and dysphagia. Paraneoplastic syndromes associated with mesothelioma include thrombocytosis, hemolytic anemia, disseminated intravascular coagulopathy, hypercalcemia, and migratory thrombophlebitis.
``Treatment Chemotherapy is the mainstay of treatment, unless there is localized disease that can be surgically resected. Surgery, radiotherapy, chemotherapy, or a combination of modalities may be attempted, but treatments are generally unsuccessful. For localized disease, pleurectomy and decortication (surgical stripping of the pleura and pericardium from apex of the lung to diaphragm) is one surgical approach and can be effective in controlling malignant pleural effusion. Previously, some thoracic surgeons favored a trimodality approach for localized disease with extrapleural pneumonectomy, adjuvant radiation, and chemotherapy, based on limited retrospective data that it prolongs survival in highly selected patients. Extrapleural pneumonectomy is a radical surgical procedure involving removal of the ipsilateral lung, parietal and visceral pleura, pericardium, and most of the hemidiaphragm. However, the Mesothelioma and Radical Surgery (MARS) trial, a small randomized study comparing extrapleural pneumonectomy with no extrapleural pneumonectomy after induction chemotherapy in 50 patients, showed that extrapleural pneumonectomy offered no survival benefit and may have caused more harm. In advanced unresectable cases, palliative chemotherapy with cisplatin and pemetrexed can extend survival as well as improve quality of life. Other alternative chemotherapy regimens include gemcitabine, anthracyclines, or vinorelbine. Drainage of pleural effusions, pleurodesis, radiation therapy, and even surgical resection may offer palliative benefit in some patients.
``Prognosis Most patients die of respiratory failure and complications of local extension. Median survival time from onset of symptoms ranges from 4 months in extensive disease to 16 months in localized disease. Five-year survival is < 5%. Tumors that are predominantly sarcomatoid are more resistant to therapy and have a worse prognosis, with median survivals < 1 year. Poor prognostic features include poor performance status, non-epithelioid histology, male gender, nodal involvement, elevated lactate dehydrogenase, high white blood cell count, low hemoglobin, and high platelet count.
Nowak AK et al. Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group. Lung Cancer. 2010 Oct;70(1):1–6. [PMID: 20541834] Stahel RA et al. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21(suppl 5):v126–8. [PMID: 20555061]
Treasure T et al. Extra-pleural pneumonectomy versus no extrapleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomized feasibility study. Lancet Oncol. 2011 Aug;12(8):763–72. [PMID: 21723781] Van Meerbeeck JP et al. Malignant pleural mesothelioma: the standard of care and challenges for future management. Crit Rev Oncol Hematol. 2011 May;78(2):92–111. [PMID: 20466560] Weder W. Mesothelioma. Ann Oncol. 2010 Oct;21(Suppl 7): vii326–33. [PMID: 20943637] Wheatley-Price P. Soluble mesothelin-related peptide and osteopontin as markers of response in malignant mesothelioma. J Clin Oncol. 2010 Jul 10;28(20):3316–22. [PMID: 20498407]
HEPATOBILIARY CANCERS Lawrence S. Friedman, MD
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In Western countries, usually a complication of cirrhosis. Characteristic CT and MRI features and elevated serum α-fetoprotein may obviate the need for a confirmatory biopsy.
``General Considerations Malignant neoplasms of the liver that arise from parenchymal cells are called hepatocellular carcinomas; those that originate in the ductular cells are called cholangiocarcinomas. Hepatocellular carcinomas are associated with cirrhosis in 80% of cases. Incidence rates are rising rapidly (twofold since 1978) in the United States and other Western countries, presumably because of the increasing prevalence of cirrhosis caused by chronic hepatitis C infection and nonalcoholic fatty liver disease. In Western countries, risk factors for hepatocellular carcinoma in patients known to have cirrhosis are male gender, age > 55 years (although there has been an increase in the number of younger cases), Asian or Hispanic ethnicity, family history in a first-degree relative, overweight, obesity, alcohol use (especially in combination with obesity), diabetes mellitus, hypothyroidism (in women), HCV infection, HBsAg and anti-HBc positivity, a prolonged prothrombin time, a low platelet count, and an elevated serum transferrin saturation. In Africa and most of Asia, hepatitis B is of major etiologic significance, whereas in Western countries and Japan, hepatitis C (particularly genotype 1b and sometimes in combination with “occult” HBV infection) and alcoholic cirrhosis are the most common risk factors. Other associations include high levels of HBV replication, HBV genotype C, hepatitis D coinfection, hemochromatosis (and possibly the C282Y carrier state), aflatoxin exposure (associated with mutation of the TP53 gene),
α1-antiprotease (α1-antitrypsin) deficiency, tyrosinemia, and radiation exposure. In patients with the metabolic syndrome, hepatocellular carcinoma may arise from a hepatocellular adenoma in the absence of cirrhosis. Evidence for an association with long-term use of oral contraceptives is inconclusive. Coffee consumption and, in diabetic patients, the use of statins appear to be protective. The fibrolamellar variant of hepatocellular carcinoma occurs in young women and is characterized by a distinctive histologic picture, absence of risk factors, and indolent course. Vinyl chloride exposure is associated with angiosarcoma of the liver.
1 cm may be difficult to characterize. Arterial phase enhancement of the lesion followed by delayed hypointensity (“washout”) is most specific for hepatocellular carcinoma. Ultrasonography is less sensitive and operator dependent but is used to screen for hepatic nodules in high-risk patients. Contrast-enhanced ultrasonography has a sensitivity and specificity approaching those of arterial phase helical CT but, unlike CT and MRI, cannot image the entire liver during the short duration of the arterial phase and is associated with false-positive results. In selected cases, endoscopic ultrasonography may be useful. PET is under study.
D. Liver Biopsy and Staging
A. Symptoms and Signs
Liver biopsy is diagnostic, although seeding of the needle tract by tumor is a potential risk (1–3%). For lesions < 1 cm, ultrasonography may be repeated every 3 months followed by further investigation of enlarging lesions. For lesions ≥ 1 cm, biopsy can be deferred when characteristic arterial hypervascularity and delayed washout are demonstrated on either multiphasic helical CT or MRI with contrast enhancement (or both) or if surgical resection is planned. Staging in the TNM classification includes the following definitions: T0: no evidence of primary tumor; T1: solitary tumor without vascular invasion; T2: solitary tumor with vascular invasion or multiple tumors none more than 5 cm; T3: multiple tumors more than 5 cm (3a) or tumor involving a major branch of the portal or hepatic vein (3b); and T4: tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of the visceral peritoneum; N1, regional lymph node metastasis; M1, distant metastasis; F0, no to moderate hepatic fibrosis; F1, severe hepatic fibrosis to cirrhosis. The Barcelona Clinic Liver Cancer (BCLC) staging system is preferred and includes the Child-Turcotte-Pugh stage, tumor stage, and liver function and has the advantage of linking overall stage with preferred treatment modalities and with an estimation of life expectancy.
The presence of a hepatocellular carcinoma may be unsuspected until there is deterioration in the condition of a cirrhotic patient who was formerly stable. Cachexia, weakness, and weight loss are associated symptoms. The sudden appearance of ascites, which may be bloody, suggests portal or hepatic vein thrombosis by tumor or bleeding from a necrotic tumor. Physical examination may show tender enlargement of the liver, occasionally with a palpable mass. In Africa, the typical presentation in young patients is a rapidly expanding abdominal mass. Auscultation may reveal a bruit over the tumor or a friction rub when the tumor has extended to the surface of the liver.
B. Laboratory Findings Laboratory tests may reveal leukocytosis, as opposed to the leukopenia that is frequently encountered in cirrhotic patients. Anemia is common, but a normal or elevated hematocrit value may be found in up to one-third of patients owing to elaboration of erythropoietin by the tumor. Sudden and sustained elevation of the serum alkaline phosphatase in a patient who was formerly stable is a common finding. HBsAg is present in a majority of cases in endemic areas, whereas in the United States anti-HCV is found in up to 40% of cases. α-Fetoprotein levels are elevated in up to 70% of patients with hepatocellular carcinoma in Western countries (although the sensitivity is lower in blacks and levels are not elevated in patients with fibrolamellar hepatocellular carcinoma); however, mild elevations (10–200 ng/mL [10–200 mcg/L]) are also often seen in patients with chronic hepatitis. Serum levels of desgamma-carboxy prothrombin are elevated in up to 90% of patients with hepatocellular carcinoma, but they may also be elevated in patients with vitamin K deficiency, chronic hepatitis, and metastatic cancer. The L3 glycoform of α-fetoprotein (AFP-L3) is under study and may not be sensitive for early hepatocellular carcinoma. Cytologic study of ascitic fluid rarely reveals malignant cells.
C. Imaging Multiphasic helical CT and MRI with contrast enhancement are the preferred imaging studies for determining the location and vascularity of the tumor. Lesions smaller than
``Screening & Prevention In the patient with chronic hepatitis B (beginning as early as age 20 in Africans and age 40 in Asians or those with a family history of hepatocellular carcinoma) or cirrhosis caused by HCV, HBV, or alcohol, surveillance for the development of hepatocellular carcinoma is recommended. Although the standard approach is α-fetoprotein testing and ultrasonography every 6 months, the value of α-fetoprotein screening has been questioned because of its low sensitivity. CT and MRI are considered too expensive for screening, but the sensitivity of ultrasonography for detecting early hepatocellular carcinoma is only 63%. The risk of hepatocellular carcinoma in a patient with cirrhosis is 3–5% a year, and patients with tumors detected by surveillance have a less advanced stage on average and greater likelihood that treatment will prolong survival than those not undergoing surveillance. In a population of patients with cirrhosis, over 60% of nodules < 2 cm in diameter detected on a screening ultrasonography prove to be hepatocellular carcinoma. Mass vaccination programs against
Cancer HBV in developing countries are leading to reduced rates of hepatocellular carcinoma. Successful treatment of hepatitis B and of hepatitis C in patients with cirrhosis also reduces the subsequent risk of hepatocellular carcinoma.
``Treatment Surgical resection of a solitary hepatocellular carcinoma may result in cure if liver function is preserved (Child class A or possibly B) and portal vein thrombosis is not present. Laparoscopic liver resection has been performed in selected cases. Treatment of underlying chronic viral hepatitis, adjuvant chemotherapy, and adaptive immunotherapy may lower postsurgical recurrence rates. Liver transplantation may be appropriate for small unresectable tumors in a patient with advanced cirrhosis, with reported 5-year survival rates of up to 75%. The recurrence-free survival may be better for liver transplantation than for resection in patients with well-compensated cirrhosis and small tumors (one tumor < 5 cm or three or fewer tumors each < 3 cm in diameter [Milan criteria]) and in those with expanded (University of California, San Francisco) criteria of one tumor ≤ 6.5 cm or three or fewer tumors ≤ 4.5 cm. Patients with stage 2 hepatocellular carcinoma receive an additional 22 points on their Model for End-Stage Liver Disease (MELD) score (see Chapter 16), markedly increasing their chances of undergoing transplantation. However, liver transplantation is often impractical because of the donor organ shortage, and living donor liver transplantation may be considered in these cases. Patients with larger tumors (3–5 cm), a serum α-fetoprotein level ≥ 455 ng/mL (455 mcg/L), or a MELD score ≥ 20 have poor posttransplantation survival. Chemotherapy, hormonal therapy with tamoxifen, and long-acting octreotide have not been shown to prolong life, but transarterial chemoembolization (TACE), transarterial chemoinfusion (TACI), and transarterial radioembolization (TARE) via the hepatic artery are palliative and may prolong survival in patients with a large or multifocal tumor in the absence of extrahepatic spread. TACI and TARE are suitable for patients with portal vein thrombosis. Injection of absolute ethanol into, radiofrequency ablation of, cryotherapy of, or microwave ablation of small tumors (< 2 cm) may prolong survival in patients who are not candidates for resection; these interventions may provide a “bridge” to liver transplantation. Radiofrequency ablation is superior to ethanol injection for tumors > 2 cm in diameter and can be performed after TACE in select cases. Sorafenib (an oral multikinase inhibitor of Raf kinase, the VEGF receptor, and the plateletderived growth factor receptor [and others]), prolongs median survival as well as the time to radiologic progression by 3 months in patients with advanced hepatocellular carcinoma; sorafenib is the standard of care in these patients. New chemotherapy and radiation therapy techniques (eg, radioembolization with yttrium-90 microspheres), novel biologic approaches (eg, bortezomib, a proteasome inhibitor; antiangiogenesis agents; other inhibitors of growth-factor signaling; and gene therapy), and multimodal approaches are under study. For patients whose disease progresses despite treatment or who present with advanced tumors, vascular invasion, or extrahepatic
spread, meticulous efforts at palliative care are essential (see Chapter 5). Severe pain may develop in such patients due to expansion of the liver capsule by the tumor and requires concerted efforts at pain management, including the use of opioids (see Chapter 5).
``Prognosis In the United States, overall 1- and 5-year survival rates for patients with hepatocellular carcinoma are 23% and 5%, respectively. Five-year survival rates rise to 56% for patients with localized resectable disease (T1, T2, selected T3 and T4; N0; M0) but are virtually nil for those with locally unresectable or advanced disease. In patients with HCVrelated hepatocellular carcinoma, the serum α-fetoprotein level at the time of diagnosis of cancer has been reported to be an independent predictor of mortality. Contrary to traditional opinion, the fibrolamellar variant does not have a better prognosis than conventional hepatocellular car cinoma without cirrhosis.
``When to Refer All patients with hepatocellular carcinoma should be referred to a specialist.
``When to Admit • Complications of cirrhosis. • Severe pain. • For surgery and other interventions.
Bruix J et al. Management of hepatocellular carcinoma: an update. Hepatology. 2011 Mar;53(3):1020–2. [PMID: 21374666] El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011 Sep 22;365(12):1118–27. [PMID: 21992124] Villanueva A et al. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011 May;140(5):1410–26. [PMID: 21406195]
CARCINOMA OF THE BILIARY TRACT
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Presents with obstructive jaundice, usually painless, often with dilated biliary tree. Pain is more common in gallbladder carcinoma than cholangiocarcinoma. A Courvoisier (dilated) gallbladder may be detected. Diagnosis by cholangiography with biopsy and brushings for cytology.
``General Considerations Carcinoma of the gallbladder occurs in approximately 2% of all people operated on for biliary tract disease. It is
notoriously insidious, and the diagnosis is often made unexpectedly at surgery. Cholelithiasis (often large, symptomatic stones) is usually present. Other risk factors are chronic infection of the gallbladder with Salmonella typhi, gallbladder polyps over 1 cm in diameter, mucosal calcification of the gallbladder (porcelain gallbladder), and anomalous pancreaticobiliary ductal junction. Genetic factors include K-ras and TP53 mutations. Spread of the cancer—by direct extension into the liver or to the peritoneal surface—may be the initial manifestation. The TNM classification includes the following stages: Tis, carcinoma in situ; T1a, tumor invades lamina propria, and T1b, tumor invades muscle layer; T2, tumor invades perimuscular connective tissue, no extension beyond serosa (visceral peritoneum) or into liver; T3, tumor perforates the serosa or directly invades the liver or adjacent organ or structure; T4, tumor invades the main portal vein or hepatic artery or invades multiple extrahepatic organs or structures; N1, regional lymph node metastasis; and M1, distant metastasis. Carcinoma of the bile ducts (cholangiocarcinoma) accounts for 10–25% of all hepatobiliary malignancies and 3% of all cancer deaths in the United States. It is more prevalent in persons aged 50–70, with a slight male predominance, and more common in Asia. Two-thirds arise at the confluence of the hepatic ducts (Klatskin tumors), and one-fourth arise in the distal extrahepatic bile duct; the remainder are intrahepatic (peripheral), the incidence of which has risen dramatically since the 1970s. Staging for extrahepatic cholangiocarcinoma is as follows: T1, tumor is confined to bile duct; T2, tumor spreads beyond the wall of the bile duct (2a) or to the adjacent liver (2b); T3, tumor spreads to unilateral branches of the portal vein or hepatic artery; T4, tumor spreads to main portal vein or its branches bilaterally, common hepatic artery, second-order biliary radicals bilaterally, or various combinations; N1, regional lymph node metastasis; M1, distant metastasis. Staging for intrahepatic cholangiocarcinoma is as follows: T1, solitary tumor without vascular invasion; T2, solitary tumor with vascular invasion or multiple tumors ≤ 5 cm; T3, multiple tumors > 5 cm or involving major branch of portal or hepatic veins; T4, tumor invades adjacent organ (except gallbladder) or perforation of visceral peritoneum; N1, regional lymph node metastasis; and M1, distant metastasis. Other staging systems consider tumor extent and form, vascular encasement, hepatic lobe atrophy, and underlying liver disease. The frequency of carcinoma in persons with choledochal cysts has been reported to be over 14% at 20 years, and surgical excision is recommended. There is an increased incidence in patients with bile duct adenoma; biliary papillomatosis; Caroli disease; a biliary-enteric anastomosis; ulcerative colitis, especially those with primary sclerosing cholangitis; biliary cirrhosis; diabetes mellitus; hyperthyroidism; chronic pancreatitis; heavy alcohol consumption; and past exposure to thorotrast, a contrast agent. In Southeast Asia, hepatolithiasis and infection of the bile ducts with helminths (Clonorchis sinensis, Opisthorchis viverrini) are associated with chronic cholangitis and an increased risk of cholangiocarcinoma. Hepatitis C virus infection, cirrhosis, HIV infection,
nonalcoholic fatty liver disease, diabetes mellitus, obesity, and tobacco smoking are additional risk factors for intrahepatic cholangiocarcinoma.
``Clinical Findings A. Symptoms and Signs Progressive jaundice is the most common and usually the first sign of obstruction of the extrahepatic biliary system. Pain in the right upper abdomen with radiation into the back is usually present early in the course of gallbladder carcinoma but occurs later in the course of bile duct carcinoma. Anorexia and weight loss are common and may be associated with fever and chills due to cholangitis. Rarely, hematemesis or melena results from erosion of tumor into a blood vessel (hemobilia). Fistula formation between the biliary system and adjacent organs may also occur. The course is usually one of rapid deterioration, with death occurring within a few months. Physical examination reveals profound jaundice. Pruritus and skin excoriations are common. A palpable gallbladder with obstructive jaundice usually is said to signify malignant disease (Courvoisier law); however, this clinical generalization has been proved to be accurate only about 50% of the time. Hepatomegaly due to hypertrophy of the unobstructed liver lobe is usually present and is associated with liver tenderness. Ascites may occur with peritoneal implants.
B. Laboratory Findings With biliary obstruction, laboratory examination reveals predominantly conjugated hyperbilirubinemia, with total serum bilirubin values ranging from 5 to 30 mg/dL. There is usually concomitant elevation of the alkaline phosphatase and serum cholesterol. AST is normal or minimally elevated. An elevated CA 19-9 level may help distinguish cholangiocarcinoma from a benign biliary stricture (in the absence of cholangitis).
C. Imaging Ultrasonography and contrast-enhanced, triple-phase, helical CT may show a gallbladder mass in gallbladder carcinoma and intrahepatic mass or biliary dilatation in carcinoma of the bile ducts. CT may also show involved regional lymph nodes and atrophy of a hepatic lobe because of vascular encasement with compensatory hypertrophy of the unaffected lobe. MRI with magnetic resonance cholangiopancreatography (MRCP) and gadolinium enhancement permits visualization of the entire biliary tree and detection of vascular invasion and obviates the need for angiography and, in some cases, direct cholangiography; it is the imaging procedure of choice but may understage malignant hilar strictures. The sensitivity and image quality can be increased with use of ferumoxide enhancement. The features of intrahepatic cholangiocarcinoma on MRI appear to differ from those of hepatocellular carcinoma, with contrast washout in the latter but not the former. In indeterminate cases, PET can detect cholangiocarcinomas as small as 1 cm and lymph node and
Cancer distant metastases, but false-positive results occur. The most helpful diagnostic studies before surgery are either percutaneous transhepatic or endoscopic retrograde cholangiography with biopsy and cytologic specimens, although false-negative biopsy and cytology results are common. Digital image analysis and fluorescent in situ hybridization of cytologic specimens improve sensitivity. Endoscopic ultrasonography with FNA of tumors, choledochoscopy, and intraductal ultrasonography may confirm a diagnosis of cholangiocarcinoma in a patient with bile duct stricture and an otherwise indeterminate evaluation.
``Treatment In young and fit patients, curative surgery may be attempted if the tumor is well localized. The 5-year survival rate for carcinoma of the gallbladder invading the lamina propria or muscularis (stage 1, T1a or 1b, N0, M0) is as high as 85% with laparoscopic cholecystectomy but drops to 60%, even with a more extended open resection, if there is perimuscular invasion (T2). The role of radical surgery for T3 and T4 tumors is debatable. If the tumor is unresectable at laparotomy, biliary-enteric bypass (eg, Roux-en-Y hepaticojejunostomy) can be performed. Carcinoma of the bile ducts is curable by surgery in < 10% of cases. If resection margins are negative, the 5-year survival rate may be as high as 47% for intrahepatic cholangiocarcinomas, 41% for hilar cholangiocarcinoma, and 37% for distal cholangiocarcinomas, but the perioperative mortality rate may be as high as 10%. Palliation can be achieved by placement of a self-expandable metal stent via an endoscopic or percutaneous transhepatic route. Covered metal stents may be more cost-effective than uncovered metal stents because of a longer duration of patency, but they are associated with a higher rate of stent migration and cholecystitis due to occlusion of the cystic duct and are not associated with longer survival. For hilar tumors, there is controversy as to whether unilateral or bilateral stents should be inserted. Plastic stents are less expensive but more prone to occlude than metal ones; they are suitable for patients expected to survive only a few months. Photodynamic therapy in combination with stent placement has been demonstrated to prolong survival when compared with stent placement alone in patients with nonresectable cholangiocarcinoma. Radiotherapy may relieve pain and contribute to biliary decompression. There is limited response to chemotherapy with gemcitabine alone, but the combination of cisplatin and gemcitabine prolongs survival by about 3 months in patients with locally advanced or metastatic cholangiocarcinoma. Few patients survive for more than 24 months. Although cholangiocarcinoma is generally considered to be a contraindication to liver transplantation because of rapid tumor recurrence, a 75% 5-year survival rate has been reported in patients with stage I and II cholangiocarcinoma undergoing chemoradiation and exploratory laparotomy followed by liver transplantation. For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5).
``When to Refer All patients with carcinoma of the biliary tract should be referred to a specialist.
``When to Admit • Biliary obstruction. • Cholangitis. DeOliveira ML et al. New staging system and a registry for perihilar cholangiocarcinoma. Hepatology. 2011 Apr;53(4):1 363–71. [PMID: 21480336] Saleem A et al. Meta-analysis of randomized trials comparing the patency of covered and uncovered self-expandable metal stents for palliation of distal malignant bile duct obstruction. Gastrointest Endosc. 2011 Aug;74(2):321–7. [PMID: 21683354] Tyson GL et al. Risk factors for cholangiocarcinoma. Hepatology. 2011 Jul;54(1):173–84. [PMID: 21488076]
CARCINOMA OF THE PANCREAS & THE PERIAMPULLARY AREA
E ssent i a l s o f d i a g nos i s
Obstructive jaundice (may be painless). Enlarged gallbladder (may be painful). Upper abdominal pain with radiation to back, weight loss, and thrombophlebitis are usually late manifestations.
`` `` ``
``General Considerations Carcinomas involving the head of the pancreas, ampulla of Vater, distal bile duct, and duodenum are considered together because they are usually indistinguishable clinically; of these, carcinomas of the pancreas constitute over 90%. Carcinoma is the most common neoplasm of the pancreas. About 75% are in the head and 25% in the body and tail of the organ. They comprise 2% of all cancers and 5% of cancer deaths. Risk factors include age, tobacco use (which is thought to cause 20–25% of cases), heavy alcohol use, obesity, chronic pancreatitis, prior abdominal radiation, family history, and possibly gastric ulcer. Newonset diabetes mellitus after age 45 years occasionally heralds the onset of pancreatic cancer. In diabetic patients, preliminary data suggest that metformin use reduces the risk but insulin use and glucagon-like peptide-1-based therapy (eg, sitagliptin) increase the risk of pancreatic cancer. About 7% of patients with pancreatic cancer have a family history of pancreatic cancer in a first-degree relative, compared with 0.6% of control subjects. Point mutations in codon 12 of the K-ras oncogene are found in 70–100% of pancreatic cancers; inactivation of the tumor suppressor genes INK4A on chromosome 9, TP53 on chromosome 17, and MADH4 on chromosome 18 is found in 95%, 75%, and 55% of pancreatic cancers,
respectively; and mutation of the palladin gene is reported to be common. In 5–10% of cases, pancreatic cancer occurs as part of several hereditary syndromes, including familial breast cancer (carriers of BRCA-2 have a 7% lifetime risk of pancreatic cancer), hereditary pancreatitis (PSS1 mutation), familial atypical multiple mole melanoma (p16/CDKN2A mutation), Peutz-Jeghers syndrome (STK11/LKB1 mutation), ataxia-telangiectasia, and hereditary nonpolyposis colorectal cancer. Polymorphisms of the genes for methylene tetrahydrofolate reductase and thymidylate synthase have been reported to be associated with pancreatic cancer. Neuroendocrine tumors account for 1–2% of pancreatic neoplasms and may be functional (producing gastrin, insulin, glucagon, vasoactive intestinal peptide, somatostatin, growth hormone–releasing hormone, adrenocorticotropic hormone, and others) or nonfunctional. Plasma chronogranin A levels are elevated in 88–100% of affected patients. Cystic neoplasms account for only 1% of pancreatic cancers, but they are important because they are often mistaken for pseudocysts. A cystic neoplasm should be suspected when a cystic lesion in the pancreas is found in the absence of a history of pancreatitis. At least 15% of all pancreatic cysts are neoplasms. Whereas serous cystadenomas (which account for 32–39% of cystic pancreatic neoplasms and also occur in patients with von Hippel-Lindau disease) are benign, mucinous cystic neoplasms (defined by the presence of ovarian stroma) (10–45%), intraductal papillary mucinous neoplasms (21–33%), solid pseudopapillary tumors (< 5%), and cystic islet cell tumors (3–5%) may be malignant, although their prognoses are better than the prognosis of adenocarcinoma of the pancreas, unless the neoplasm is locally advanced.
``Clinical Findings A. Symptoms and Signs Pain is present in over 70% of cases and is often vague, diffuse, and located in the epigastrium or left upper quadrant when the lesion is in the tail. Radiation of pain into the back is common and sometimes predominates. Sitting up and leaning forward may afford some relief, and this usually indicates that the lesion has spread beyond the pancreas and is inoperable. Diarrhea, perhaps due to maldigestion, is an occasional early symptom. Migratory thrombophlebitis is a rare sign. Weight loss is a common but late finding and may be associated with depression. Occasionally a patient presents with acute pancreatitis in the absence of an alternative cause. Jaundice is usually due to biliary obstruction by a cancer in the pancreatic head. A palpable gallbladder is also indicative of obstruction by neoplasm (Courvoisier law), but there are frequent exceptions. A hard, fixed, occasionally tender mass may be present. In advanced cases, a hard periumbilical (Sister Joseph’s) nodule may be palpable.
B. Laboratory Findings There may be mild anemia. Glycosuria, hyperglycemia, and impaired glucose tolerance or true diabetes mellitus are found in 10–20% of cases. The serum amylase or lipase
level is occasionally elevated. Liver biochemical tests may suggest obstructive jaundice. Steatorrhea in the absence of jaundice is uncommon. Occult blood in the stool is suggestive of carcinoma of the ampulla of Vater (the combination of biliary obstruction and bleeding may give the stools a distinctive silver appearance). CA 19-9, with a sensitivity of 70% and a specificity of 87%, has not proved sensitive enough for early detection of pancreatic cancer; increased values are also found in acute and chronic pancreatitis and cholangitis.
C. Imaging Multiphase thin-cut helical CT is generally the initial diagnostic procedure and detects a mass in over 80% of cases. CT identifies metastases, delineates the extent of the tumor, and allows for percutaneous FNA for cytologic studies and tumor markers. MRI is an alternative to CT. Ultrasonography is not reliable because of interference by intestinal gas. PET is a sensitive technique for detecting pancreatic cancer and metastases, but PET-CT is not a routine staging procedure. Selective celiac and superior mesenteric arteriography may demonstrate vessel invasion by tumor, a finding that would preclude attempts at surgical resection, but it is less widely used since the advent of multiphase helical CT. Endoscopic ultrasonography is more sensitive than CT for detecting pancreatic cancer and equivalent to CT for determining nodal involvement and resectability. A normal endoscopic ultrasonogram excludes pancreatic cancer. Endoscopic ultrasonography may also be used to guide FNA for tissue diagnosis, tumor markers, and DNA analysis. Endoscopic retrograde cholangiopancreatography (ERCP) may clarify an ambiguous CT scan or MRI study by delineating the pancreatic duct system or confirming an ampullary or biliary neoplasm. MRCP appears to be at least as sensitive as ERCP in diagnosing pancreatic cancer. In some centers, pancreatoscopy or intraductal ultrasonography can be used to evaluate filling defects in the pancreatic duct and assess resectability of intraductal papillary mucinous tumors. With obstruction of the splenic vein, splenomegaly or gastric varices are present, the latter delineated by endoscopy, endoscopic ultrasonography, or angiography. Cystic neoplasms can be distinguished by their appearance on CT, endoscopic ultrasonography, and ERCP and features of the cyst fluid on gross and cytologic analysis. For example, serous cystadenomas may have a central scar or honeycomb appearance; mucinous cystadenomas are unilocular or multilocular and contain mucin-rich fluid with high carcinoembryonic antigen levels (> 200 ng/mL) (200 mcg/L); and intraductal papillary mucinous neoplasms are associated with a dilated pancreatic duct and extrusion of gelatinous material from the ampulla.
``Staging Staging of pancreatic cancer by the TNM classification includes the following definitions: Tis: carcinoma in situ; T1: tumor limited to the pancreas, 2 cm or less in greatest dimension; T2: tumor limited to the pancreas, more than
Cancer 2 cm in greatest dimension; T3: tumor extends beyond the pancreas but without involvement of the celiac axis or the superior mesenteric artery; T4, tumor involves the celiac axis or the superior mesenteric artery (unresectable primary tumor); N1, regional lymph node metastasis; M1, distant metastasis.
``Treatment Abdominal exploration is usually necessary when cytologic diagnosis cannot be made or if resection is to be attempted, which includes about 30% of patients. In a patient with a localized mass in the head of the pancreas and without jaundice, laparoscopy may detect tiny peritoneal or liver metastases and thereby avoid resection in 4–13% of patients. Radical pancreaticoduodenal (Whipple) resection is indicated for lesions strictly limited to the head of the pancreas, periampullary area, and duodenum (T1, N0, M0). Five-year survival rates are 20–25% in this group and as high as 40% in those with negative resection margins and without lymph node involvement. Preoperative endoscopic decompression of an obstructed bile duct is often achieved with a plastic stent or short metal stent but does not reduce operative mortality and is associated with complications. The best surgical results are achieved at centers that specialize in the multidisciplinary treatment of pancreatic cancer. Adjuvant or neoadjuvant chemotherapy with gemcitabine or fluorouracil (or both), possibly combined with irradiation, is of benefit (Table 39–4). Chemoradiotherapy downstages about 30% of patients with locally advanced disease to allow resection. When resection is not feasible, endoscopic stenting of the bile duct is performed to relieve jaundice. A plastic stent is generally placed if the patient’s anticipated survival is < 6 months (or surgery is planned). A metal stent is preferred when anticipated survival is 6 months or greater. Whether covered metal stents designed to prevent tumor ingrowth offer an advantage over uncovered stents is uncertain because covered stents are associated with higher rates of migration and acute cholecystitis due to occlusion of the cystic duct. Surgical biliary bypass may be considered in patients expected to survive at least 6 months. Surgical duodenal bypass may be considered in patients in whom duodenal obstruction is expected to develop later; alternatively, endoscopic placement of a self-expandable duodenal stent may be feasible. Chemoradiation may be used for palliation of unresectable cancer confined to the pancreas. Chemotherapy has been disappointing in metastatic pancreatic cancer, although improved response rates have been reported with the combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX). The addition of erlotinib (an inhibitor of the EGFR receptor), capecitabine (an oral fluoropyrimidine), or a platinum agent may improve survival but also increases toxicity. The high rate of K-ras mutations in pancreatic cancer limits the benefit of erlotinib. Nucleoside cytidine analogues and topoisomerase inhibitors are under study. Celiac plexus nerve block (under CT or endoscopic ultrasound guidance) or thoracoscopic splanchnicectomy may improve pain control. Photodynamic therapy is under study.
Surgical resection is the treatment of choice for neuroendocrine tumors, when feasible. Metastatic disease may be controlled with long-acting somatostatin analogs, interferon, peptide-receptor radionuclide therapy, and chemoembolization. There is a growing consensus that asymptomatic incidental pancreatic cysts ≤ 2 cm are at low risk for harboring invasive carcinoma. The cysts may be monitored by imaging tests at 6- to 12-month intervals and every 3–6 months in those > 2 cm, with surgery or possibly endoscopic ultrasound-guided cyst ablation performed if a cyst enlarges or exceeds 2.5 cm. Surgical resection is indicated for mucinous cystic neoplasms, symptomatic serous cystadenomas, solid pseudopapillary tumors (which have a 15% risk of malignant transformation), and cystic tumors > 2 cm in diameter that remain undefined after helical CT, endoscopic ultrasonography, and diagnostic aspiration. All intraductal papillary mucinous neoplasms of the main pancreatic duct should be resected, but those of branch ducts may be followed with serial imaging if they are asymptomatic and exhibit benign features (eg, diameter < 3 cm [some authorities recommend a diameter ≤ 1.5 cm], absence of nodules or a thick wall); most of the latter remain stable on follow-up, but the risk of pancreatic ductal carcinoma and of nonpancreatic cancers may also be increased in this group of patients. In the absence of locally advanced disease, survival is higher for malignant cystic neoplasms than for adenocarcinoma. Endoscopic resection or ablation, with temporary placement of a pancreatic duct stent, may be feasible for ampullary adenomas, but patients must be followed for recurrence.
``Prognosis Carcinoma of the pancreas, especially in the body or tail, has a poor prognosis; 80–85% of patients present with advanced unresectable disease, and reported 5-year survival rates range from 2% to 5%. Lesions of the ampulla have a better prognosis, with reported 5-year survival rates of 20–40% after resection; jaundice and lymph node involvement are adverse prognostic factors. In carefully selected patients, resection of cancer of the pancreatic head is feasible and results in reasonable survival. In persons with a family history of pancreatic cancer in at least two first-degree relatives, screening with endoscopic ultrasonography and helical CT or MRI/MRCP should be considered beginning at age 40–45 or 10 years before the age at which pancreatic cancer was diagnosed in a family member. For those patients whose disease progresses despite treatment, meticulous efforts at palliative care are essential (see Chapter 5).
``When to Refer All patients with carcinoma involving the pancreas and the periampullary area should be referred to a specialist.
``When to Admit Patients who require surgery and other interventions should be hospitalized.
Table 39–4. Treatment choices for cancers responsive to systemic agents. Diagnosis
Current Treatment of Choice
Acute lymphoblastic leukemia (ALL)
Induction combination chemotherapy: Vincristine, prednisone, daunorubicin, asparaginase, intrathecal methotrexate Consolidation combination chemotherapy: Cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper-CVAD) alternated with cytarabine, methotrexate Maintenance chemotherapy: Methotrexate, 6-mercaptopurine
Imatinib mesylate (Ph positive ALL), autologous or allogeneic transplantation for high risk or at relapse
Acute myeloid leukemia (AML)
Combination chemotherapy: Cytarabine, daunorubicin or Cytarabine, idarubicin
Mitozantrone, doxorubicin, cladribine, fludarabine, prednisone
Chronic myeloid leukemia (CML)
Imatinib mesylate or nilotinib or dasatinib
Dasatinib, nilotinib, allogeneic bone marrow transplantation, hydroxyurea, interferon-α, cytarabine, busulfan
Chronic lymphocytic leukemia (CLL)
Combination chemotherapy: Fludarabine, cyclophosphamide, rituximab (FCR); or Fludarabine, or Bendamustine or Chlorambucil
Alemtuzumab, bendamustine, pentostatin, cladribine, cyclophosphamide, vincristine, doxorubicin, prednisone
Hairy cell leukemia
Pentostatin, rituximab, interferon-α
Hodgkin disease (stages III and IV)
Combination chemotherapy: Doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) or Doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone (Stanford V)
Gemcitabine, vinorelbine, ifosfamide, cyclophosphamide, procarbazine, transplantation for relapse
Combination chemotherapy: Cyclophosphamide, doxorubicin, vinNon-Hodgkin lymcristine, prednisone, rituximab (CHOP-R) phoma (intermediate and high grade)
Combination chemotherapy second line: Dexamethasone, cisplatin, cytarabine (DHAP) or Etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) or Ifosfamide, carboplatin, etoposide (ICE) or Mesna, ifosfamide, mitoxantrone, etoposide (MINE); transplantation for high risk or first relapse
Non-Hodgkin lymphoma (low grade)
Combination chemotherapy: Fludarabine, cyclophosphamide, rituximab (FCR) or Fludarabine, rituximab (FR) or Bendamustine, rituximab or Cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab (CHOP-R), or Cyclophosphamide, vincristine, prednisone, rituximab (CVP-R) or Chlorambucil
Combination chemotherapy (transplant candidates): Bortezomib, dexamethasone, thalidomide or Bortezomib, dexamethasone, lenalidomide or Dexamethasone, thalidomide or Dexamethasone, lenalidomide Followed by autologous or miniallogeneic stem cell transplantation Combination chemotherapy (non-transplant candidates): Melphalan, prednisone, bortezomib, or Melphalan, prednisone, lenalidomide, or Melphalan, prednisone, thalidomide, or Melphalan, prednisone
Bortezomib, lenalidomide, thalidomide, dexamethasone, cyclophosphamide, liposomal doxorubicin
Plasmapheresis alone or followed by combination chemotherapy: Bortezomib with or without rituximab or, cyclophosphamide, prednisone or thalidomide with or without rituximab
Cladribine, thalidomide, bortezomib, chlorambucil, bendamustine, autologous bone marrow transplantation, prednisone
Anagrelide, radiophosphorus 32P, interferon-α, busulfan, chlorambucil, cyclophosphamide
Non-small cell lung cancer
Combination chemotherapy: Cisplatin, vinorelbine or Cisplatin, etoposide or Paclitaxel, carboplatin or Cisplatin, gemcitabine (squamous histology) Cisplatin, pemetrexed (nonsquamous histology) All regimens with or without bevacizumab Erlotinib (EGFR mutation positive) Crizotinib (ALK mutation positive)
Docetaxel, vinorelbine, erlotinib, cetuximab
I tositumomab, 90Y ibritumomab tiuxetan, bendamustine, autologous or allogeneic transplantation
Table 39–4. Treatment choices for cancers responsive to systemic agents. (continued) Diagnosis
Current Treatment of Choice
Small cell lung cancer
Combination chemotherapy: Cisplatin, etoposide
Irinotecan, cyclophosphamide, doxorubicin, vincristine, topotecan, gemcitabine, paclitaxel
Combination chemotherapy: Cisplatin, pemetrexed or Carboplatin, pemetrexed or Gemcitabine, cisplatin
Head and neck cancer
Combination chemotherapy: Cisplatin, fluorouracil or Paclitaxel, carboplatin or Docetaxel, cisplatin, fluorouracil or Cisplatin or cetuximab with radiation therapy
Hydroxyurea, bleomycin, methotrexate, cetuximab
Combination chemotherapy: Cisplatin, fluorouracil or Paclitaxel, carboplatin
Paclitaxel, irinotecan, oxaliplatin, capecitabine, docetaxel, epirubicin
Progestins, tamoxifen, aromatase inhibitors or Combination chemotherapy: Cisplatin, doxorubicin, or Paclitaxel or Cisplatin, doxorubicin or Carboplatin, paclitaxel
Fluorouracil, docetaxel, liposomal doxorubicin
Combination chemotherapy: Paclitaxel, carboplatin or Intraperitoneal cisplatin, paclitaxel or Docetaxel, carboplatin or Paclitaxel, cisplatin
Gemcitabine, liposomal doxorubicin, topotecan, cyclophosphamide, etoposide, docetaxel
With radiation: Cisplatin Combination chemotherapy: Cisplatin, paclitaxel or Cisplatin, topotecan or Carboplatin, paclitaxel or Cisplatin, gemcitabine
Docetaxel, ifosfamide, vinorelbine, irinotecan, epirubicin, mitomycin, fluorouracil
Adjuvant endocrine therapy: Premenopausal: Tamoxifen Postmenopausal: Aromatase inhibitors (anastrozole, letrozol, exemestane) Adjuvant chemotherapy (without trastuzumab): Doxorubicin, cyclophosphamide, docetaxel or Doxorubicin, cyclophosphamide, paclitaxel or Docetaxel, cyclophosphamide or Doxorubicin, cyclophosphamide Adjuvant chemotherapy (with trastuzumab): Doxorubicin, cyclophosphamide, paclitaxel, trastuzumab or Docetaxel, carboplatin, trastuzumab
Megestrol, aminoglutethimide, capecitabine, mitoxantrone, cisplatin, etoposide, vinblastine, fluorouracil, ixabepilone, gemcitabine
Choriocarcinoma (trophoblastic neoplasms)
Single agents: Methotrexate or dactinomycin for low risk disease Combination chemotherapy: Etoposide/methotrexate, dactinomycin, cyclophosphamide, vincristine (EMA-CO) for high-risk disease
Vinblastine, cisplatin, mercaptopurine, chlorambucil, doxorubicin
Combination chemotherapy: Bleomycin, etoposide, cisplatin (BEP) or Cisplatin, etoposide (EP) or Etoposide, mesna, ifosfamide, cisplatin (VIP)
Vinblastine, ifosfamide, paclitaxel, gemcitabine, oxaliplatin
Sunitinib or temsirolimus or bevacizumab or sorafenib, or pazopanib or interleukin-2
Interferon-α, vinblastine, capecitabine, fluorouracil
Combination chemotherapy: Gemcitabine, cisplatin or Methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)
Carboplatin, paclitaxel, docetaxel, fluorouracil, pemetrexed, methotrexate
Luteinizing hormone-releasing agonist (leuprolide, goserelin, triptorelin, degarelix) plus an antiandrogen (flutamide, bicalutamide, nilutamide)
Ketoconazole, docetaxel, abiraterone, mitoxantrone, cabazitaxel, sipuileucel-T, estramustine, prednisone
Brain cancer (anaplastic astrocytoma and glioblastoma multiforme)
Bevacizumab, irinotecan, procarbazine, carmustine, lomustine
Table 39–4. Treatment choices for cancers responsive to systemic agents. (continued) Diagnosis
Current Treatment of Choice
Combination chemotherapy: Cyclophosphamide, doxorubicin, cisplatin, etoposide
Vincristine, topetecan, irinotecan, ifosfamide, carboplatin, 13-cis-retinoic acid, 131I-MIBG, autologous or allogeneic transplantation
Radioiodine (131I) or sorafenib or vandetanib (medullary thyroid cancer)
Doxorubicin, etoposide, cisplatin
Combination chemotherapy: Epirubicin, cisplatin, fluorouracil or Docetaxel, cisplatin, fluorouracil or Fluorouracil, leucovorin, oxaliplatin Trastuzumab added for Her2-neu overexpressing adenocarcinomas
Capecitabine, sorafenib, trastuzumab, irinotecan
Combination chemotherapy: Gemcitabine, cisplatin or Gemcitabine, erlotinib or Fluorouracil, leucovorin, irinotecan, oxaliplatin (FOLFIRINOX) Gemcitabine
Combination chemotherapy: Fluorouracil, leucovorin, oxaliplatin (FOLFOX6) or Capecitabine, oxaliplatin (CapeOx) or Fluorouracil, leucovorin, irinotecan (FOLFIRI) each regimen with or without bevacizumab
Cetuximab, irinotecan, panitumumab
Chemotherapy with radiation: Fluorouracil; For advanced disease same regimens used with colon cancer
Cetuximab, irinotecan, panitumumab
Combination chemotherapy with radiation: Fluorouracil, mitomycin
Combination chemotherapy: Streptozocin, fluorouracil or Bevacizumab or sorafenib or sunitinib
Doxorubicin, dacarbazine, octreotide, interferon-α
Interferon or streptozocin
Doxorubicin, fluorouracil, mitomycin
Combination chemotherapy with two of these agents: Doxorubicin, cisplatin, ifosfamide, high-dose methotrexate
Soft tissue sarcomas
Combination chemotherapy: Doxorubicin, dacarbazine (AD) or Doxorubicin, ifosfamide, mesna (AIM) or Mesna, doxorubicin, ifosfamide, dacarbazine (MAID) Imatinib or Sunitinib (Gastrointestinal Stromal Tumors)
Liposomal doxorubicin, methotrexate, gemcitabine, docetaxel, temozolomide
Ipilimumab or vemurafenib or dacarbazine or Temozolomide or high-dose interleukin-2
Paclitaxel, cisplatin, carboplatin, interferon-α, vinblastine
Liposomal doxorubicin or liposomal daunorubicin
Paclitaxel, vinblastine, vincristine, etoposide, doxorubicin
Al-Haddad M et al. Diagnosis and treatment of cystic pancreatic tumors. Clin Gastroenterol Hepatol. 2011 Aug;9(8):635–48. [PMID: 21397725] Butte JM et al. Solid pseudopapillary tumors of the pancreas. Clinical features, surgical outcomes, and long-term survival in 45 consecutive patients from a single center. J Gastrointest Surg. 2011 Feb;15(2):350–7. [PMID: 20824369] Conroy T et al; PRODIGE Intergroup. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011 May 12;364(19):1817–25. [PMID: 21561347] Hidalgo M. Pancreatic cancer. N Engl J Med. 2010 Apr 29;362 (17): 1605–17. [PMID: 20427809] Kang MJ et al. Cyst growth rate predicts malignancy in patients with branch duct intraductal papillary mucinous neoplasms. Clin Gastroenterol Hepatol. 2011 Jan;9(1):87–93. [PMID: 20851216] Vincent A et al. Pancreatic cancer. Lancet. 2011 Aug 13;378 (9791): 607–20. [PMID: 21620466]
ALIMENTARY TRACT CANCERS Kenneth R. McQuaid, MD Robin K. Kelley, MD
E ssent i a l s o f d i a g nos i s
Progressive solid food dysphagia.
Weight loss common.
Endoscopy with biopsy establishes diagnosis.
D. Upper Endoscopy
Esophageal cancer usually develops in persons between 50 and 70 years of age. The overall ratio of men to women is 3:1. There are two histologic types: squamous cell carcinoma and adenocarcinoma. In the United States, squamous cell cancer is much more common in blacks than in whites. Squamous cell cancer has a high incidence in certain regions of China and Southeast Asia. Half of all cases occur in the distal third of the esophagus. Chronic alcohol and tobacco use are strongly associated with an increased risk of squamous cell carcinoma. The risk of squamous cell cancer is also increased in patients with tylosis, achalasia, caustic-induced esophageal stricture, and other head and neck cancers. Adenocarcinoma is more common in whites. It is increasing dramatically in incidence and now is as common as squamous carcinoma. The majority of adenocarcinomas develop as a complication of Barrett metaplasia due to chronic gastroesophageal reflux. Thus, most adenocarcinomas arise in the distal third of the esophagus. Obesity also is strongly associated with adenocarcinoma, even after controlling for gastroesophageal reflux; however, no causal relationship has been convincingly shown.
Endoscopy with biopsy establishes the diagnosis of esophageal carcinoma with a high degree of reliability. In some cases, significant submucosal spread of the tumor may yield nondiagnostic mucosal biopsies. Repeated biopsy may be necessary.
``Clinical Findings A. Symptoms and Signs Most patients with esophageal cancer present with advanced, incurable disease. Over 90% have solid food dysphagia, which progresses over weeks to months. Odynophagia is sometimes present. Significant weight loss is common. Local tumor extension into the tracheo bronchial tree may result in a tracheoesophageal fistula, characterized by coughing on swallowing or pneumonia. Chest or back pain suggests mediastinal extension. Recurrent laryngeal involvement may produce hoarseness. Physical examination is often unrevealing. The presence of supraclavicular or cervical lymphadenopathy or of hepatomegaly implies metastatic disease.
B. Laboratory Findings Laboratory findings are nonspecific. Anemia related to chronic disease or occult blood loss is common. Elevated aminotransferase or alkaline phosphatase concentrations suggest hepatic or bony metastases. Hypoalbuminemia may result from malnutrition.
C. Imaging A barium esophagogram may be the first study obtained to evaluate dysphagia. The appearance of a polypoid, obstructive, or ulcerative lesion is suggestive of carcinoma and requires endoscopic evaluation. However, even lesions believed to be benign by radiography warrant endoscopic evaluation. Chest radiographs may show adenopathy, a widened mediastinum, pulmonary or bony metastases, or signs of tracheoesophageal fistula such as pneumonia.
``Staging After confirmation of the diagnosis of esophageal carcinoma, the stage of the disease should be determined since doing so influences the choice of therapy. Patients should undergo evaluation with CT of the chest and abdomen to look for evidence of pulmonary or hepatic metastases, lymphadenopathy, and local tumor extension. If there is no evidence of distant metastases or extensive local spread on CT, endoscopic ultrasonography with guided FNA biopsy of lymph nodes should be performed, which is superior to CT in demonstrating the level of local mediastinal extension and local lymph node involvement. PET with fluorodeoxyglucose or integrated PET-CT imaging is indicated to look for regional or distant spread in patients thought to have localized disease after other diagnostic studies. Bronchoscopy is sometimes required in esophageal cancers above the carina to exclude tracheobronchial extension. Laparoscopy to exclude occult peritoneal carcinomatosis should be considered in tumors at gastroesophageal junction.
``Differential Diagnosis Esophageal carcinoma must be distinguished from other causes of progressive dysphagia, including peptic stricture, achalasia, and adenocarcinoma of the gastric cardia with esophageal involvement. Benign-appearing peptic strictures should be biopsied at presentation to exclude occult malignancy.
``Treatment The approach to esophageal cancer depends on the tumor stage, patient preference and functional status, and the expertise of the surgeons, oncologists, gastroenterologists, and radiotherapists. There is no consensus about the optimal treatment approach. It is helpful, however, to classify patients into two general categories.
A. Therapy for “Curable” Disease Superficial esophageal cancers confined to the epithelium (high-grade dysplasia or carcinoma in situ [Tis]), lamina propria (T1a), or submucosal (T1b) are increasingly recognized in endoscopic screening and surveillance programs. Esophagectomy achieves high cure rates for superficial tumors but is associated with mortality (2%) and morbidity. If performed by experienced physicians, endoscopic mucosal resection of superficial cancers (especially Tis and T1a) achieves equivalent long-term survival with less morbidity. For a full discussion of management options in superficial adenocarcinoma, see the section on Barrett Esophagus in Chapter 15.
1. Surgery with or without neoadjuvant chemoradiation therapy—There is debate over the optimal surgical approach for invasive (non-superficial) but potentially “curable” esophageal cancers (stage I, II, or IIIA). The procedure with the lowest morbidity is transhiatal esophagectomy with anastomosis of the stomach to the cervical esophagus; however, this approach does not involve sampling or removal of mediastinal lymph nodes. Alternatively, surgeons may perform en bloc transthoracic excision of the esophagus with extended dissection of lymph nodes in the mediastinum and upper abdomen. In a randomized controlled trial comparing these two approaches, en bloc resection was associated with higher perioperative morbidity but a nonsignificant trend toward improved 5-year survival (39% vs 27%). Transhiatal resection may be more appropriate for patients who are elderly or have comorbid illness, and en bloc resection more appropriate in younger or healthier patients with a better prognosis. Patients with stage I tumors have high cure rates with surgery alone and do not require radiation or chemotherapy. If regional lymph node metastases have occurred (stages IIB and III), the rate of cure with surgery alone is reduced to < 20%. Meta-analysis of trials comparing neoadjuvant (preoperative) therapy followed by surgery with surgery alone suggests a 13% absolute improvement in 2-year survival with combined therapy. A 2008 randomized phase III trial of surgery alone versus a combined modality approach with neoadjuvant chemoradiation followed by surgery also demonstrated a significant survival benefit, with 5-year survival of 39% in the combined modality group versus 16% for surgery alone. Therefore, preoperative (neoadjuvant) chemoradiation therapy is recommended for stage IIA, IIB, and III tumors in fit patients. The chemotherapy regimens used with radiation include weekly carboplatin plus paclitaxel or two cycles of cisplatin plus 5-fluorouracil, based on the randomized phase III CROSS trial and CALGB 9781, respectively. Perioperative chemotherapy without radiation is also appropriate for tumors of the gastroesophageal junction based on the randomized, multicenter, phase III MAGIC trial. 2. Chemotherapy plus radiation therapy without surgery—Combined treatment with chemotherapy and radiation therapy is superior to radiation therapy alone and has achieved long-term survival rates in up to 25% of patients. Chemoradiation therapy alone should be considered in patients with localized disease (stage II or IIIA) who are poor surgical candidates due to serious medical illness or poor functional status (Eastern Cooperative Oncology Group score > 2). Chemoradiation alone as definitive, nonsurgical therapy is more likely to achieve long-term diseasefree survival in patients with squamous cell carcinoma than in patients with adenocarcinoma.
B. Therapy for Incurable Disease More than half of patients have either locally extensive tumor spread (T4) that is unresectable or distant metastases (M1) ie, stage IIIB and stage IV tumors. Surgery is not warranted in these patients. Since prolonged survival can be achieved in few patients, the primary goal is to provide
relief from dysphagia and pain, optimize quality of life, and minimize treatment side effects. The optimal palliative approach depends on the presence or absence of metastatic disease, expected survival, patient preference, and local institutional experience. Many patients with advanced disease may prefer concerted efforts at pain relief and care directed at symptom management (see Chapter 5). 1. Radiation therapy, chemotherapy, and combined therapy—Combined radiation therapy and chemotherapy may achieve palliation in two-thirds of patients but is associated with significant side effects. It should be considered for patients with locally advanced tumors without distant metastases (stage IIIB) who have good functional status and no significant medical problems, in whom prolonged survival may be achieved. Improvement in dysphagia occurs within 2–4 weeks in almost 90% of patients. Combination chemotherapy may be considered in patients with metastatic disease who still have good functional status and expected survival of several months. Although there is no consensus on optimal therapy, three drug combinations are commonly used: (1) epirubicin or a taxane (docetaxel or paclitaxel), (2) cisplatin or oxaliplatin, and (3) a fluoropyrimidine (5-FU or capecitabine). For patients with poor functional status, single-agent therapy with a fluoropyrimidine, a taxane, or irinotecan may be used. In patients with metastatic distal esophageal and gastroesophageal junction adenocarcinomas positive for amplification of the HER-2 gene (approximately 15% of cases), addition of the monoclonal antibody trastuzumab to chemotherapy is associated with prolonged survival. Radiation therapy alone may afford short-term relief of pain and dysphagia and may be suitable for patients with poor functional status or underlying medical problems. This can generally be performed in a short course over a few weeks or less, but may be complicated by temporary worsening of dysphagia and odynophagia. For patients with frank obstruction or near obstruction, local anti tumor therapies may be preferred. 2. Local therapy—Patients with advanced esophageal cancer often have a poor functional and nutritional status with an average survival of < 12 weeks from diagnosis. In patients with poor performance status, chemoradiation or radiation may be associated with greater toxicity than potential for long-term benefit. Rapid palliation of dysphagia may be achieved by peroral placement of permanent expandable wire stents, application of endoscopic laser therapy, or photodynamic therapy. Palliative feeding tube placement may be considered for hydration and nutrition in selected cases if the obstruction is not amenable or if it is refractory to stenting, radiation, or other local therapies. Although dysphagia and quality of life are improved significantly, patients can seldom eat normally. Stents are most commonly used because of their relative ease of placement, although the choice of treatment depends on available expertise and equipment. Complications of stents occur in 20–40% and include perforation, migration, and tumor ingrowth.
``Prognosis The overall 5-year survival rate of esophageal carcinoma is < 20%. Apart from distant metastasis (M1b), the two most important predictors of poor survival are adjacent mediastinal spread (T4) and lymph node involvement. Whereas cure may be achieved in patients with regional lymph node involvement (stages IIB and III), involvement of nodes outside the chest (M1a) is indicative of metastatic disease (stage IV) that is incurable. For those patients whose disease progresses despite chemotherapy, meticulous efforts at palliative care are essential (see Chapter 5).
Stahl M et al; ESMO Guidelines Working Group. Esophageal cancer: clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21(Suppl 5):v46–9. [PMID: 20555101] Tepper J et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol. 2008 Mar 1;26(7):1086–92. [PMID: 18309943] Umar SB et al. Esophageal cancer: epidemiology, pathogenesis and prevention. Nat Clin Pract Gastroenterol Hepatol. 2008 Sep;5(9):517–26. [PMID: 18679388] Zingg U et al. Minimally invasive versus open esophagectomy for patients with esophageal cancer. Ann Thorac Surg. 2009 Mar;87(3):911–9. [PMID: 19231418]
``When to Refer • Patients should be referred to gastroenterologist for evaluation and staging (endoscopy with biopsy, endoscopic ultrasonography) and palliative endoscopic antitumor therapy (stent).
• Patients with metastatic disease and obstructive tumors not amenable or refractory to palliative radiation or stenting may require referral to an interventional radiologist, gastroenterologist, or surgeon for feeding tube placement. • Patients with curable and resectable disease (stage IIB or IIIA) and those with locally advanced or metastatic disease should be referred to an oncologist for consideration of neoadjuvant chemoradiotherapy or palliative chemotherapy, respectively.
``When to Admit Patients with high-grade esophageal obstruction with inability to manage oral secretions or maintain hydration should be admitted. Bang Y et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687–97. [PMID: 20728210] Bedenne L et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol. 2007 Apr 1;25(10):1160–8. [PMID: 17401004] Courrech Staal EF et al. Systematic review of the benefits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg. 2010 Oct;97(10):1482–96. [PMID: 20645400] Cunningham D et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1): 36–46. [PMID: 18172173] Krasna MJ. Multimodality therapy for esophageal cancer. Oncology (Williston Park). 2010 Nov 15;24(12):1134–8. [PMID: 21141694] Schuchert MJ et al. Management of esophageal cancer. Curr Probl Surg. 2010 Nov;47(11):845–946. [PMID: 20937424] Sharma P et al. Role of esophageal stents in benign and malignant diseases. Am J Gastroenterol. 2010 Feb;105(2):258–73. [PMID: 20029413]
E ssent i a l s o f d i a g nos i s
Dyspeptic symptoms with weight loss in patients over age 40 years. Iron deficiency anemia: occult blood in stools. Abnormality detected on upper gastrointestinal series or endoscopy.
``General Considerations Gastric adenocarcinoma remains the second most common cause of cancer death worldwide. However, its incidence has declined rapidly over the last 70 years, especially in western countries, which may be attributable to changes in diet (more fruits and vegetables), food refrigeration (allowing more fresh foods and reduced salted, smoked, and preserved foods), reduced toxic environmental exposures, and a decline in Helicobacter pylori. The incidence of gastric cancer remains high (70/100,000) in Japan and many developing regions, including eastern Asia, Eastern Europe, Chile, Colombia, and Central America. In the United States, there are an estimated 21,500 new cases and 10,800 deaths/year. The incidence is higher in Latinos, African Americans, and Asian Americans. There are two main histologic variants of gastric cancer: “intestinal-type” (which resembles intestinal cancers in forming glandular structures) and “diffuse” (which is poorly differentiated, has signet-ring cells, and lacks glandular formation). Although both types are declining in incidence, intestinal-type has had the most dramatic reduction. Intestinal-type is still more common (70–80%), occurs twice as often in men as women, primarily affects older people (mean age 63 years), and is more strongly associated with environmental factors. It is believed to arise through a gradual, multi-step progression from inflammation (most commonly due to H pylori), to atrophic gastritis, to intestinal metaplasia, and finally dysplasia or cancer. Chronic H pylori gastritis is the strong risk factor for gastric carcinoma, increasing the relative risk 3.5- to 20-fold. It is estimated that 60–90% of cases of gastric carcinomas may be attributable to H pylori. Other risk factors for
intestinal-type gastric cancer include pernicious anemia, a history of partial gastric resection more than 15 years previously, smoking, and diets that are high in nitrates or salt and low in vitamin C. Diffuse gastric cancer accounts for 20–30% of gastric cancer. In contrast to intestinal-type cancer, it affects men and women equally, occurs more commonly in young people, is not as strongly related to H pylori infection, has a worse prognosis, and has not declined in incidence. Most diffuse gastric cancers are attributable to acquired or hereditary mutations in the genes regulating the E-cadherin cell adhesion protein. Familial diffuse gastric cancer accounts for 1–3% of gastric cancers. The cancer may arise at a young age, is often multifocal and infiltrating with signet ring cell histology, and confers poor prognosis. Many of these families have a germline mutation of E-cadherin CDH1, which is inherited in an autosomal dominant pattern and carries a > 60% lifetime risk of gastric cancer. Prophylactic gastrectomy should be considered in patients known to carry this mutation. Most gastric cancers arise in the body and antrum. These may occur in a variety of morphologic types: (1) polypoid or fungating intraluminal masses; (2) ulcerating masses; (3) diffusely spreading (linitis plastica), in which the tumor spreads through the submucosa, resulting in a rigid, atonic stomach with thickened folds (prognosis dismal); and (4) superficially spreading or “early” gastric cancer—confined to the mucosa or submucosa (with or without lymph node metastases) and associated with a favorable prognosis. In contrast to the dramatic decline in cancers of the distal stomach, a rise in incidence of tumors of the gastric cardia has been noted. These tumors have demographic and pathologic features that resemble Barrett-associated esophageal adenocarcinomas (see Esophageal Cancer).
``Clinical Findings A. Symptoms and Signs Gastric carcinoma is generally asymptomatic until the disease is quite advanced. Symptoms are nonspecific and are determined in part by the location of the tumor. Dyspepsia, vague epigastric pain, anorexia, early satiety, and weight loss are the presenting symptoms in most patients. Patients may derive initial symptomatic relief from over-the-counter remedies, further delaying diagnosis. Ulcerating lesions can lead to acute gastrointestinal bleeding with hematemesis or melena. Pyloric obstruction results in postprandial vomiting. Lower esophageal obstruction causes progressive dysphagia. Physical examination is rarely helpful. A gastric mass is palpated in < 20% of patients. Signs of metastatic spread include a left supraclavicular lymph node (Virchow node), an umbilical nodule (Sister Mary Joseph nodule), a rigid rectal shelf (Blumer shelf), and ovarian metastases (Krukenberg tumor). Guaiac-positive stools may be detectable.
abnormalities, particularly elevation of alkaline phosphatase, may be present if there is metastatic liver spread. Other tumor markers are of no value.
C. Endoscopy Upper endoscopy should be obtained in all patients over age 55 years with new onset of epigastric symptoms (dyspepsia) and in anyone with dyspepsia that is persistent or fails to respond to a short trial of antisecretory therapy. Endoscopy with biopsies of suspicious lesions is highly sensitive for detecting gastric carcinoma. It can be difficult to obtain adequate biopsy specimens in linitis plastica lesions.
D. Imaging A barium upper gastrointestinal series is an acceptable alternative when endoscopy is not readily available but may not detect small or superficial lesions and cannot reliably distinguish benign from malignant ulcerations. Any abnormalities detected with this procedure require endoscopic confirmation. Once a gastric cancer is diagnosed, preoperative evaluation with CT of chest and abdomen (including pelvis in females) and endoscopic ultrasonography is indicated to delineate the local extent of the primary tumor as well as nodal or distant metastases. PET or combined PET-CT imaging may be more sensitive than CT for detection of distant metastasis. Endoscopic ultrasonography is superior to CT in determining the depth of tumor penetration and is useful for evaluation of early gastric cancers that may be removed by endoscopic mucosal resection.
``Screening Because of its unproven efficacy and cost-effectiveness, screening for H pylori infection and treating it to prevent gastric cancer is not recommended for asymptomatic adults in the general population but may be considered in patients who have immigrated from regions with a high incidence of gastric cancer or who have a family history of gastric cancer. Because of the high incidence of gastric carcinoma in Japan, screening upper endoscopy is performed to detect early gastric carcinoma. Approximately 40% of tumors detected by screening are early, with a 5-year survival rate of almost 90%. Screening programs are not recommended in the United States.
``Staging Staging is defined according to the TNM system, in which T1 tumors invade the lamina propria (T1a) or submucosa (T1b), T2 invade the muscularis propria, T3 penetrate the serosa, and T4 invade adjacent structures. Lymph nodes are graded as N0 if there is no involvement, and N1, N2, or N3 if there are is involvement of 1–6, 7–15, or more than 15 regional nodes. M1 signifies the presence of metastatic disease.
B. Laboratory Findings
Iron deficiency anemia due to chronic blood loss or anemia of chronic disease is common. Liver function test
Ulcerating gastric adenocarcinomas are distinguished from benign gastric ulcers by biopsies. Approximately 3% of
Cancer gastric ulcers initially believed to be benign later prove to be malignant. To exclude malignancy, all gastric ulcers identified at endoscopy should be biopsied. Ulcers that are suspicious for malignancy to the endoscopist or that have atypia or dysplasia on histologic examination warrant repeat endoscopy in 2–3 months to verify healing and exclude malignancy. Nonhealing ulcers should be considered for resection. Infiltrative carcinoma with thickened gastric folds must be distinguished from lymphoma and other hypertrophic gastropathies.
``Treatment A. Curative Surgical Resection Surgical resection is the only therapy with curative potential. After preoperative staging, about two-thirds of patients will be found to have localized disease (ie, stages I–III). In Japan and in specialized centers in the United States, endoscopic mucosal resection is performed in selected patients with small (< 1–2 cm), early (intramucosal or T1aN0) gastric cancers after careful staging with endoscopic ultrasonography. Approximately 25% of patients undergoing surgery will be found to have locally unresectable tumors or peritoneal, hepatic, or distant lymph node metastases that are incurable. The remaining patients with confirmed localized disease should undergo radical surgical resection with curative intent. For adenocarcinoma localized to the distal two-thirds of the stomach, a subtotal distal gastrectomy should be performed. For proximal gastric cancer or diffusely infiltrating disease, total gastrectomy is necessary. Vitamin B12 supplementation is required postgastrectomy. Although lymph node dissection should be performed for curative resections, there has been ongoing debate about whether an extended (perigastric; D1), regional (D2), or distant (porta hepatic and periaortic; D3) lymph node dissection is needed. A 2008 large Japanese trial found no difference in survival between patients treated with D2 and D3 (para-aortic) lymphadenectomy. Current NCCN treatment guidelines recommend regional (D2) node resection with 15 or more lymph nodes sampled. The role of preoperative (neoadjuvant) or postoperative (adjuvant) chemotherapy or radiochemotherapy after curative resection is controversial. Recommended options include either adjuvant chemoradiotherapy (commonly 5-FU and leucovorin) or a perioperative chemotherapy regimen of epirubicin, 5-FU, and cisplatin (ECF) without radiation. Treatment of tumors arising in the gastroesophageal junction may be treated following algorithms for either gastric or esophageal primary tumors; multidisciplinary treatment decision-making involving the surgeon, radiation oncologist, and medical oncologist is imperative.
B. Palliative Modalities Many patients will be found either preoperatively or at the time of surgical exploration to have advanced disease that is not amenable to “curative” surgery due to peritoneal or distant metastases or local invasion of other organs. In some of these cases, palliative resection of the tumor
nonetheless may be indicated to alleviate pain, bleeding, or obstruction. For patients with unresectable disease, gastrojejunostomy may be indicated to prevent obstruction. Alternatively, unresected tumors may be treated with endoscopic laser or stent therapy, radiation therapy, or angiographic embolization to relieve bleeding or obstruction. Chemotherapy may be considered in patients with metastatic disease who still have good functional status and expected survival of several months. Multiple chemotherapy regimens have demonstrated activity in metastatic gastric adenocarcinoma. A combination of epirubicin, cisplatin, and 5-FU or a modification thereof is commonly used in first-line treatment for fit patients. A 2009 randomized, phase III study showed that addition of the biologic agent trastuzumab to standard chemotherapy prolonged survival in the subset (approximately 15%) of patients with advanced gastric adenocarcinomas harboring amplification of the EGFR-2 (HER-2). Trastuzumab is not recommended for combination with anthracyclines such as epirubicin, however, due to risk for cardiotoxicity.
``Prognosis The long-term survival of gastric carcinoma is < 15%. However, 5-year survival in patients who undergo successful curative resection is over 45%. Survival is related to tumor stage, location, and histologic features. Stage I and stage II tumors resected for cure have a > 50% long-term survival. Patients with stage III tumors have a poor prognosis (< 20% long-term survival) and should be considered for enrollment in clinical trials. Tumors of the diffuse type have a worse prognosis than the intestinal type. Tumors of the proximal stomach (fundus and cardia) carry a far worse prognosis than distal lesions. Even with apparently localized disease, proximal tumors have a 5-year survival of < 15%. For those whose disease progresses despite therapy, meticulous efforts at palliative care are essential (see Chapter 5).
``When to Refer • Patients with dysphagia, weight loss, protracted vomiting, iron-deficiency anemia, or new-onset of dyspepsia (especially if age 55 years or older or associated with other alarm symptoms) in whom gastric cancer is suspected should be referred to a gastroenterologist for endoscopic screening. • Patients should be referred to a surgeon for attempt at curative resection in stage I, II, or III cancer as well as to an oncologist to evaluate for adjuvant or neoadjuvant chemotherapy (or both) or chemoradiotherapy. • Patients who have undergone gastrectomy require consultation with a nutritionist due to propensity for malnutrition and complications, such as dumping syndrome, postoperatively. • Patients with unresectable or metastatic disease should be referred to an oncologist for consideration of adjuvant chemotherapy or chemoradiotherapy after curative resection or palliative therapy.
``When to Admit
Patients with protracted vomiting, inability to maintain oral intake, or acute bleeding.
Gastric lymphomas may be primary (arising from the gastric mucosa) or may represent a site of secondary involvement in patients with nodal lymphomas. Distinguishing advanced primary gastric lymphoma with adjacent nodal spread from advanced nodal lymphoma with secondary gastric spread can be problematic. Because the prognosis and treatment of primary and secondary gastric lymphomas are entirely different, the distinction is important. Primary lymphoma is the second most common gastric malignancy, accounting for 3% of cancers. More than 95% of these are non-Hodgkin B cell lymphomas. Most primary gastric lymphomas are believed to arise from mucosa-associated lymphoid tissue (MALT). Primary gastric lymphomas comprise two main types: 60% are diffuse large B-cell lymphomas (previously called “high-grade” MALT lymphomas) and 40% are marginal zone B-cell lymphomas of the MALT-type (previously call “low-grade” MALT lymphoma). Infection with H pylori is an important risk factor for the development of primary gastric lymphoma. Chronic infection with H pylori causes an intense lymphocytic inflammatory response that may lead to the development of lymphoid follicles. Over 90% of low-grade primary gastric MALT-type lymphomas are associated with H pylori infection. It is hypothesized that chronic antigenic stimulation may result in a monoclonal lymphoproliferation that may culminate in low-grade or high-grade lymphoma.
Ajani JA et al; NCCN Gastric Cancer Panel. Gastric cancer. J Natl Compr Canc Netw. 2010 Apr;8(4):378–409. [PMID: 20410333] Bang Y et al; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010 Aug 28;376(9742):687–97. [PMID: 20728210] Cunningham D et al; MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11–20. [PMID: 16822992] Cunningham D et al; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom. Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med. 2008 Jan 3;358(1): 36–46. [PMID: 18172173] de Bree E et al. The extent of lymph node dissection for gastric cancer: a critical appraisal. J Surg Oncol. 2010 Nov 1; 102(6):552–62. [PMID: 20976727] De Vita F et al. Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new therapeutic target. Cancer Treat Rev. 2010 Nov;36(Suppl 3):S11–5. [PMID: 21129604] Ohtani H et al. A meta-analysis of randomized controlled trials that compared laparoscopy-assisted and open distal gastrectomy for early gastric cancer. J Gastrointest Surg. 2010 Jun;14(6):958–64. [PMID: 20354807] Okines A et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21(Suppl 5):v50–4. [PMID 20555102] Polk DB et al. Helicobacter pylori: gastric cancer and beyond. Nat Rev Cancer. 2010 Jun;10(6):403–14. [PMID: 20495574] Rogers WM et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol. 2008 Jun;32(6): 799–809. [PMID: 18391748] Sasako M et al; Japan Clinical Oncology Group. D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med. 2008 Jul 31;359(5):453–62. [PMID: 18669424] Schrader K et al. Hereditary diffuse gastric cancer. Cancer Treat Res. 2010;155:33–63. [PMID: 20517687] Shi Y et al. The role of surgery in the treatment of gastric cancer. J Surg Oncol. 2010 Jun 15;101(8):687–92. [PMID: 20512944] Wagner AD et al. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2010 Mar 17;(3):CD004064. [PMID: 20238327]
Symptoms of dyspepsia, weight loss, or anemia. Variable abnormalities on upper gastrointestinal series or endoscopy including thickened folds, ulcer, mass or infiltrating lesions; diagnosis established by endoscopic biopsy. Abdominal CT and endoscopic ultrasonography required for staging.
E ssent i a l s o f d i a g nos i s
``Clinical Findings The clinical presentation and endoscopic appearance of gastric lymphoma are similar to those of adenocarcinoma. Most patients have abdominal pain, weight loss, or bleeding. Patients with diffuse large B-cell lymphoma are more likely to have systemic symptoms and advanced tumor stage. At endoscopy, lymphoma may appear as an ulcer, mass, or diffusely infiltrating lesion. The diagnosis is established with endoscopic biopsy. All patients should undergo staging with abdominal and chest CT. Endoscopic ultrasonography is the most sensitive test for determining the level of invasion and presence of perigastric lymphadenopathy.
``Treatment Nodal lymphomas with secondary gastrointestinal involvement usually present at an advanced stage with widely disseminated disease and are seldom curable. Their treatment is addressed in Chapter 13. Treatment of primary gastric lymphomas depends on the tumor histology, grade, and stage. Marginal B-cell lymphomas of the MALT type that are low-grade and localized to the stomach wall (stage IE) or perigastric lymph nodes (stage IIE1) have an excellent prognosis. Endoscopic ultrasonography should be performed to accurately determine tumor stage. Patients with primary gastric MALT-lymphoma should be tested for H pylori infection and treated if positive. Complete lymphoma regression after successful H pylori eradication occurs in 75% of cases of stage IE and 55% with stage II1 low-grade lymphoma. Remission may take as long as a year, and relapse occurs in 2% of
Cancer cases per year. Endoscopic surveillance after H pylori eradication is recommended every 6 months for 2 years to look for recurrence. Remission rates (22%) are much lower in patients whose tumors have an API2-MALT1 gene translocation. Patients with localized marginal zone MALT-type lymphomas who either are not infected with H pylori or do not respond to eradication therapy may be treated with radiation therapy or rituximab, if not a candidate for radiation. Data from a 2010 study, however, suggest that many patients with minimal disease after successful H pylori eradication may be observed closely without further therapy. The long-term survival of lowgrade MALT lymphoma for stage I is over 90% and for stage II is 35–65%. Patients with diffuse large cell (highgrade) lymphomas or disseminated MALT-type lymphomas should be treated with combination chemotherapy (eg, CHOP with rituximab). Because of a low risk of perforation with either radiation therapy or chemotherapy, surgical resection is no longer recommended. Sagaert X et al. Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development. Nat Rev Gastroenterol Hepatol. 2010 Jun;7(6):336–46. [PMID: 20440281] Zullo A et al. Effects of Helicobacter pylori eradication on early stage gastric mucosa-associated lymphoid tissue lymphoma. Clin Gastroenterol Hepatol. 2010 Feb;8(2):105–10. [PMID: 19631287]
GASTRIC CARCINOID TUMORS Gastric carcinoids are rare neuroendocrine tumors that make up < 1% of gastric neoplasms. They may occur sporadically or secondary to chronic hypergastrinemia that results in hyperplasia and transformation of enterochromaffin cells in the gastric fundus. Sporadic carcinoids account for 20% of gastric carcinoids. Most are solitary, over 2 cm in size, and have a strong propensity for metastatic spread. Most sporadic carcinoids already have carcinoid syndrome and hepatic or pulmonary metastatic involvement at initial presentation. Localized sporadic carcinoids should be treated with radical gastrectomy. The majority of carcinoids caused by hypergastrinemia occur in association with either pernicious anemia (75%) or Zollinger-Ellison syndrome (5%). Carcinoids associated with Zollinger-Ellison syndrome occur almost exclusively in patients with MEN 1, in which loss of 11q13 has been reported. Carcinoids caused by hypergastrinemia tend to be multicentric, < 1 cm in size, and have a low potential for metastatic spread or development of carcinoid syndrome. Small lesions may be successfully treated with endoscopic resection followed by periodic endoscopic surveillance. Antrectomy reduces serum gastrin levels and may lead to regression of small tumors. Patients with large or multiple carcinoids should undergo surgical tumor resection (see Carcinoid Tumors section). Landry CS et al. A proposed staging system for gastric carcinoid tumors based on an analysis of 1,543 patients. Ann Surg Oncol. 2009 Jan;16(1):51–60. [PMID: 18953609]
GASTROINTESTINAL MESENCHYMAL TUMORS Gastrointestinal mesenchymal tumors occur throughout the gastrointestinal tract, but approximately two-thirds occur in the stomach. These tumors (which include stromal tumors, leiomyomas, and schwannomas) derive from mesenchymal stem cells and have an epithelioid or spindle cell histologic pattern, resembling smooth muscle. The most common stromal tumors are gastrointestinal stromal tumors (“GISTs”), which appear to originate from interstitial cells of Cajal. GISTs occur throughout the gastrointestinal tract but most commonly in the stomach (50%) and small intestine (30%). About 85–90% of GISTs have mutations in KIT, a receptor tyrosine kinase that binds stem cell factor, or a homologous tyrosine kinase, platelet-derived growth factor alpha that lead to constitutive activation. Approximately 90% of stromal tumors stain positively for CD117 (part of the KIT protein). Other mesenchymal tumors such as leiomyomas, which derive from smooth muscle cells, stain negative for CD117. Mesenchymal tumors may be discovered incidentally on imaging studies or endoscopy or may cause symptoms, mainly obstruction by large tumors or acute or chronic bleeding due to central ulceration within the tumor. At endoscopy, they appear as a submucosal mass that may have central umbilication or ulceration. Endoscopic ultrasonography (possibly with guided FNA biopsy) is the optimal study for diagnosing mesenchymal tumors and distinguishing them from other submucosal lesions. While almost all GISTs have malignant potential, the risk of developing metastasis is related to the tumor size (> 2 cm), location (small bowel is highest risk), and mitotic index (> 5 mitoses per high-powered field); however, mitotic index can only be assessed after resection. It is difficult to distinguish with certainty benign from malignant (sarcoma) tumors before resection by endoscopic ultrasonographic appearance or FNA. In general, lesions that are smaller than 2 cm, have a smooth border, and have a homogeneous echo pattern on endoscopic ultrasonogram are more likely benign. Surgery is recommended for all patients with tumors that are symptomatic, ≥ 2 cm, are increasing in size, or have an endoscopic ultrasonographic appearance suspicious for malignancy. PET-CT scan should be obtained prior to surgery to look for metastatic disease. The management of asymptomatic benign-appearing lesions ≤ 2 cm in size is problematic. Because of a low risk of malignancy, surgical resection should be considered in younger, otherwise healthy patients; however, other patients may be followed up with serial endoscopic ultrasonographic examinations or, in selected cases, endoscopic resections. (GIST tumors with high-risk features have a 50% 5-year survival rate after complete surgical resection.) Adjuvant therapy with the tyrosine kinase inhibitor imatinib delays recurrence and prolongs survival in patients with high-risk tumors. Three years of adjuvant imatinib is superior to 1 year, although optimal duration remains unknown. Metastatic tumors are aggressive and carry a poor prognosis. Imatinib induces disease control in up to 85% of patients with metastatic disease with a progression free-survival of 20–24 months and median overall survival of almost 5 years. Patients whose
tumors harbor exon 11 mutations in the KIT gene (approximately 70%) are more likely to respond to imatinib than those with exon 9 mutations in the KIT gene (approximately 12%), platelet-derived growth factor receptor alpha (PDGFRA) mutations (5–8%), or wild-type tumors (10–15%). Resistant tumors may respond to high-dose imatinib or to sunitinib, another tyrosine kinase inhibitor that is approved as second-line therapy for metastatic GIST. Clinical trials of potent new KIT inhibitors and other multikinase inhibitors are underway. Chen P et al. Efficacy evaluation of imatinib treatment in patients with gastrointestinal stromal tumors: a metaanalysis. World J Gastroenterol. 2010 Sep 7;16(33):4227–32. [PMID: 20806443] Dematteo RP et al; American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumor: a randomised, doubleblind, placebo-controlled trial. Lancet. 2009 March 28;373(9669):1097–104. [PMID: 19303137] Dematteo RP et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer. 2008 Feb 1;112(3):608–15. [PMID: 18076015] Demetri GD et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol. 2009 Jul 1;27(19):3141–7. [PMID: 19451435] Demetri GD et al. NCCN Task Force Report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw. 2010 Apr;8(Suppl 2):S1–41. [PMID: 20457867] Joensuu H et al. Twelve vs. 36 months of adjuvant imatinib as treatment of operable GIST with high risk of recurrence: final results of a randomized trial (SSGXVIII/AIO). Presented at American Society of Clinical Oncology Annual Meeting, 2011. Chicago, IL. Reichardt P. Optimal use of targeted agents for advanced gastrointestinal stromal tumors. Oncology. 2010;78(2):130–40. [PMID: 20389135]
MALIGNANCIES OF THE SMALL INTESTINE 1. Adenocarcinoma These are aggressive tumors that occur most commonly in the duodenum or proximal jejunum. The ampulla of Vater is the most common site of small bowel carcinoma, and the incidence of ampullary carcinoma is increased more than 200-fold in patients with familial adenomatous polyposis. Ampullary carcinoma may present with jaundice due to bile duct obstruction or bleeding. Surgical resection of early lesions is curative in up to 40% of patients. Periodic endoscopic surveillance to detect early ampullary neoplasms therefore is recommended in patients with this disorder. Nonampullary adenocarcinoma of the small intestine accounts for < 3% of all gastrointestinal cancers but onethird of small bowel cancers. Peak incidence is in the sixth decade. Most cases present with symptoms of obstruction, acute or chronic bleeding, or weight loss. The majority of small bowel cancers have already metastasized at the time of diagnosis. Resection is recommended for control of symptoms. The role of adjuvant therapy is unclear but is generally administered using chemotherapy agents active
in colorectal cancer. The prognosis is poor with a 5-year overall survival of 20–30%. Patients with Crohn disease have an increased risk of small intestine adenocarcinoma, most commonly in the ileum, which may be difficult to distinguish from disease-related fibrous strictures. Small bowel adenocarcinoma in young patients or those with a family history of gastrointestinal adenocarcinomas should prompt screening for the Lynch syndrome.
2. Lymphoma Gastrointestinal lymphomas may arise in the gastrointestinal tract or involve it secondarily with disseminated disease. In Western countries, primary gastrointestinal lymphomas account for 5% of lymphomas and 20% of small bowel malignancies. They occur most commonly in the distal small intestine. The majority are non-Hodgkin high-grade marginal zone B cell lymphomas. There is an increased incidence of small intestinal lymphomas in patients with AIDS, immunosuppressive therapy, and Crohn disease. T cell lymphomas may arise in patients with celiac sprue. In the Middle East, lymphomas may arise in the setting of immunoproliferative small intestinal disease. In this condition, there is diffuse lymphoplasmacytic infiltration with IgA-secreting B lymphocytes of the mucosa and submucosa that results in weight loss, diarrhea, and malabsorption, which may lead to lymphomatous transformation. A characteristic feature of the disease is the presence of α heavy chains in the serum in 70% produced by clones of IgA plasma cells. Other types of intestinal lymphomas include mantle cell and Burkitt. Presenting symptoms or signs of primary lymphoma include abdominal pain, weight loss, nausea and vomiting, distention, anemia, and occult blood in the stool. Fevers are unusual. Protein-losing enteropathy may result in hypoalbuminemia, but other signs of malabsorption are unusual. Barium radiography or CT enterography helps localize the site of the lesion. The diagnosis requires endoscopic, percutaneous, or laparoscopic biopsy. Imaging and bone marrow biopsy are required to determine stage. Treatment depends on the tumor histologic grade and stage of disease. Resection of primary intestinal lymphoma, if feasible, is usually recommended. Even in cases of stage III or stage IV disease, surgical debulking may improve survival. In patients with limited disease (stage IE) in whom resection is performed, the role of adjuvant chemotherapy is unclear. Most patients with more extensive disease are treated with combination chemotherapy (eg, CHOP with rituximab) with or without radiation therapy.
3. Carcinoid Tumors
Majority are asymptomatic and discovered incidentally at endoscopy or surgery. Carcinoid syndrome occurs in < 10%; hepatic metastases are generally present. Risk of metastasis related to tumor size and location.
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``General Considerations Gastrointestinal carcinoids are slow growing neuroendocrine tumors that may arise anywhere in the gastrointestinal tract but most commonly occur in the small intestine (30%), rectum (12%), colon (8%), appendix (8%), and stomach (10–30%; see above). Carcinoids may contain a variety of hormones, including serotonin, somatostatin, gastrin, and substance P that may or may not be secreted, and usually display immunoreactivity to chromogranin A. Although many carcinoids behave in an indolent fashion, the overall 5-year survival rate for patients with carcinoids is 50%, suggesting that most are malignant. The risk of metastatic spread is closely related to tumor size and tumor location. Many small carcinoids are detected incidentally at endoscopy or autopsy. It is not possible by histologic examination to distinguish benign from malignant disease. The best indicator of prognosis is evidence of invasive growth and the presence of regional or distant metastasis. Carcinoids account for one-third of small intestinal tumors. Small intestinal carcinoids most commonly arise in the ileum. Up to one-third are multicentric. Although 60% are < 2 cm in size, even these small carcinoids may metastasize. Almost all small intestinal carcinoids over 2 cm are associated with metastasis. Appendiceal carcinoids are identified in 0.3% of appendectomies, usually as an incidental finding. Almost 80% of these tumors are < 1 cm in size, and 90% are < 2 cm. Rectal carcinoids are usually detected incidentally as submucosal nodules during proctoscopic examination. Rectal carcinoids < 1 cm and localized appendiceal carcinoids < 2 cm virtually never metastasize and are treated effectively with local excision or simple appendectomy. Tumors larger than 2 cm are associated with the development of metastasis in over 20% of appendiceal carcinoids and 10% of rectal carcinoids. Hence, in younger patients who are good candidates for surgery, a more extensive cancer resection operation is warranted.
``Clinical Findings A. Symptoms and Signs Most smaller lesions (< 1–2 cm) are asymptomatic and difficult to detect by endoscopy or imaging studies. Through local extension or metastasis to mesenteric lymph nodes, carcinoids engender a fibroblastic reaction with contraction and kinking of the bowel or encasement of mesenteric vessels. Small intestinal carcinoids may present with abdominal pain, bowel obstruction, bleeding, or bowel infarction. Appendiceal and rectal carcinoids usually are small and asymptomatic but large lesions can cause bleeding, obstruction, or altered bowel habits. Carcinoid syndrome occurs in < 10% of patients. More than 90% of patients with carcinoid syndrome have hepatic metastases, usually from carcinoids of small bowel origin. About 10% of patients with carcinoid syndrome have primary bronchial or ovarian tumors without hepatic metastases. Carcinoid syndrome is caused by tumor secretion of hormonal mediators. The manifestations include facial flushing, edema of the head and neck (especially
with bronchial carcinoid), abdominal cramps and diarrhea, bronchospasm, cardiac lesions (pulmonary or tricuspid stenosis or regurgitation in 10–30%), and telangiectases.
B. Laboratory Findings Serum chromogranin A (CgA) is elevated in the majority of neuroendocrine tumors, although its sensitivity for small, localized carcinoid tumors is unknown. CgA is elevated in almost 90% of patients with advanced small bowel carcinoid. Urinary 5-hydroxyindoleacetic acid (5-HIAA) and platelet serotonin levels are also elevated in patients with metastatic carcinoid; however, these tests are less sensitive than CgA. There is increased urinary 5-HIAA in carcinoid syndrome; symptomatic patients usually excrete more than 25 mg of 5-HIAA per day in the urine. Ideally, all drugs should be withheld for several days prior to a 24-hour urine collection.
C. Imaging Abdominal CT may demonstrate a mesenteric mass with tethering of the bowel, lymphadenopathy, and hepatic metastasis. Abdominal CT or enterography may reveal kinking of the bowel, but because the lesion is extra luminal, the diagnosis may be overlooked for several years. Somatostatin receptor scintigraphy, which is positive in up to 90% of patients with metastatic carcinoid, is routinely used in staging. Most patients with carcinoid syndrome have liver metastasis on abdominal imaging.
``Treatment Small intestinal carcinoids are extremely indolent tumors with slow spread. Patients with disease confined to the small intestine should be treated with surgical excision, for which the cure rate exceeds 85%. In patients with resectable disease who have lymph node involvement, the 5-year disease-free survival is 80%; however, by 25 years, < 25% remain disease free. Even patients with hepatic metastases may have an indolent course with a median survival of 3 years. In patients with advanced disease, therapy historically has been deferred until the patient is symptomatic, although a 2009 phase III, randomized, placebo-controlled trial demonstrated that early initiation of somatostatin analog therapy delayed time to progression of hepatic metastases. Surgery should be directed toward palliation of obstructive symptoms. In patients with carcinoid syndrome, resection of hepatic metastases may provide dramatic improvement. The somatostatin analog octreotide, 100–500 mcg subcutaneously three times daily or administered as a longacting intramuscular depot formulation, inhibits hormone secretion from the carcinoid tumor. This results in dramatic relief of symptoms of carcinoid syndrome, including diarrhea or flushing, in 90% of patients for a median period of 1 year. Thereafter, many patients stop responding to octreotide. Hepatic artery occlusion, liver-directed debulking procedures, and chemotherapy may provide symptomatic improvement in some patients with hepatic metastases.
4. Small Intestine Sarcoma
Most small intestine sarcomas arise from stromal tumors (GISTs) that stain positive for CD117; a minority arise from smooth muscle tumors (leiomyosarcomas) (see Gastrointestinal Mesenchymal Tumors above). Kaposi sarcoma was at one time a common complication in AIDS, but the incidence is declining with highly active antiretroviral therapy (HAART). It is strongly associated with infection with human herpesvirus 8. Lesions may be present anywhere in the intestinal tract. Visceral involvement usually is associated with cutaneous disease. Most lesions are clinically silent; however, large lesions may be symptomatic. Interferon-α induces regression in up to one-third of patients who have a CD4 cell count of > 200/ mcL. Widespread involvement may be best treated by systemic chemotherapy using combinations of vincristine, bleomycin, or doxorubicin, to which the tumor is very responsive.
Colorectal cancer is the second leading cause of death due to malignancy in the United States. Colorectal cancer will develop in approximately 6% of Americans and 40% of those will die of the disease. In 2010, there were an estimated 142,570 new cases and 51,370 deaths from colorectal cancer in the United States. Colorectal cancers are almost all adenocarcinomas, which tend to form bulky exophytic masses or annular constricting lesions. Slightly < 50% of cancers are located distal to the splenic flexure (within the descending colon or rectosigmoid region). The current belief is that the majority of colorectal cancers arise from malignant transformation of an adenomatous polyp (tubular, tubulovillous, or villous adenoma) or serrated polyp (hyperplastic polyp, traditional serrated adenoma, or sessile serrated adenoma). Polyps that are “advanced” (ie, polyps at least 1 cm in size, adenomas with villous features, or adenomas with high-grade dysplasia) are associated with a greater risk of cancer. Approximately 85% of sporadic colorectal cancers arise from adenomatous polyps and have loss of function of one or more tumor suppressor genes (eg, p53, APC, or DCC) due to a combination of spontaneous mutation of one allele combined with chromosomal instability and aneuploidy (abnormal DNA content) that leads to deletion and loss of heterozygosity of the other allele (eg, 5q, 17q, or 18p deletion). Activation of oncogenes such as K-ras and B-raf is present in a subset of colorectal cancers with prognostic and therapeutic implications discussed further below. Approximately 10–20% of colorectal cancers arise from serrated polyps, most of which have hypermethylation of CpG-rich promoter regions that leads to inactivation of the DNA mismatch repair gene MLH1, resulting in microsatellite instability, and activation of mutations of the BRAF gene. Serrated colon cancers have distinct clinical and pathologic characteristics, including diploid DNA content, predominance in the proximal colon, poor differentiation, and more favorable prognosis. Up to 5% of colorectal cancers are caused by inherited germline mutations resulting in polyposis syndromes (eg, familial adenomatous polyposis) or hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome). These conditions are discussed further in Chapter 15.
Bilimoria KY et al. Small bowel cancer in the United States: changes in epidemiology, treatment, and survival over the last 20 years. Ann Surg. 2009 Jan;249(1):63–71. [PMID: 19106677] Chambers AJ et al. The palliative benefit of aggressive surgical intervention for both hepatic and mesenteric metastases from neuroendocrine tumors. Surgery. 2008 Oct;144(4):645–51. [PMID: 18847650] Ellis L et al. Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971. Am J Gastroenterol. 2010 Dec;105(12):2563–9. [PMID: 20823835] Massironi S et al. Plasma chromogranin A response to octreotide test: prognostic value for clinical outcome in endocrine digestive tumors. Am J Gastroenterol. 2010 Sep;105(9):2072–8. [PMID: 20372113] Pasieka JL. Carcinoid tumors. Surg Clin North Am. 2009 Oct; 89(5):1123–37. [PMID: 19836488] Rinke A et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009 Oct 1;27(28):4656–63. [PMID: 19704057] Yamagami H et al. Usefulness of double-balloon endoscopy in the diagnosis of malignant small-bowel tumors. Clin Gastroenterol Hepatol. 2008 Nov;6(11):1202–5. [PMID: 18799359]
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``Risk Factors A number of factors increase the risk of developing colorectal cancer. Recognition of these has impact on screening strategies. However, 75% of all cases occur in people with no known predisposing factors.
The incidence of colorectal cancer rises sharply after age 45 years, and 90% of cases occur in persons over the age of 50 years.
`` `` ``
Personal or family history of adenomatous polyps or colorectal cancer are important risk factors. Symptoms or signs depend on tumor location. Proximal colon: fecal occult blood, anemia. Distal colon: change in bowel habits, hematochezia. Diagnosis established with colonoscopy.
B. Family History of Neoplasia A family history of colorectal cancer is present in 20% of patients with colon cancer. Hereditary factors are believed
Cancer to contribute to 20–30% of colorectal cancers; however, the genes responsible for most of these cases have not yet been identified. (See Chapter 15 for discussion of inherited polyposis syndromes.) Approximately 6% of the Ashkenazic Jewish population has a missense mutation in the APC gene (APC I1307K) that confers a modestly increased lifetime risk of developing colorectal cancer (OR 1.4–1.9) but phenotypically resembles sporadic colorectal cancer rather than familial adenomatous polyposis. Genetic screening is available, and patients harboring the mutation merit intensive screening. A family history of colorectal cancer or adenomatous polyps is one of the most important risk factors for colorectal cancer. The risk of colon cancer is proportionate to the number and age of affected first-degree family members with colon neoplasia. People with one first-degree family member with colorectal cancer have an increased risk approximately two times that of the general-population; however, the risk is almost four times if the family member’s cancer was diagnosed at < 45 years of age. Patients with two first-degree relatives have a fourfold, or 25–30% lifetime, risk of developing colon cancer. Firstdegree relatives of patients with adenomatous polyps also have a twofold increased risk for colorectal neoplasia, especially if the polyp was large (≥ 10 mm) or detected before age 60 years.
C. Inflammatory Bowel Disease The risk of adenocarcinoma of the colon begins to rise 7–10 years after disease onset in patients with ulcerative colitis and Crohn colitis. The cumulative risk approaches 5–10% after 20 years and 20% after 30 years. Chronic treatment with 5-ASA agents and folate is associated with a lower risk of cancer in patients with ulcerative colitis.
D. Dietary Factors and Chemoprevention In epidemiologic studies, diets rich in fats and red meat are associated with an increased risk of colorectal adenomas and cancer, whereas diets high in fruits, vegetables, and fiber are associated with a decreased risk. However, prospective, randomized controlled trials failed to demonstrate a risk reduction in the recurrence of adenomatous polyps after treatment with a diet low in fat and high in fiber, fruits, and vegetables, or with fiber supplementation. Calcium carbonate (3 g/d) has been shown in large cohort studies as well as small prospective trials to yield a modest reduction in the relative risk of developing colorectal neoplasia; however, a prospective study of 36,000 women did not show a protective benefit of calcium (500 mg) and vitamin D (200 international units twice daily) in preventing colon cancer. Similarly, the risk of colon cancer is not decreased in persons taking folic acid supplements. The antioxidant vitamins A, C, E, and beta carotene also have not been shown to be of benefit in prospective controlled studies. A US Preventive Services Task Force meta-analysis of cohort and case-control studies suggest that prolonged (> 6 years) regular use of aspirin (at least 325 mg twice weekly) or NSAIDs is associated with a 22–33% relative risk reduction in the incidence of colorectal cancer. Two
prospective, blinded clinical trials have shown that daily low-dose aspirin (80–325 mg) reduces the number of recurrent adenomas at 1–3 years in patients with a history of colorectal adenomas or cancer; however, two large randomized controlled trials in the United States did not demonstrate a reduction in colorectal cancer incidence in patients taking low-dose aspirin over a 5–10 years. Because long-term aspirin use is associated with a low incidence of serious complications (gastrointestinal hemorrhage, stroke), the US Preventive Services Task Force concluded that it should not be prescribed as a chemopreventive agent in people without polyps or with small adenomas unless there are other medical indications. Long-term administration of low-dose aspirin may be considered in patients with a personal or family history of colorectal cancer or advanced adenomas; however, they do not obviate the need for colonoscopy screening and surveillance.
E. Other Factors The incidence of colon adenocarcinoma is higher in blacks than in whites. It is unclear whether this is due to genetic or socioeconomic factors (eg, diet or reduced access to screening). Diabetes, metabolic syndrome, obesity, and cigarette smoking are associated with a modest increase in cancer risk.
``Clinical Findings A. Symptoms and Signs Adenocarcinomas grow slowly and may be present for several years before symptoms appear. However, some asymptomatic tumors may be detected by the presence of fecal occult blood (see Colorectal Cancer Screening, below). Symptoms depend on the location of the carcinoma. Chronic blood loss from right-sided colonic cancers may cause iron deficiency anemia, manifested by fatigue and weakness. Obstruction, however, is uncommon because of the large diameter of the right colon and the liquid consistency of the fecal material. Lesions of the left colon often involve the bowel circumferentially. Because the left colon has a smaller diameter and the fecal matter is solid, obstructive symptoms may develop with colicky abdominal pain and a change in bowel habits. Constipation may alternate with periods of increased frequency and loose stools. The stool may be streaked with blood, though marked bleeding is unusual. With rectal cancers, patients note tenesmus, urgency, and recurrent hematochezia. Weight loss is uncommon. Physical examination is usually normal except in advanced disease. A mass may be palpable in the abdomen. The liver should be examined for hepatomegaly, suggesting metastatic spread. For cancers of the distal rectum, digital examination is necessary to determine whether there is extension into the anal sphincter or fixation, suggesting extension to the pelvic floor.
B. Laboratory Findings A complete blood count is obtained to look for evidence of anemia. Elevated liver function tests, particularly the
``Staging The TNM system is the commonly used classification to stage colorectal cancer. Staging is important not only because it correlates with the patient’s long-term survival but also because it is used to determine which patients should receive adjuvant therapy.
s Figure 39–1. Cecal adenocarcinoma on colonoscopy. (Courtesy of Marvin Derezin, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)
alkaline phosphatase, are suspicious for metastatic disease. Carcinoembryonic antigen (CEA) should be measured in all patients with proved colorectal cancer. A preoperative CEA level > 5 ng/mL is a poor prognostic indicator. After complete surgical resection, CEA levels should normalize; persistently elevated levels suggest the presence of persistent disease and warrant further evaluation.
C. Colonoscopy Colonoscopy is the diagnostic procedure of choice in patients with a clinical history suggestive of colon cancer or in patients with an abnormality suspicious for cancer detected on radiographic imaging. Colonoscopy permits biopsy for pathologic confirmation of malignancy (Figure 39–1). In patients in whom the colonoscope is unable to reach the cecum (< 5% of cases) or when a nearly obstructing tumor precludes passage of the colonoscope, barium enema or CT colonography examination should be performed.
D. Imaging Chest, abdominal, and pelvic CT scans are required for preoperative staging. CT scans may demonstrate distal metastases but are less accurate in the determination of the level of local tumor extension (T stage) or lymphatic spread (N stage). Intraoperative assessment of the liver by direct palpation and ultrasonography is more accurate than CT scanning for the detection of hepatic metastases. For rectal cancer, pelvic MRI or endorectal ultrasonography identifies the depth of penetration of the cancer through the rectal wall (T stage) and perirectal lymph nodes, informing decisions about preoperative (neoadjuvant) chemoradiotherapy and operative management. PET is not routinely used for staging or surveillance in colorectal cancers.
The nonspecific symptoms of colon cancer may be confused with those of irritable bowel syndrome, diverticular disease, ischemic colitis, inflammatory bowel disease, infectious colitis, and hemorrhoids. Neoplasm must be excluded in any patient over age 40 years who reports a change in bowel habits or hematochezia or who has an unexplained iron deficiency anemia or occult blood in stool samples.
``Treatment A. Surgery Resection of the primary colonic or rectal cancer is the treatment of choice for almost all patients who have resectable lesions and can tolerate general anesthesia. For colon cancer, multiple studies demonstrate that minimally invasive, laparoscopically assisted colectomy results in similar outcomes and rates of recurrence to open colectomy. Regional dissection of at least 12 lymph nodes should be performed to determine staging, which guides decisions about adjuvant therapy. For rectal carcinoma, preoperative (neoadjuvant) chemoradiation with 5-FU is recommended in all nodepositive tumors, and in T3 and greater tumors, due to increased risk of local recurrence. Neoadjuvant chemoradiation is discussed further below. After neoadjuvant therapy, the operative approach depends on the level of the tumor above the anal verge, the size and depth of penetration, and the patient’s overall condition. Clinical staging by endorectal ultrasound or MRI with endorectal coil is important in guiding the clinical approach. In carefully selected patients with small, mobile (< 4 cm), welldifferentiated T1 or T2 rectal tumors that are < 8 cm from the anal verge and that appear on endosonography to be localized to the rectal wall, transanal excision may be performed. This approach avoids laparotomy and spares the rectum and anal sphincter, preserving normal bowel continence. All other patients will require either a low anterior resection with a colorectal anastomosis or an abdominoperineal resection with a colostomy, depending on how far above the anal verge the tumor is located and the extent of local tumor spread. Careful dissection of the entire mesorectum at the time of surgery has been shown to reduce local recurrence to 8%. With improvements in surgical stapling techniques, it is possible to perform low anterior resection provided there is a margin of at least 2 cm of normal tissue below the tumor. Although low anterior resections obviate a colostomy, they are associated with increased immediate postsurgical complications (leak, dehiscence, stricture) and defecatory complaints (increased stool frequency, defecatory problems, and incontinence).
Cancer With unresectable rectal cancer, the patient may be palliated with a diverting colostomy, laser fulguration, or placement of an expandable wire stent.
B. Systemic Chemotherapy for Colon Cancer Chemotherapy and radiotherapy have been demonstrated to improve overall and tumor-free survival in selected patients with colorectal cancers depending on stage. 1. Stage I—Because of the excellent 5-year survival rate (90–100%), no adjuvant therapy is recommended. 2. Stage II (node-negative disease)—The expected 5-year survival rate is 80%. A survival benefit from adjuvant chemotherapy has not been demonstrated in most controlled trials for stage II colon cancer (see discussion for stage III disease). However, otherwise healthy patients with stage II disease that is at higher risk for recurrence (perforation, obstruction, T4 tumors, or fewer than 12 lymph nodes sampled) may benefit from adjuvant chemotherapy. 3. Stage III (node-positive disease)—With surgical resection alone, the expected 5-year survival rate is 30–50%. Postoperative adjuvant chemotherapy significantly increases disease-free survival as well as overall survival by up to 30% and is recommended for all fit patients. Large, well-designed studies of adjuvant therapy for stage III colon cancer reported a higher rate of disease-free survival at 5 years for patients treated with a combination of oxaliplatin, 5-FU, and leucovorin (FOLFOX) (73.3%) than with 5-FU and leucovorin (FL) alone (67.4%). The addition of oxaliplatin is associated with an increased incidence of diarrhea, myelosuppression, and peripheral sensory neuropathy, all of which generally are reversible. Based on these studies, FOLFOX currently is the preferred adjuvant therapy for most patients with stage III disease (see Table 39–11). The addition of a biologic agent (bevacizumab or cetuximab) to FOLFOX does not improve outcomes in the adjuvant setting. 4. Stage IV (metastatic disease)—Approximately 20% of patients have metastatic disease at the time of initial diagnosis, and another 30% eventually develop metastasis. A subset of these patients has limited disease that is potentially curable with surgical resection. Resection of isolated liver or lung metastases may result in long-term (over 5 years) survival in 35–55% of cases. For those with unresectable hepatic metastases, local ablative techniques (cryosurgery, radio-frequency or microwave coagulation, embolization, hepatic intra-arterial chemotherapy) may provide long-term tumor control. The majority of patients with metastatic disease do not have resectable (curable) disease. In the absence of other treatment, the median survival is only 6 months. The goals of therapy are to slow tumor progression while maintaining a reasonable quality of life for as long as possible. Currently, either FOLFOX (the addition of oxaliplatin to 5-FU and folinic acid) or FOLFIRI (the addition of irinotecan to 5-FU and folinic acid) is the preferred first-line treatment regimens for most patients with metastatic colorectal cancer, increasing median survival to 15–20 months. For convenience, oral capecitabine (instead of intravenous 5-FU and leucovorin) can be used in combination with
oxaliplatin; however, combination with irinotecan should not be used due to increased toxicity (diarrhea). Addition of a biologic agent to combination chemotherapy improves response rates and overall survival and is recommended in the first-line of treatment in suitable patients. Bevacizumab is a monoclonal antibody targeting VEGF. Combination therapy with bevacizumab and FOLFOX or FOLFIRI prolongs mean survival 2–5 months compared with either regimen alone (see Table 39–11). Cetuximab and panitumumab are monoclonal antibodies targeting EGFR. Activating codon 12 and 13 K-ras gene mutations downstream of EGFR are present in approximately 35% of patients with metastatic colorectal cancer and are a biomarker for nonresponse to cetuximab and panitumumab, for which reason the use of these agents is restricted to patients with tumors wild-type for K-ras. In stage 4 patients with K-ras wild-type tumors, the addition of panitumumab or cetuximab to FOLFOX or FOLFIRI prolongs survival by approximately 4 months. Bevacizumab may cause serious side effects, including arterial thromboembolic events, bowel perforation, or serious bleeding, in up to 5% of patients. EGFR-targeted agents cause an acneiform rash in the majority of patients. Cetuximab is associated with anaphylaxis in a small subset. When disease progresses with FOLFOX or FOLFIRI (often in conjunction with bevacizumab or an EGFRtargeted antibody), therapy is switched to the alternative regimen. Patients progressing with one regimen may respond to the alternative regimen, prolonging mean survival to > 20 months. A phase III study randomizing patients to receive either cetuximab or bevacizumab in addition to standard first-line chemotherapy (FOLFIRI or FOLFOX) is ongoing to determine whether one biologic agent is superior. The simultaneous combination of both classes of biologic agents (anti-EGFR and anti-VEGF) with chemotherapy has been associated with worse outcomes in multiple studies. This is a sobering finding that demonstrates the complexity of the signaling pathways involved. Single-agent, palliative therapy with cetuximab or panitumumab can benefit patients with K-ras wildtype tumors whose disease has progressed after first-line and second-line chemotherapies. Clinical trial participation should be considered for eligible patients whose tumors have progressed despite standard treatment, including 5-FU, oxaliplatin, irinotecan, an EGFR-inhibitor (if K-ras gene is wild-type), and bevacizumab. Patients with metastatic colorectal cancer whose tumors harbor a mutation in the B-raf oncogene (approximately 8% in metastatic disease) have a significantly worse prognosis than patients whose tumors are wild-type for B-raf. Unlike activating K-ras mutations, randomized phase 3 data suggest potential benefit from cetuximab or panitumumab in combination with chemotherapy in patients whose tumors harbor an activating B-raf mutation (which almost never coexist with K-ras mutations).
C. Adjuvant Therapy for Rectal Cancer Compared with colon cancer, rectal cancer has lower longterm survival rates and significantly higher rates of local
tumor recurrence (25%) due to the difficulty of achieving adequate surgical resection margins. When initial imaging studies suggest stage I disease, surgery may be performed first. Combination therapy with 5-FU (as a radiation sensitizing agent) and radiation has been shown to improve the disease-free survival rate and to decrease pelvic recurrence and is recommended for all patients with stage II and stage III rectal cancers (see Table 39–11). Preoperative chemoradiation has been shown to be superior to postoperative chemoradiation and is recommended for patients with distal rectal cancers that are determined to be stage II or III by endorectal ultrasound or MRI. Following surgical resection with total mesorectal excision, 5-FU–based therapy (generally with the FOLFOX regimen extrapolating from its benefit in patients with similarly-staged colon cancers) may be administered for an additional 4 months.
``Follow-Up after Surgery Patients who have undergone resections for cure are followed closely to look for evidence of symptomatic or asymptomatic tumor recurrence that may be amenable to curative resection in a small number of patients. The optimal cost-effective strategy is not clear. Two randomized trials reported that intense follow-up with yearly colonoscopy, abdominal CT, and chest radiography did not improve overall outcome compared with most standard follow-up protocols. Patients should be evaluated every 3–6 months for 3–5 years with history, physical examination, and CEA determinations. The NCCN recommends surveillance CT scans of chest, abdomen, and pelvis annually for the first 3 years post-resection in high-risk patients. Patients who had a complete preoperative colonoscopy should undergo another colonoscopy 1 year after surgical resection. Patients who did not undergo full colonoscopy preoperatively also should undergo colonoscopy within 3–6 months postoperatively to exclude other synchronous colorectal neoplasms. If a colonoscopy does not detect new adenomatous polyps 1 year postoperatively, surveillance colonoscopy should be performed every 3–5 years thereafter to look for metachronous polyps or cancer. Because of the high incidence of local tumor recurrence in patients with rectal cancer, proctoscopy surveillance of the low anterior resection anastomotic site may also be performed periodically. New onset of symptoms or a rising CEA warrants investigation with chest, abdominal, and pelvic CT to look for recurrent or metastatic disease that may be amenable to therapy. For patients with a rising CEA with unrevealing CT imaging, a PET scan is more sensitive for the detection of occult metastatic disease.
``Prognosis The stage of disease at presentation is the most important determinant of long-term survival: stage I, > 90%; stage II, 70–85%; stage III with fewer than four positive lymph nodes, 67%; stage III with more than four positive lymph nodes, 33%; and stage IV, 5–7%. For each stage, rectal cancers have a worse prognosis. For those patients whose disease progresses despite therapy, meticulous efforts at palliative care are essential (see Chapter 5).
``Screening for Colorectal Neoplasms Colorectal cancer is ideal for screening because it is a common disease that is fatal in almost 50% of cases yet is curable if detected at an earlier stage. Furthermore, most cases arise from benign adenomatous or serrated polyps that progress over many years to cancer, and removal of these polyps has been shown to prevent the majority of cancers. Colorectal cancer screening is endorsed by the US Preventive Services Task Force, the Agency for Health Care Policy and Research, the American Cancer Society, and every professional gastroenterology and colorectal surgery society. Although there is continued debate about the optimal costeffective means of providing population screening, there is unanimous consent that screening of some kind should be offered to every patient over the age of 50 years. Several analyses suggest that screening is cost effective. It is important for primary care providers to understand the relative merits of various options and to discuss them with their patients. Despite growing awareness of the importance of screening on the part of medical professionals and the public, < 50% of patients have undergone screening of any kind. Discussion and encouragement by the primary care provider are the most important factors in achieving patient compliance with screening programs. Recommendations for screening from the US MultiSociety Task Force are listed in Table 39–5. Screening is recommended for all men and women ages 50 through 75 years of age who are at average risk for cancer. Some
Table 39–5. Recommendations for colorectal cancer screening.1 Average-risk individuals ≥ 50 years old2 Annual fecal occult blood testing using higher sensitivity tests (Hemeoccult SENSA) Annual fecal immunochemical test (FIT) Fecal DNA test (interval uncertain) Flexible sigmoidoscopy every 5 years Colonoscopy every 10 years CT colonography every 5 years Individuals with a family history of a first-degree member with colorectal neoplasia3 Single first-degree relative with colorectal cancer diagnosed at age ≥ 60 years: Begin screening at age 40. Screening guidelines same as average-risk individual; however, preferred method is colonoscopy every 10 years. Single first-degree relative with colorectal cancer or advanced adenoma diagnosed at age < 60 years, or two first-degree relatives: Begin screening at age 40 or at age 10 years younger than age at diagnosis of the youngest affected relative, whichever is first in time. Recommended screening: colonoscopy every 5 years. 1 For recommendations for families with inherited polyposis syndromes or hereditary nonpolyposis colon cancer, see Chapter 15. 2 Joint Guideline from the American Cancer Society, the US MultiSociety Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology 2008 May; 134(5):1570. 3 American College of Gastroenterology. Guidelines for Colorectal Cancer Screening. Am J Gastroenterol. 2009 Mar;104(3):739.
Cancer guidelines recommend screening for African Americans beginning at age 45. The potential for harm from screening must be weighed against the likelihood of benefit, especially in elderly patients with comorbid illnesses and shorter life expectancy. Although routine screening is not recommended in adults above age 75, it may be considered on a case-by-case basis in adults age 76 through 85 years who have excellent health and functional status. Patients with first-degree relatives with colorectal neoplasms (cancer or adenomatous polyps) are at increased risk; earlier and more frequent screening is recommended (preferably with colonoscopy) for these individuals. Recommendations for screening in families with inherited cancer syndromes or inflammatory bowel disease are provided in Chapter 15. For patients at average risk for colorectal cancer, the recommendations of the Task Force are discussed below. Screening tests may be classified into two broad categories: stool-based tests and exams that visualize the structure of the colon by direct endoscopic inspection or radiographic imaging.
A. Stool-based Tests 1. Fecal occult blood test—Most colorectal cancers and some large adenomas result in increased chronic blood loss. A variety of tests for fecal occult blood are commercially available that have varying sensitivities and specificities for colorectal neoplasia. These include guaiac-based tests (Hemoccult I and II and Hemeoccult SENSA) that detect the pseudoperoxidase activity of heme or hemoglobin and fecal immunochemical tests (FITs) that detect human globin. Guaiac-based tests have undergone the most extensive testing and currently have the greatest clinical use. For optimal detection, one specimen card must be prepared from three consecutive bowel movements. To reduce the likelihood of false-positive tests, patients should abstain from aspirin (in doses > 325 mg/d), NSAIDs, red meat, poultry, fish, and vegetables with peroxide activity (turnips, horseradish) for 72 hours. Vitamin C may cause a false-negative test. Slides should be developed within 7 days after preparation. The reported sensitivities of a single guaiac-based test for detection of colorectal cancer vary widely, but are lower for Hemeoccult II (35%) than Hemeoccult SENSA (65%). When fecal occult blood test is administered to the general population as part of a screening program, 2–6% of tests are positive. Of those with positive tests, 5–18% have colorectal cancer that is more likely to be at an earlier stage (stage I or II). Several FITs are commercially available. These tests are highly specific for detecting human globin and therefore eliminate the need for pretest dietary restrictions. As with guaiac-based tests, sampling of three consecutive bowel movements is recommended. In clinical trials that compare FIT with guaiac-based tests, FIT had at least comparable sensitivity to Hemeoccult SENSA for detection of cancers (60–85%) with higher specificity. Because FITs are not affected by diet or medications and have superior accuracy, they are increasingly being substituted for guaiac-based tests despite a higher cost per test ($10–20).
The US Multi-Society Task Force emphasizes that colon cancer prevention should be the primary goal of screening. For that reason, the lower sensitivity of fecal occult blood tests for advanced neoplasia (cancer and advanced adenomatous polyps) makes them a less attractive choice for population-based screening than endoscopic or radiographic tests. Currently, fecal occult blood tests are most suitable in settings where health care resources are limited or in patients who desire a noninvasive method of screening. The Task Force recommends that tests with higher sensitivity for colorectal cancer (Hemeoccult SENSA or FIT) be used rather than less sensitive tests (Hemeoccult II). Regardless of which stool-based test is used, patients should understand that annual testing is required to achieve the maximum screening benefit and that a positive test will require evaluation by colonoscopy accompanied by removal of any polyps identified. If colonoscopy reveals no colorectal neoplasm, further screening for colorectal cancer can be deferred for 10 years. In a meta-analysis of four large, prospective, longitudinal studies, annual or biennial screening with Hemeoccult or Hemeoccult II reduced mortality from colorectal cancer by 25% among those who were compliant with regular testing. Long-term studies with more sensitive stool tests (Heme SENSA or FIT) have not been performed. 2. Multitarget DNA assay—A fecal DNA assay (Pre-Gen Plus) is available for screening for colorectal neoplasia. The test analyzes fecal DNA for 22 gene mutations and DNA integrity. The commercially available first-generation fecal DNA panel detected only one-half of cancers; however, a second-generation assay detected almost 90%. Although the Multi-Society Task Force concluded that fecal DNA is an acceptable option for colorectal cancer screening, this test is not yet practical for populationbased screening due to its high cost and cumbersome requirements for stool collection and mailing.
B. Endoscopic Examinations of the Colon 1. Flexible sigmoidoscopy—Use of a 60-cm flexible sigmoidoscope permits visualization of the rectosigmoid and descending colon. It requires no sedation and in many centers is performed by a nurse specialist or physician’s assistant. Adenomatous polyps are identified in 10–20% and colorectal cancers in 1% of patients. Case-control studies suggest that screening sigmoidoscopy programs lead to a 60% reduction in colorectal cancer mortality. A 2010 randomized controlled trial in 170,000 participants in the United Kingdom comparing a one-time flexible sigmoidoscopy screening to usual care confirmed a 50% reduction in distal colorectal cancer incidence and 43% reduction in mortality after a median follow-up of 11 years. The risk of serious complications (perforation) associated with flexible sigmoidoscopy is < 1:10,000 patients. The chief disadvantage of screening with flexible sigmoidoscopy is that is does not examine the proximal colon. The prevalence of proximal versus distal neoplasia is higher in people over age 65 years of age, African Americans, and women. In men, approximately 50%
of advanced neoplasms (cancer, adenomas ≥ 1 cm in size, polyps with villous histology, or high-grade dysplasia) are located in the proximal colon, compared with 60–70% in women. The finding at sigmoidoscopy of an adenomatous polyp in the distal colon increases the likelihood at least twofold that an advanced neoplasm is present in the proximal colon. Therefore, patients found on screening sigmoidoscopy to have an adenomatous polyp of any size should subsequently undergo colonoscopy to evaluate the proximal colon. Using this strategy in men, it is estimated that screening sigmoidoscopy programs will detect approximately 65% of advanced colonic neoplasms. In women, however, sigmoidoscopy screening programs may fail to detect up to 65% of advanced neoplasia. 2. Colonoscopy—Colonoscopy permits examination of the entire colon. In addition to detecting early cancers, colonoscopy allows removal of adenomatous polyps by biopsy or polypectomy, which is believed to reduce the risk of subsequent cancer. Over the past decade, there has been a dramatic increase in screening colonoscopy and a similar decrease in screening sigmoidoscopy due to poor reimbursement and the perceived inferiority of sigmoidoscopy compared with colonoscopy. Colonoscopy requires aggressive bowel cleansing prior to the examination. To alleviate discomfort, intravenous sedation is used for most patients. The incidence of serious complications after colonoscopy (perforation, bleeding, cardiopulmonary events) is 0.1%. In asymptomatic individuals between 50 and 75 years of age undergoing screening colonoscopy, the prevalence of advanced neoplasia is 4–11% and of cancer is 0.1–1%. Although colonoscopy is believed to be the most sensitive test for detecting adenomas and cancer, it is not infallible. In several studies, the rate of colorectal cancer within 3 years of a screening colonoscopy was 0.7–0.9%, ie, approximately 1 in 110 patients. This may be attributable to adenomatous polyps and early cancers that were overlooked during colonoscopy. Studies of back-to-back colonoscopies confirm that endoscopists overlook 6–12% of polyps > 1 cm and up to 25% of smaller adenomas. Polyps that are small, flat, or located behind folds are easily missed, especially if the bowel preparation is poor. Population-based case-control and cohort studies suggest that colonoscopy is associated with greater reduction in colorectal cancer incidence and mortality in the distal colon than the proximal colon. This may be attributable to incomplete examination of the proximal colon, and differences between the proximal and distal colon that include worse bowel preparation, suboptimal colonoscopic technique, and a higher prevalence of serrated polyps and flat adenomas. The latter are more common than previously recognized, are more likely to contain advanced pathology, and are more difficult to identify than raised (sessile or pedunculated) polyps. To optimize diagnostic accuracy as well as patient safety and comfort, colonoscopy should be performed after optimal bowel preparation by a welltrained endoscopist who spends sufficient time (at least 7 minutes) carefully examining the colon (especially the proximal colon) while withdrawing the endoscope.
C. Radiographic Examinations of the Colon 1. CT colonography—Using helical CT with computerassisted image reconstruction, two- and three-dimensional views can be generated of the colon lumen that simulate the view of colonoscopy (virtual colonoscopy). CT colonography requires a similar bowel cleansing regimen as colonoscopy as well as insufflation of air into the colon through a rectal tube, which may be associated with discomfort. Nonetheless, this examination is performed rapidly and requires no sedation or intravenous contrast. It has minimal acute risk although there is controversy about potential long-term risks related to radiation exposure from CT examinations. Several large studies have compared the accuracy of virtual colonoscopy with colonoscopy for colorectal screening. Using current imaging software with multidetector helical scanners, the sensitivity is > 95% for the detection of cancer and > 84–92% for the detection of polyps ≥ 10 mm in size. The sensitivity for polyps 6–9 mm in size ranges from 57% to 84%; for polyps 5 mm or less, the sensitivity is extremely poor. Patients undergoing screening with CT colonography should be managed appropriately. If no polyps are found, the interval for repeat screening examination is uncertain; however, 5 years may be reasonable. All patients with polyps ≥ 10 mm in size should be referred for colonoscopy with polypectomy because of the high prevalence (30%) of advanced pathology (cancer, high-grade dysplasia, or villous features) within these polyps. The optimal management of patients with polyps < 10 mm in size is controversial. The likelihood of advanced pathology in polyps 6–9 mm in size is 4–7% and in polyps 1–5 mm is < 2%. The US Multi-Society Task Force currently recommends that colonoscopy with polypectomy be offered to patients with one or more 6–9 mm polyps. Patients who refuse or who have increased risk of carcinoma should undergo surveillance CT colonography in 3–5 years. At the present time, there is no consensus on the management of patients with polyps < 6 mm; however, some radiologists choose not even to report these findings. 2. Barium enema—Double-contrast barium enema was previously used as a screening technique because it was widely available, relatively inexpensive, and safe. However, compared to CT colonography, it is more time consuming and difficult to perform, less comfortable, and less accurate. Although it continues to be included among recommended screening options, it has been supplanted by CT colonography, where available. A multicenter trial demonstrated that the sensitivity of barium enema is only 50% for polyps ≥ 1 cm and 55–85% for early-stage cancers when compared with colonoscopy. At present, barium enema may be recommended when screening of the entire colon is desired but expertise in CT colonography is unavailable and the patient is unable or unwilling to undergo colonoscopy.
``When to Refer • Patients with symptoms (change in bowel habits, hematochezia), signs (mass on abdominal examination or digital rectal examination [DRE]), or laboratory tests
Cancer (iron deficiency anemia) suggestive of colorectal neoplasia should be referred for colonoscopy. • Patients with suspected cancer or adenomatous polyps of any size should be referred for colonoscopy. • Virtually all patients with proven colorectal cancer should be referred to a surgeon for resection. Patients with clinical stage T3 or node-positive rectal tumors (or both) also should be referred to an oncologist preoperatively for neoadjuvant therapy. Patients with stage III or IV colorectal tumors should be referred to an oncologist.
``When to Admit • Patients with complications of colorectal cancer (obstruction, acute bleeding) requiring urgent evaluation and intervention. • Patients with severe complications of chemotherapy. • Patients with advanced metastatic disease requiring palliative care. Ahnen DJ. The American College of Gastroenterology Emily Couric lecture—the adenoma-carcinoma sequence revisited: has the era of genetic tailoring finally arrived? Am J Gastroenterol. 2011 Feb;106(2):190–8. [PMID: 21266962] Allison JE. FIT: a valuable but underutilized screening test for colorectal cancer—it’s time for a change. Am J Gastroenterol. 2010 Sep;105(9):2026–8. [PMID: 20818351] André T et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. N Engl J Med. 2009 Jul 1;27(19):3109–16. [PMID: 19451431] Atkin WS et al; UK Flexible Sigmoidoscopy Trial Investigators. Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. 2010 May 8;375(9726):1624–33. [PMID: 20430429] Baxter NN et al. Analysis of administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal cancer. Gastroenterology. 2011 Jan;140(1):65–72. [PMID: 20854818] Bokemeyer C et al. Cetuximab with chemotherapy (CT) as firstline treatment for metastatic colorectal cancer (mCRC): analysis of the CRYSTAL and OPUS studies according to KRAS and BRAF mutation status. Presented at American Society of Clinical Oncology Annual Meeting, 2010. Chicago, IL. Brenner H et al. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med. 2011 Jan 4;154(1):22–30. [PMID: 21200035] Day LW et al. Colorectal cancer screening and surveillance in the elderly patient. Am J Gastroenterol. 2011 Jul;106(7): 1197–206. [PMID: 21519362] Douillard JY et al. Final results from PRIME: randomized phase 3 study of panitumumab (pmab) with FOLFOX4 for 1st-line metastatic colorectal cancer (mCRC). Presented at American Society of Clinical Oncology Annual Meeting, 2011. Chicago, IL. Hecht JR et al. A randomized phase IIIB trial of chemotherapy, bevacizumab, and panitumumab compared with chemotherapy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol. 2009 Feb 10;27(5):672–80. [PMID: 19114685] Jemal A et al. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep–Oct;60(5):277–300. [PMID: 20610543] Kaminski MF et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. 2010 May 13;362(19): 1795–803. [PMID: 20463339]
Karpetis CS et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008 Oct 23;359(17):1757–65. [PMID: 18946061] Lakoff J et al. Risk of developing a proximal versus distal colorectal cancer after a negative colonoscopy: a population-based study. Clin Gastroenterol Hepatol. 2008 Oct;6(10):1117–21. [PMID: 18691942] Levin B et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology. 2008 May;134(5):1570–95. [PMID: 18384785] Lieberman DA. Clinical Practice. Screening for colorectal cancer. N Engl J Med. 2009 Sep 17;361(12):1179–87. [PMID: 19759380] Pohl H et al. Colorectal cancers detected after colonoscopy frequently result from missed lesions. Clin Gastroenterol Hepatol. 2010 Oct;8(10):858–64. [PMID: 20655393] Regge D et al. Diagnostic accuracy of computed tomographic colonography for the detection of advanced neoplasia in individuals at increased risk of colorectal cancer. JAMA. 2009 Jun 17;301(23):2453–61. [PMID: 19531785] Rex D et al. American College of Gastroenterology Guidelines for colorectal cancer screening 2009. Am J Gastroenterol. 2009 Mar;104(3):739–50. [PMID: 19240699] Singh H et al. The reduction in colorectal cancer mortality after colonoscopy varies by site of cancer. Gastroenterology. 2010 Oct;139(4):1128–37. [PMID: 20600026] Singh H et al. Rate and predictors of early/missed colorectal cancers after colonoscopy in Manitoba: a population-based study. Am J Gastroenterol. 2010 Dec;105(12):2588–96. [PMID: 20877348] Soetikno RM et al. Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. JAMA. 2008 Mar 5;299(9):1027–35. [PMID: 18319413] Terdiman JP et al. Surveillance guidelines should be updated to recognize the importance of serrated polyps. Gastroenterology. 2010 Nov;139(5):1444–7. [PMID: 20875785] Tol J et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009 Feb 5;360(6): 563–72. [PMID: 19196673] Van Cutsem E et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009 Apr 2;360(14):1408–17. [PMID: 19339720] Van Rossum LG et al. Random comparison of guaiac and immunochemical fecal occult blood tests for colorectal cancer in a screening population. Gastroenterology. 2008 Jul;135(1):82–90. [PMID: 18482589]
CARCINOMA OF THE ANUS The anal canal is lined from its proximal to distal extent by columnar, transitional and non-keratinized squamous epithelium, which merges at the anal verge with the keratinized perianal skin. Tumors arising from the mucosa of the anal canal are relatively rare, comprising only 1–2% of all cancers of the anus and large intestine. Squamous cancers make up the majority of anal cancers. Anal cancer is increased among people practicing receptive anal intercourse and those with a history of anorectal warts. In over 80% of cases, HPV may be detected, suggesting that this virus is a major causal factor. Women with anal cancer are at increased risk for cervical cancer, which may be due to a field effect of oncogenic HPV infection, and require gynecologic screening and surveillance. Anal cancer is increased in HIV-infected individuals, possibly due to interaction
with HPV. Bleeding, pain, and local tumor are the most common symptoms. The lesion is often confused with hemorrhoids or other common anal disorders. These tumors tend to become annular, invade the sphincter, and spread upward via the lymphatics into the perirectal mesenteric lymphatic nodes. CT or MRI scans of the abdomen and pelvis are required to identify regional lymphadenopathy or metastatic disease at diagnosis. PET imaging may be used in conjunction. Treatment depends on the tumor location and histologic stage. Small (< 3 cm) superficial lesions of the perianal skin may be treated with wide local excision. Adenocarcinoma of the anal canal is treated in similar fashion to rectal cancer (see above), commonly by abdominoperineal resection with neoadjuvant chemoradiotherapy and adjuvant chemotherapy. Squamous cancer of the anal canal and large perianal tumors invading the sphincter or rectum are treated with combined-modality therapy that includes external radiation with simultaneous chemotherapy (5-FU and mitomycin). Local control is achieved in approximately 80% of patients. Radical surgery (abdominoperineal resection) is reserved for patients who fail chemotherapy and radiation therapy. Metastatic disease is generally treated with 5-FU in combination with cisplatin. The 5-year survival rate is 60–70% for localized tumors and over 25% for metastatic (stage IV) disease. Ajani JA et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008 Apr 23;299(16):1914–21. [PMID: 18430910] Glynne-Jones R et al. Anal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21(Suppl 5):v87–92. [PMID: 20555110] National Cancer Institute. Anal Cancer Treatment (PDQ). http://www.cancer.gov/cancertopics/pdq/treatment/anal/ HealthProfessional Shia J. An update on tumors of the anal canal. Arch Pathol Lab Med. 2010 Nov;134(11):1601–11. [PMID: 21043813] Zeller JL et al. JAMA patient page. Anal cancer. JAMA. 2008 Apr 23;299(16):1980. [PMID: 18430917]
CANCERS OF the GENITOURINARY TRACT Maxwell V. Meng, MD, FACS
E ssent i a l s o f d i a g nos i s
Prostatic induration on DRE or elevation of PSA. Most often asymptomatic. Rarely: systemic symptoms (weight loss, bone pain).
`` `` ``
``General Considerations Prostatic cancer is the most common noncutaneous cancer detected in American men and the second leading
cause of cancer-related death. In the United States, over 241,000 new cases of prostate cancer are diagnosed annually, and about 28,000 deaths result. However, the clinical incidence of the disease does not match the prevalence noted at autopsy, where more than 40% of men over 50 years of age are found to have prostatic carcinoma. Most such occult cancers are small and contained within the prostate gland; few are associated with regional or distant disease. The incidence of prostatic cancer increases with age. Whereas 30% of men aged 60–69 years will have the disease, autopsy incidence increases to 67% in men aged 80–89 years. Although the global prevalence of prostatic cancer at autopsy is relatively consistent, the clinical incidence varies considerably (high in North America and European countries, intermediate in South America, and low in the Far East), suggesting that environmental or dietary differences among populations may be important for prostatic cancer growth. A 50-year-old American man has a lifetime risk of 40% for latent cancer, 16% for developing clinically apparent cancer, and a 2.9% risk of death due to prostatic cancer. Blacks, men with a family history of prostatic cancer, and those with a history of high dietary fat intake are at increased risk for developing prostate cancer.
``Clinical Findings A. Symptoms and Signs Prostate cancer may manifest as focal nodules or areas of induration within the prostate at the time of DRE. However, currently most prostate cancers are associated with palpably normal prostates and are detected solely on the basis of elevations in serum PSA. Patients rarely present with signs of urinary retention or neurologic symptoms as a result of epidural metastases and cord compression. Obstructive voiding symptoms are most often due to benign prostatic hyperplasia, which occurs in the same age group. Nevertheless, large or locally extensive prostatic cancers can cause obstructive voiding symptoms while lymph node metastases can lead to lower extremity lymphedema. As the axial skeleton is the most common site of metastases, patients may present with back pain or pathologic fractures.
B. Laboratory Findings 1. Serum tumor markers—PSA is a glycoprotein produced only by cells, either benign or malignant, of the prostate gland. The serum level is typically low and correlates with the volume of both benign and malignant prostate tissue. Measurement of serum PSA is useful in detecting and staging prostate cancer, monitoring response to treatment, and detecting recurrence before it becomes clinically evident. As a screening test, PSA will be elevated in 10–15% of men. Approximately 18–30% of men with intermediate degrees of elevation (4.1–10 ng/mL) will be found to have prostate cancer. Between 50% and 70% of those with elevations >10 ng/mL will have prostate cancer. Patients with intermediate levels of PSA usually have localized and therefore potentially curable cancers. It should be remembered that approximately 20% of patients
Cancer who undergo radical prostatectomy for localized prostate cancer have normal levels of PSA. In untreated patients with prostate cancer, the level of PSA correlates with the volume and stage of the disease. Whereas most organ-confined cancers are associated with PSA levels <10 ng/mL, advanced disease (seminal vesicle invasion, lymph node involvement, or occult distant metastases) is more common in patients with PSA levels in excess of 40 ng/mL. Approximately 98% of patients with metastatic prostate cancer will have elevated PSA. However, there are rare cancers that are localized despite substantial elevations in PSA. Therefore, initial treatment decisions cannot be made on the basis of PSA testing alone. A rising PSA after therapy is usually consistent with progressive disease, either locally recurrent or metastatic. 2. Miscellaneous laboratory testing—Patients in urinary retention or those with ureteral obstruction due to loco-regionally advanced prostate cancers may present with elevations in blood urea nitrogen or creatinine. Patients with bony metastases may have elevations in alkaline phosphatase or hypercalcemia. Laboratory and clinical evidence of disseminated intravascular coagulation can occur in patients with advanced prostate cancers. 3. Prostate biopsy—Transrectal ultrasound-guided biopsy is the standard method for detection of prostate cancer. The use of a spring-loaded, 18-gauge biopsy needle has allowed transrectal biopsy to be performed with minimal patient discomfort and morbidity. Local anesthesia is routinely used and increases the tolerability of the procedure. The specimen preserves glandular architecture and permits accurate grading. Prostate biopsy specimens are taken from the apex, mid-portion, and base in men who have an abnormal DRE or an elevated serum PSA, or both. Extended-pattern biopsies, including a total of at least ten biopsies, are associated with improved cancer detection and risk stratification of patients with newly diagnosed disease. Patients with abnormalities of the seminal vesicles can have these structures specifically biopsied to identify local tumor invasion.
C. Imaging Transrectal ultrasonography has primarily been used for the staging of prostate carcinomas, where tumors typically appear as hypoechoic areas. In addition, transrectal ultrasound-guided, rather than digitally-guided, biopsy of the prostate is a more accurate way to evaluate suspicious lesions. Use of imaging should be tailored to the likelihood of advanced disease in newly diagnosed cases. Asymptomatic patients with well-differentiated to moderately differentiated cancers, thought to be localized to the prostate on DRE and transurethral ultrasound and associated with modest elevations of PSA (ie, < 10 ng/mL), need no further imaging. MRI allows for evaluation of the prostate as well as regional lymph nodes. The positive predictive value for detection of both capsular penetration and seminal vesicle invasion is similar for transrectal ultrasound and MRI. CT
plays little role because of its inability to accurately identify or stage prostate cancers, but it can be used to detect regional lymphatic metastases and intra-abdominal metastases. Radionuclide bone scan is superior to conventional plain skeletal radiographs in detecting bony metastases. Most prostate cancer metastases are multiple and most commonly localized to the axial skeleton. Men with more advanced local lesions, symptoms of metastases (eg, bone pain), high-grade disease, or elevations in PSA > 20 ng/mL should undergo radionuclide bone scan. Because of the high frequency of abnormal scans in patients in this age group resulting from degenerative joint disease, plain films are often necessary in evaluating patients with indeterminate findings on bone scan. Cross-sectional imaging either by CT or MRI is usually indicated only in those patients in the latter group who have negative bone scans in an attempt to detect lymph node metastases. Patients found to have enlarged pelvic lymph nodes are candidates for FNA. Intravenous urography and cystoscopy are not routinely needed to evaluate patients with prostate cancer. Despite application of modern, sophisticated techniques, understaging of prostate cancer occurs in at least 20% of patients.
``Screening for Prostate Cancer Whether screening for prostate cancer results in a decrease in mortality rates due to the disease is the subject of much debate. The screening tests currently available include DRE, PSA testing, and transrectal ultrasound. Depending on the patient population being evaluated, detection rates using DRE alone vary from 1.5% to 7%. Unfortunately, most cancers detected in this manner are advanced (stage T3 or greater). Transrectal ultrasound should not be used as a first-line screening tool because of its expense, low specificity (and therefore high biopsy rate), and minimal improvement in detection rate when compared with the combined use of DRE and PSA testing. PSA testing increases the detection rate of prostate cancers compared with DRE. Approximately 2–2.5% of men older than 50 years of age will be found to have prostate cancer using PSA testing compared with a rate of approximately 1.5% using DRE alone. PSA is not specific for cancer, and there is considerable overlap of values between men with benign prostate hyperplasia and those with prostate cancers. The sensitivity, specificity, and positive predictive value of PSA and DRE are listed in Table 39–6. PSA-detected cancers are more likely to be localized compared with those detected by DRE alone. The Prostate Cancer Prevention Trial provided data demonstrating a significant risk of prostate cancer even in men with PSA less than 4.0 ng/mL (Table 39–7) and a web-based calculator has been developed to estimate the risk of harboring both cancer and high-grade prostate cancer (http://deb. uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp). To improve the performance of PSA as a screening test, several investigators have developed alternative methods for its use. These include establishment of ageand race-specific reference ranges, measurement of free serum and protein-bound levels of PSA (percent free
Table 39–6. Screening for prostatic cancer: Test performance.
Positive Predictive Value
Abnormal PSA (> 4 ng/mL)
Abnormal PSA or DRE
Abnormal PSA and DRE
DRE, digital rectal examination; PSA, prostate-specific antigen. Modified, with permission, from Kramer BS et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med. 1993 Nov 1;119(9):914–23.
PSA), and calculation of changes in PSA over time (PSA velocity). Generally, men with PSA free fractions exceeding 25% are unlikely to have prostate cancer, whereas those with free fractions < 10% have an approximately 50% chance of having prostate cancer. The frequency of PSA testing remains a matter of some debate. The traditional yearly screening approach may not be the most efficient, rather, earlier PSA testing at younger age may allow less frequent testing as well as provide information regarding PSA velocity. Studies from the Baltimore Longitudinal Study of Aging suggest that men with PSA above the agebased median when tested between 40 and 60 years are at significantly increased risk for subsequent cancer detection over 25 years. Therefore, men with lower PSA (0.6 ng/mL ages 40–50 and 0.71 ages 50–60) may require less frequent PSA tests. In addition, men with PSA velocity greater than 0.35 ng/mL per year measured 10–15 years before diagnosis had significantly worse cancer-specific survival compared with those with lower PSA velocity. The current NCCN guidelines (http://www.nccn.org/professionals/ physician_gls/f_guidelines.asp) for prostate cancer early detection incorporate many of these factors (Figure 39–2). Table 39-7. Risk of prostate cancer in men with PSA ≤ 4.0 ng/mL.
PSA Level (ng/mL)
Percentage with prostate cancer
Two large, randomized trials question the benefit of screening men for prostate cancer. In the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, no mortality benefit was observed after combined screening with PSA testing and digital rectal examination during follow-up of 13 years. Although screening resulted in a 12% increase in prostate cancer detection, the cancerspecific mortality rate was similar in the screening and control arms (3.7 and 3.4 deaths per 10,000 person-years, respectively). Similarly in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial, the benefit of PSA screening was minimal with a 20% relative reduction in death rate from prostate at follow-up of 9 years, with an absolute reduction of 7 prostate cancer deaths per 10,000 men screened. A subset of these patients from Göteborg, Sweden, in an independently designed and initiated population-based screening trial, was analyzed separately. During a median follow-up of 14 years, the absolute risk reduction of death from prostate cancer in the screening group was 40% and the relative risk of prostate-cancer death in the attendees of screening was 0.44. Based on these data, the US Preventive Services Task Force recommended against PSA-based screening for prostate cancer in asymptomatic men (grade D recommendation). Criticisms of the negative PLCO study include use of a relatively high PSA threshold (4 ng/mL), significant screening of men in the 3 years prior to enrolling in the trial (44%), and significant number of men in the control arm undergoing screening during the trial (> 50%).
``Staging The majority of prostate cancers are adenocarcinomas. Most arise in the periphery of the prostate (peripheral zone), though a small percentage arise in the central (5–10%) and transition zones (20%) of the gland. Pathologists utilize the Gleason grading system whereby a “primary” grade is applied to the architectural pattern of malignant glands occupying the largest area of the specimen and a “secondary” pattern is assigned to the next largest area of cancer. Grading is based on architectural rather than histologic criteria, and five “grades” are possible (Figure 39–3). Adding the score of the primary and secondary patterns (grades) gives a Gleason score. Grade correlates with tumor volume, pathologic stage, and prognosis (Figure 39–4).
Percentage with high-grade prostate cancer
A. Localized Disease
The optimal treatment for patients with clinically localized prostate cancers remains controversial. Patients need to be advised of all treatment options, including active surveillance, with the specific benefits, risks, and limitations. Currently, treatment decisions are made based on tumor grade and stage as well as the age and health of the patient. Although selected patients may be candidates for surveillance based on age or health and evidence of smallvolume or well-differentiated cancers, most men with an anticipated life expectancy in excess of 10 years should be
Data from Thompson IM et al. Prevalence of prostate cancer among men with a prostate-specific antigen level ≤4.0 ng per milliliter. N Engl J Med. 2004 May 27;350(22):2239-46. [PMID: 15163773] High-grade cancer was defined as Gleason score ≥ 7.
Discussion of risks and benefits Assessment including: family history, medications, prostate history, ethnicity Baseline evaluation at age 40 DRE and PSA
PSA ≥ 0.6 ng/mL or family history or African American or taking 5-ARI
PSA < 0.6 ng/mL1
Annual screening with DRE and PSA
PSA < 0.6 ng/mL
Repeat PSA at age 45
PSA < 0.6 ng/mL
PSA < 0.6 ng/mL Begin annual screening at age 50
Annual follow up
PSA ≤ 2.5 ng/mL and PSAV ≤ 0.35
PSA 2.6-4.0 ng/mL or PSAV ≥ 0.35 when PSA ≤ 2.5 ng/mL
PSA > 4.0 ng/mL
Consider biopsy (Free PSA < 25% or PSAV ≥ 0.75)
Annual follow up
Transrectalultrasound guided biopsy
Discontinue or reduce frequency of screening Life expectancy < 10 years; PSA < 3.0 ng/mL at age 75; PSA < 1.0 ng/mL at age 65 1NCCN guidelines utilize PSA threshold of 1.0 ng/mL in men < 50 years, the 75th percentile range for this age group; the median PSA value for men 40–49 years is 0.6 ng/mL.
s Figure 39–2. An algorithm for prostate cancer early detection. DRE, digital rectal examination; 5-ARI, 5α-reductase inhibitor; PSAV, PSA velocity (ng/mL/year) calculated on at least three consecutive values over at least an 18–24 month period. (Based on NCCN guidelines, data from the Baltimore Longitudinal Study on Aging, and Prostate Cancer Prevention Trial.) considered for treatment. Both radiation therapy and radical prostatectomy result in acceptable levels of local control. A large, prospective, randomized trial compared surveillance with radical prostatectomy in 695 men with clinically localized and well- differentiated to moderately differentiated tumors for a median of 12.8 years. Radical prostatectomy significantly reduced disease-specific mortality, overall mortality, and risks of metastasis and local progression. The relative reduction in the risk of death at
15 years was 0.62 in the prostatectomy group, with the number needed to treat to avert one death of 15; the benefit was confined to men younger than 65 years of age. This trial accrued patients in Sweden between 1989 and 1999, thus likely including patients with greater cancer burden compared with that in patients currently diagnosed using PSA screening. Nevertheless, the survival benefit in the trials was still observed in men with low-risk prostate cancer.
Pattern 1 Circumscribed nodule of closely-packed but separate, uniform, rounded to oval, medium-sized acini.
Pattern 2 Like Pattern 1, fairly circumscribed, yet at the edge of the tumor nodule there may be minimal infiltration. Glands are more loosely arranged and not quite as uniform as pattern 1.
Pattern 3 Discrete glandular units. Typically smaller glands than seen in Gleason pattern 1 or 2. Infiltrates in and amongst non-neoplastic prostate acini. Marked variation in size and shape. Smoothly circumscribed small cribriform nodules of tumor. Pattern 4 Fused microacinar glands. Ill-defined glands with poorly formed glandular lumina. Large cribriform glands.Cribriform glands with an irregular border. Hypernephromatoid.
Pattern 5 Essentially no glandular differentiation, composed of solid sheets, cords, or single cells. Comedocarcinoma with central necrosis surrounded by papillary, cribiform, or solid masses.
s Figure 39â€“3.â€‚ Patterns of prostate cancer according to the 2005 International Society of Urological Pathology modified Gleason system. (Adapted with permission from Epstein JI et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29(9):1228-1242.)
B. Radical Prostatectomy During radical prostatectomy, the seminal vesicles, prostate, and ampullae of the vas deferens are removed. Refinements in technique have allowed preservation of urinary continence in most patients and erectile function
in selected patients. Radical prostatectomy can be performed via open retropubic, transperineal, or laparoscopic (with or without robotic assistance) surgery. Local recurrence is uncommon after radical prostatectomy, and the incidence is related to pathologic stage. Organ-confined
Survival Non-Prostate Cancer Mortality Prostate Cancer Mortality Age at diagnosis, y 60–64 Gleason Score 7
0 Gleason Score 8–10
Years Following Diagnosis
s Figure 39–4. Prostate cancer mortality as a factor of Gleason grade and age at diagnosis in men managed conservatively. (Adapted, with permission, from Albertsen PC et al. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005 May 4;293(17):2095-101.)
cancers rarely recur; however, cancers with adverse pathologic features (capsular penetration, seminal vesicle invasion) are associated with higher local (10–25%) and distant (20–50%) relapse rates. Ideal candidates for prostatectomy include healthy patients with stages T1 and T2 prostate cancers. Patients with advanced local tumors (T4) or lymph node metastases are rarely candidates for prostatectomy alone, although surgery is sometimes used in combination with hormonal therapy and postoperative radiation therapy for select high-risk patients. Patients with advanced pathologic stage or positive surgical margins are at an increased risk for local and distant tumor relapse. Such patients are candidates for adjuvant therapy (radiation for positive margins or androgen deprivation for lymph node metastases). Two randomized clinical trials (EORTC 22911 and SWOG 8794) have demonstrated improved progression-free and metastasisfree survival with early radiotherapy in these men, and subsequent analysis of SWOG 8794 showed improved overall survival in men receiving adjuvant radiation therapy. Evidence suggests that salvage radiotherapy after radical prostatectomy, within 2 years of PSA relapse, increases prostate cancer-specific survival in men with shorter PSA doubling time (< 6 months).
C. Radiation Therapy Radiation can be delivered by a variety of techniques including use of external beam radiotherapy and transperineal implantation of radioisotopes. Morbidity is limited, and the survival of patients with localized cancers (T1, T2, and selected T3) approaches 65% at 10 years. As with surgery, the likelihood of local failure correlates with technique and tumor characteristics. The likelihood of a positive prostate biopsy more than 18 months after radiation varies between 20% and 60%. Patients with local recurrence are at an increased risk of cancer progression and cancer death compared with those who have negative biopsies. Ambiguous target definitions, inadequate radiation doses, and understaging of the tumor may be responsible for the failure noted in some series. Newer techniques of radiation (implantation, conformal therapy using three-dimensional reconstruction of CT-based tumor volumes, heavy particle, charged particle, and heavy charged particle) may improve local control rates. Three-dimensional conformal radiation delivers a higher dose because of improved targeting and appears to be associated with greater efficacy as well as lower likelihood of adverse side effects compared with previous techniques. As a result of improvements in imaging, most
notably transrectal ultrasound, there has been a resurgence of interest in brachytherapy—the implantation of permanent or temporary radioactive sources (palladium, iodine, or iridium) into the prostate. Brachytherapy can be combined with external beam radiation in patients with higher-grade or higher-volume disease or as monotherapy in those with low-grade or low-volume malignancies. The PSA may rise after brachytherapy because of prostate inflammation and necrosis. This transient elevation (PSA bounce) should not be mistaken for recurrence and may occur up to 20 months after treatment.
D. Surveillance A beneficial impact of treating localized prostate cancer with respect to survival has not been conclusively demonstrated. Therefore, surveillance alone may be an appropriate form of management for selected patients with prostate cancer. Patients included in observational series are typically older with small volume, well-differentiated cancers. Many men with prostate cancer may be candidates for surveillance due to the significant migration to lower stage as well as lower grade, resulting from screening for prostate cancer using PSA testing. Depending on the age and health of the patient, some of these very low-volume, low-grade cancers may never become clinically relevant and can be monitored with serial PSA levels, rectal examinations, and periodic prostate biopsies to assess grade and extent of tumor. The goal of surveillance is to avoid treatment in men who never experience disease progression while recognizing and effectively treating men with evidence of progression. End points for intervention in patients on surveillance, particularly PSA changes, have not been clearly defined and surveillance regimens remain investigational.
E. Cryosurgery Cryosurgery is a technique whereby liquid nitrogen is circulated through small hollow-core needles inserted into the prostate under ultrasound guidance. The freezing process results in tissue destruction. There has been a resurgence of interest in less invasive forms of therapy for localized prostate cancer as well as several recent technical innovations, including improved percutaneous techniques, expertise in transrectal ultrasound, improved cryotechnology, and better understanding of cryobiology. The positive biopsy rate after cryoablation ranges between 7% and 23%.
F. Locally and Regionally Advanced Disease Prostate cancers associated with minimal degrees of capsular penetration are candidates for standard irradiation or surgery. Those with locally extensive cancers, including those with seminal vesicle and bladder neck invasion, are at increased risk for both local and distant relapse despite conventional therapy. Currently, a variety of investigational regimens are being tested in an effort to improve
cancer outcomes in such patients. Combination therapy (androgen deprivation combined with surgery or irradiation), newer forms of irradiation, and hormonal therapy alone are being tested, as is neoadjuvant and adjuvant chemotherapy. Neoadjuvant and adjuvant androgen deprivation therapy combined with external beam radiation therapy have demonstrated improved survival compared with external beam radiation therapy alone.
G. Metastatic Disease Since death due to prostate carcinoma is almost invariably the result of failure to control metastatic disease, research has emphasized efforts to improve control of distant disease. It is well known that most prostate carcinomas are hormone dependent and approximately 70–80% of men with metastatic prostate carcinoma will respond to various forms of androgen deprivation. Androgen deprivation may be affected at several levels along the pituitary–gonadal axis using a variety of methods or agents (Table 39–8). Use of luteinizing hormone-releasing hormone (LHRH) agonists (leuprolide, goserelin) achieves androgen deprivation without orchiectomy or administration of diethylstilbestrol and is currently the most common method of reducing testosterone levels. A single LHRH antagonist (degarelix) is FDA approved and has no short-term testosterone “flare” associated with LHRH agonists. Because of its rapid onset of action, ketoconazole should be considered in patients with advanced prostate cancer who present with spinal cord compression, bilateral ureteral obstruction, or disseminated intravascular coagulation. Although testosterone is the major circulating androgen, the adrenal gland secretes the androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. Some investigators believe that suppressing both testicular and adrenal androgens allows for a better initial and longer response than methods that only inhibit production of testicular androgens. Complete androgen blockade can be achieved by combining an antiandrogen with use of an LHRH agonist/antagonist or orchiectomy. Nonsteroidal antiandrogen agents appear to act by competitively binding the receptor for dihydrotestosterone, the intracellular androgen responsible for prostate cell growth and development. A meta-analysis of trials comparing the use of either an LHRH agonist or orchiectomy alone with the use of either in combination with an antiandrogen agent shows little benefit of combination therapy. However, patients at risk for disease-related symptoms (bone pain, obstructive voiding symptoms) due to the initial elevation of serum testosterone that accompanies the use of an LHRH agonist should receive antiandrogens initially. Bisphosphonates can prevent osteoporosis associated with androgen deprivation, decrease bone pain from metastases, and reduce skeletal related events. Denosumab, a RANK ligand inhibitor, is approved for the prevention of skeletal-related events in patients with bone metastases from prostate cancer and also appears to delay the development of these metastases. Docetaxel is the first cytotoxic chemotherapy agent to improve survival in patients with hormone-refractory
Table 39–8. Androgen deprivation for prostatic cancer. Level Pituitary, hypothalamus
1–3 mg orally daily
Gynecomastia, hot flushes, thromboembolic disease, erectile dysfunction
LHRH agonists Leuprolide Goserelin
Monthly or 3-monthly depot injection
Erectile dysfunction, hot flushes, gynecomastia, rarely anemia
240 mg subcutaneously initial dose, then 80 mg subcutaneously monthly
Hot flushes, weight gain, erectile dysfunction, increased liver function tests
400 mg three times orally daily
Adrenal insufficiency, nausea, rash, ataxia
250 mg four times orally daily
Adrenal insufficiency, nausea, rash, ataxia
20–40 mg orally daily
Gastrointestinal bleeding, fluid retention
CYP17a1 inhibitor Abiraterone
500 mg orally daily
Weight gain, fluid retention, hypokalemia, hypertension
LHRH antagonist Degarelix Adrenal
Antiandrogens Flutamide Bicalutamide
Gynecomastia, hot flushes, erectile dysfunction 250 mg three times orally daily 50 mg orally daily
No erectile dysfunction when used alone; nausea, diarrhea
LHRH, luteinizing-hormone-releasing hormone.
prostate cancer. Current research is underway combining docetaxel with androgen deprivation therapy, radiation therapy, and surgery to determine whether combinations are effective in patients with high-risk prostate cancer. Immune therapies are also under investigation and have shown promise for patients with advanced prostate cancer. Sipuleucel-T, an autologous cellular immunotherapy, is FDA approved in asymptomatic or minimally symptomatic men with metastatic hormone-refractory prostate cancer. Other agents—cabazitaxel and abiraterone—are also approved for advanced prostate cancer after clinical trials have demonstrated improvements in survival in men having received prior docetaxel, and it is expected that MDV3100, cabozantinib, and alpharadin will be approved shortly.
recurrence 3 and 5 years after radical prostatectomy (Tables 39–9 and 39–10). The CAPRA has been validated on large multicenter and international radical prostatectomy cohorts.
Table 39–9. The UCSF Cancer of the Prostate Risk Assessment (CAPRA). Variable PSA (ng/mL)
T1 or T2
% positive biopsies (biopsy cores positive divided by the number of biopsies obtained)
< 50 years
> 50 years
``Prognosis The likelihood of success of surveillance or treatment can be predicted using risk assessment tools that usually combine stage, grade, PSA level, and number and extent of positive prostate biopsies. Several tools are available on the Internet (eg, http://mskcc.org/mskcc/html/5794.cfm). One of the most widely used is the Kattan nomogram; it incorporates tumor stage, grade, and PSA level to predict the likelihood that a patient will be disease-free after radical prostatectomy or radiation therapy. The University of California San Francisco CAPRA nomogram uses serum PSA, Gleason grade, clinical stage, percent positive biopsies, and patient age in a point system to risk stratify and predict the likelihood of PSA
Table 39–10. CAPRA: Probability of freedom from PSA recurrence after radical prostatectomy by CAPRA point total.
3-Year Recurrence Free Survival (%) (95% CI)
5-Year Recurrence Free Survival (%) (95% CI)
PSA, prostate-specific antigen.
The patterns of prostate cancer progression have been well defined. Small and well-differentiated cancers (Gleason grades 1 and 2) are usually confined within the prostate, whereas large-volume (> 4 mL) or poorly differentiated (Gleason grades 4 and 5) cancers are more often locally extensive or metastatic to regional lymph nodes or bone. Penetration of the prostate capsule by cancer is common and occurs along perineural spaces. Seminal vesicle invasion is associated with a high likelihood of regional or distant disease, and disease recurrence. Lymphatic metastases can be identified in the obturator and internal iliac lymph node chains. The axial skeleton, as mentioned previously, is the most common site of distant metastases.
``When to Refer • All patients should be referred to an urologist. PSA remains integral in prostate cancer diagnosis. Low-risk disease may be managed by active surveillance, surgery, or radiation therapy. • High-risk disease often requires multimodal treatment strategies. Albertsen PC et al. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA. 2005 May 4;293(17):2095–101. [PMID: 15870412] Andriole GL et al; PLCO Project Team. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012 Jan 18;104(2):125–32. [PMID: 22228146] Andriole GL et al; REDUCE Study Group. Effect of dutasteride on the risk of prostate cancer. N Engl J Med. 2010 Apr 1;362(13):1192–202. [PMID: 20357281] Bill-Axelson A et al; Scandinavian Prostate Cancer Study Group No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005 May 12;352(19):1977–84. [PMID: 15888698]
Dall’Era MA et al. Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer. 2008 Jun 15;112(12):2664–70. [PMID: 18433013] Freedland SJ et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005 Jul 27;294(4):433–9. [PMID: 16046649] Hugosson J et al. Mortality results from the Göteborg randomized population-based prostate-cancer screening trial. Lancet Oncol. 2010 Aug 11(8):725–32. [PMID: 20598634] Meng MV et al. Treatment of patients with high risk localized prostate cancer: results from cancer of the prostate strategic urological research endeavor (CaPSURE). J Urol. 2005 May; 173(5):1557–61. [PMID: 15821485] Schröder FH et al; ERSPC Investigators. Screening and prostatecancer mortality in a randomized European study. N Engl J Med. 2009 Mar;360(13):1320–8. [PMID: 19297566] Thompson IM et al. Prediction of prostate cancer for patients receiving finasteride: results from the Prostate Cancer Prevention Trial. J Clin Oncol. 2007 Jul 20;25(21):3076–81. [PMID: 17634486] Trock BJ et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008 Jun 18;299(23):2760–9. [PMID: 18560003] Walsh PC et al. Clinical practice. Localized prostate cancer. N Engl J Med. 2007 Dec 27;357(26):2696–705. [PMID: 18160689] Zeller JL et al. JAMA patient page. Prostate cancer. JAMA. 2008 Jul 9;300(2):236. [PMID: 18612121]
E ssent i a l s o f d i a g nos i s
Gross or microscopic hematuria. Irritative voiding symptoms. Positive urinary cytology in most patients. Filling defect within bladder noted on imaging.
`` `` `` ``
``General Considerations Bladder cancer is the second most common urologic cancer; it occurs more commonly in men than women (3.1:1), and the mean age of patients at diagnosis is 73 years. Cigarette smoking and exposure to industrial dyes or solvents are risk factors for the disease and account for approximately 60% and 15% of new cases, respectively. Ninety-eight percent of primary bladder cancers are epithelial malignancies, with the majority being urothelial cell carcinomas (90%). Adenocarcinomas and squamous cell cancers account for approximately 2% and 7%, respectively, of all bladder cancers detected in the United States. The latter is often associated with schistosomiasis, vesical calculi, or prolonged catheter use.
``Clinical Findings A. Symptoms and Signs Hematuria—gross or microscopic, chronic or intermittent—is the presenting symptom in 85–90% of patients with bladder cancer (also see the section on Hematuria, in
Cancer Chapter 23). Irritative voiding symptoms (urinary frequency and urgency) occur in a small percentage of patients as a result of the location or size of the cancer. Most patients with bladder cancer do not have signs of the disease because of its superficial nature. Abdominal masses detected on bimanual examination may be present in patients with large-volume or deeply infiltrating cancers. Hepatomegaly or palpable lymphadenopathy may be present in patients with metastatic disease, and lymphedema of the lower extremities may be present as a result of locally advanced cancers or metastases to pelvic lymph nodes.
B. Laboratory Findings Urinalysis reveals microscopic or gross hematuria in the majority of cases. On occasion, hematuria may be accompanied by pyuria. Azotemia may be present in a small number of cases associated with ureteral obstruction. Anemia may occasionally be due to chronic blood loss or to bone marrow metastases. Exfoliated cells from normal and abnormal urothelium can be readily detected in voided urine specimens. Cytology can be useful in detecting the disease at the time of initial presentation or to detect recurrence. Cytology is sensitive in detecting cancers of higher grade and stage (80–90%) but less so in detecting superficial or welldifferentiated lesions (50%). There are numerous urinary tumor markers under investigation for screening, assessing recurrence, progression, prognosis or response to therapy; the NMP22 point-of-care assay for a specific urinary protein has shown utility in detecting recurrent tumors.
C. Imaging Bladder cancers may be identified using ultrasound, CT, or MRI where masses within the bladder are noted. However, the presence of cancer is confirmed by cystoscopy and biopsy, with imaging primarily used to evaluate the upper urinary tract and stage more advanced lesions.
D. Cystourethroscopy and Biopsy The diagnosis and staging of bladder cancers are made by cystoscopy and transurethral resection. If cystoscopy— performed usually under local anesthesia—confirms the presence of bladder cancer, the patient is scheduled for transurethral resection under general or regional anesthesia. Random bladder and, on occasion, prostate urethral biopsies are performed to detect occult disease elsewhere in the bladder and potentially identify patients at greater risk for tumor recurrence and progression.
``Pathology & Staging Grading is based on cellular features: size, pleomorphism, mitotic rate, and hyperchromatism. Bladder cancer staging is based on the extent of bladder wall penetration and the presence of regional or distant metastases. The natural history of bladder cancer is based on two separate but related processes: tumor recurrence within the bladder and progression to higher-stage disease. Both are correlated with tumor grade and stage.
``Treatment Patients with superficial cancers (Ta, T1) are treated with complete transurethral resection and selective use of intravesical chemotherapy. In the subset of patients with large, high-grade, recurrent Ta lesions or T1 cancers and those with carcinoma in situ are good candidates for adjuvant intravesical therapy. Patients with invasive (T2, T3) but still localized cancers are at risk for both nodal metastases and progression and require radical cystectomy, irradiation, or the combination of chemotherapy and selective surgery or irradiation due to the much higher risk of progression compared with patients with lower-stage lesions. For patients with muscle invasive (T2 or greater) transitional cell carcinoma, neoadjuvant systemic chemotherapy prior to radical cystectomy is superior to radical cystectomy alone. This is particularly important for higher stage or bulky tumors in order to improve their surgical resectability.
A. Intravesical Chemotherapy Immunotherapeutic or chemotherapeutic agents delivered directly into the bladder via a urethral catheter can reduce the likelihood of recurrence in those who have undergone complete transurethral resection. Most agents are administered weekly for 6–12 weeks. Efficacy may be increased by prolonging contact time to 2 hours. The use of maintenance therapy after the initial induction regimen is beneficial. Common agents include thiotepa, mitomycin, doxorubicin, and BCG, the last being the most effective agent when compared with the others with respect to reducing disease progression. Side effects of intravesical chemotherapy include irritative voiding symptoms and hemorrhagic cystitis. Patients in whom symptoms or infection develop from BCG may require antituberculous therapy.
B. Surgical Treatment Although transurethral resection is the initial form of treatment for all bladder tumors since it is diagnostic, allows for proper staging, and controls superficial cancers, muscle-infiltrating cancers require more aggressive treatment. Partial cystectomy is indicated in selected patients with solitary lesions or those with cancers in a bladder diverticulum. Radical cystectomy entails removal of the bladder, prostate, seminal vesicles, and surrounding fat and peritoneal attachments in men and the uterus, cervix, urethra, anterior vaginal vault, and usually the ovaries in women. Bilateral pelvic lymph node dissection is performed in all patients. Urinary diversion can be performed using a conduit of small or large bowel. However, continent forms of diversion have been developed that avoid the necessity of an external appliance and can be considered in a significant number of patients.
C. Radiotherapy External beam radiotherapy delivered in fractions over a 6- to 8-week period is generally well tolerated, but approximately 10–15% of patients will develop bladder,
bowel, or rectal complications. Local recurrence is common after radiotherapy alone (30–70%) and is therefore combined with systemic chemotherapy in an effort to reduce the need for radical cystectomy or to treat patients who are poor candidates for radical cystectomy.
D. Chemotherapy Metastatic disease is present in 15% of patients with newly diagnosed bladder cancer, and metastases develop within 2 years in up to 40% of patients who were believed to have localized disease at the time of cystectomy or definitive radiotherapy. Cisplatin-based combination chemotherapy results in partial or complete responses in 15–45% of patients (see Table 39–4). Combination chemotherapy has been integrated into trials of surgery and radiotherapy. It has been used to decrease recurrence rates with both modalities and to attempt bladder preservation in those treated with radiation. Chemotherapy should be considered before surgery in those with bulky lesions or those suspected of having regional disease, and recent evidence suggests that neoadjuvant chemotherapy may benefit all patients with muscle-invasive disease prior to planned cystectomy. Chemoradiation is best suited for those with T2 or limited T3 disease without ureteral obstruction. Alternatively, chemotherapy has been used after cystectomy in patients at high risk for recurrence, such as those who have lymph node involvement or local invasion.
``Prognosis The frequency of recurrence and progression are correlated with grade. Whereas progression may be noted in few grade I cancers (19–37%), it is common with poorly differentiated lesions (33–67%). Carcinoma in situ is most often found in association with papillary bladder cancers. Its presence identifies patients at increased risk for recurrence and progression. At initial presentation, approximately 50–80% of bladder cancers are superficial: stage Ta, Tis, or T1. When properly treated, lymph node metastases and progression are uncommon in this population and survival is excellent at 81%. Five-year survival of patients with T2 and T3 disease ranges from 50% to 75% after radical cystectomy. Long-term survival for patients with metastatic disease at presentation is rare.
``When to Refer • All patients should be referred to an urologist. Hematuria often deserves evaluation with upper urinary tract imaging and cystoscopy, particularly in a high-risk group (ie, older men). • Histologic diagnosis and staging require endoscopic resection of tumor. Grossman HB et al. Surveillance for recurrent bladder cancer using a point-of-care proteomic assay. JAMA. 2006 Jan 18; 295(3):299–305. [PMID: 16418465]
International Collaboration of Trialists et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011 Jun 1;29(16):2171–7. [PMID: 21502557] Parekh DJ et al. Superficial and muscle-invasive bladder cancer: principles of management for outcomes assessments. J Clin Oncol. 2006 Dec 10;24(35):5519–27. [PMID: 17158537] Stenzl A et al. Treatment of muscle-invasive and metastatic bladder cancer: update of the EAU guidelines. Eur Urol. 2011 Jun;59(6):1009–18. [PMID: 21454009] Yafi FA et al. Contemporary outcomes of 2287 patients with bladder cancer who were treated with radical cystectomy: a Canadian multicentre experience. BJU Int. 2011 Aug;108(4): 539–45. [PMID: 21166753]
CANCERS OF THE URETER & RENAL PELVIS Cancers of the renal pelvis and ureter are rare and occur more commonly in patients with bladder cancer, smokers, those with Balkan nephropathy, those exposed to Thorotrast (a contrast agent with radioactive thorium in use until the 1960s), or those with a long history of analgesic abuse. The majority are urothelial cell carcinomas. Gross or microscopic hematuria is present in most patients, and flank pain secondary to bleeding and obstruction occurs less commonly. Like primary bladder tumors, urinary cytology is often positive. The most common signs identified at the time of intravenous urography or CT include an intraluminal filling defect, unilateral nonvisualization of the collecting system, and hydronephrosis. Ureteral and renal pelvic tumors must be differentiated from calculi, blood clots, papillary necrosis, or inflammatory and infectious lesions. On occasion, upper urinary tract lesions are accessible for biopsy, fulguration, or resection using a ureteroscope. Treatment is based on the site, size, grade, depth of penetration, and number of tumors present. Most are excised with laparoscopic or open nephroureterectomy (renal pelvic and upper ureteral lesions) or segmental excision of the ureter (distal ureteral lesions). Endoscopic resection may be indicated in patients with limited renal function or focal, low-grade, cancers.
RENAL CELL CARCINOMA
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Gross or microscopic hematuria. Flank pain or mass in some patients. Systemic symptoms such as fever, weight loss may be prominent. Solid renal mass on imaging.
`` `` ``
``General Considerations Renal cell carcinoma accounts for 2.6% of all adult cancers. In the United States, approximately 60,000 cases of renal cell carcinoma are diagnosed and 12,500 deaths result
Cancer annually. Renal cell carcinoma has a peak incidence in the sixth decade of life and a male-to-female ratio of 2:1. It may be associated with a number of paraneoplastic syndromes (see below and Table 39–2). The cause is unknown. Cigarette smoking is the only significant environmental risk factor that has been identified. Familial settings for renal cell carcinoma have been identified (von Hippel–Lindau syndrome, hereditary papillary renal cell carcinoma, hereditary leiomyoma-renal cell carcinoma, Birt-Hogg-Dube syndrome) as well as an association with dialysis-related acquired cystic disease and specific genetic aberrations (eg, Xp11.2 translocation), but sporadic tumors are far more common. Renal cell carcinoma originates from the proximal tubule cells. Various histologic cell types are recognized (clear cell, papillary, chromophobe, collecting duct and sarcomatoid).
``Clinical Findings A. Symptoms and Signs Historically, 60% of patients presented with gross or microscopic hematuria. Flank pain or an abdominal mass was detected in approximately 30% of cases. The triad of flank pain, hematuria, and mass was found in only 10–15% of patients and is often a sign of advanced disease. Fever may be present as a paraneoplastic symptom (see Table 39–2). Symptoms of metastatic disease (cough, bone pain) occur in 20–30% of patients at presentation. Because of the widespread use of ultrasound and CT scanning, renal tumors are frequently detected incidentally in individuals with no urologic symptoms. There has been profound stage migration toward lower stages of disease over the past 10 years, likely due to the increased use of abdominal imaging. However, population mortality rates remain stable.
B. Laboratory Findings Hematuria is present in 60% of patients. Erythrocytosis from increased erythropoietin production occurs in 5%, though anemia is more common; hypercalcemia may be present in up to 10% of patients. Stauffer syndrome is a reversible syndrome of hepatic dysfunction (with elevated liver function tests) in the absence of metastatic disease.
C. Imaging Solid renal masses are often first identified by abdominal ultrasonography or CT. CT and MRI scanning are the most valuable imaging tests for renal cell carcinoma. It confirms the character of the mass and further stages the lesion with respect to regional lymph nodes, renal vein, or hepatic involvement. CT and MRI also provide valuable information regarding the contralateral kidney (function, bilaterality of neoplasm). Chest radiographs exclude pulmonary metastases, and bone scans should be performed for large tumors and in patients with bone pain or elevated alkaline phosphatase levels. MRI and duplex Doppler ultrasonography are excellent methods of assessing for the presence and extent of tumor thrombus within the renal vein or vena cava.
``Differential Diagnosis Solid lesions of the kidney are renal cell carcinoma until proved otherwise. Other solid masses include angiomyolipomas (fat density usually visible by CT), urothelial cell cancers of the renal pelvis (more centrally located, involvement of the collecting system, positive urinary cytologic tests), adrenal tumors (superoanterior to the kidney) and oncocytomas (indistinguishable from renal cell carcinoma preoperatively), and renal abscesses.
``Treatment Surgical expiration is the primary treatment for localized renal cell carcinoma. Patients with a single kidney, bilateral lesions, or significant medical renal disease should be considered for partial nephrectomy. Patients with a normal contralateral kidney and good renal function but a small cancer are also candidates for partial nephrectomy, while radical nephrectomy is indicated in cases of larger tumors (> 7 cm) and those where partial nephrectomy is not technically feasible. The use of radiofrequency or cryosurgical ablation is being studied and likely yield equivalent shortterm oncologic outcomes with reduced morbidity. No effective chemotherapy is available for metastatic renal cell carcinoma. Vinblastine is the single most efficacious agent, with short-term partial response rates of 15%. Bevacizumab can prolong time to progression in those with metastatic disease (see Table 39–4). Biologic response modifiers have received much attention, including interferon-α and interleukin-2. Partial response rates of 15–20% and 15–35%, respectively, have been reported. Responders tend to have lower tumor burdens, metastatic disease confined to the lung, and a high performance status. Patients with metastatic kidney cancer and good performance status who have resectable primary tumors should undergo cytoreductive nephrectomy. Two randomized trials have shown a survival benefit of surgery followed by the use of systemic therapy—specifically, biologic response modifiers—compared with the use of systemic therapy alone. Several targeted drugs, specifically VEGF, Raf-kinase, and mTOR inhibitors, are effective (40% response rates) in patients with advanced kidney cancer. The drugs are oral agents, well tolerated, and particularly active for clear cell carcinoma. The appropriate timing and combination of these agents, with and without surgery and cytokine therapy, remains to be determined.
``Prognosis After radical or partial nephrectomy, tumors confined to the renal capsule (T1–T2) demonstrate 5-year disease-free survivals of 90–100%. Tumors extending beyond the renal capsule (T3 or T4) and node-positive tumors have 50–60% and 0–15% 5-year disease-free survival, respectively. One subgroup of patients with nonlocalized disease has reasonable long-term survival, namely, those with solitary resectable metastases. In this setting, radical nephrectomy with resection of the metastasis results in 5-year disease-free survival rates of 15–30%.
``When to Refer • Patients with solid renal masses or complex cysts require further evaluation and should be referred to an urologist. • Surgical excision of renal cell carcinoma remains the gold standard. • Patients with metastatic disease should be referred to an oncologist. Antonelli A et al. Elective partial nephrectomy is equivalent to radical nephrectomy in patients with clinical T1 renal cell carcinoma: results of a retrospective, comparative, multi-institutional study. BJU Int. 2012 Apr;109(7):1013–8. [PMID: 21883829] Escudier B et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007 Jan 11;356(2):125–34. [PMID: 17215530] Flanigan RC et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renalcell cancer. N Engl J Med. 2001 Dec 6;345(23):1655–9. [PMID: 11759643] Heng DY et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009 Dec 1;27(34): 5794–9. [PMID: 19826129] Hudes G et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271–81. [PMID: 17538086] Motzer RJ et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006 Jun 7;295(21):2516–24. [PMID: 15479931] Rini BI et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011 Dec 3;378(9807):1931–9. [PMID: 22056247]
OTHER PRIMARY TUMORS OF THE KIDNEY Oncocytomas account for 3–5% of renal tumors, are usually benign, and are indistinguishable from renal cell carcinoma on preoperative imaging. These tumors are seen in other organs, including the adrenals, salivary glands, and thyroid and parathyroid glands. Angiomyolipomas are rare benign tumors composed of fat, smooth muscle, and blood vessels. They are most commonly seen in patients with tuberous sclerosis (often multiple and bilateral) or in young to middle-aged women. CT scanning may identify the fat component, which is diagnostic for angiomyolipoma. Asymptomatic lesions < 5 cm in diameter usually do not require intervention; large lesions can spontaneously bleed. Acute bleeding can be treated by angiographic embolization or, in rare cases, nephrectomy. Lesions over 5 cm are often prophylactically treated with angioembolization to reduce the risk of bleeding.
SECONDARY TUMORS OF THE KIDNEY The kidney is not an infrequent site for metastatic disease. Of the solid tumors, lung cancer is the most common (20%), followed by breast (10%), stomach (10%), and the contralateral kidney (10%). Lymphoma, both Hodgkin and non-Hodgkin, may also involve the kidney, although
it tends to appear as a diffusely infiltrative process resulting in renal enlargement rather than a discrete mass.
PRIMARY TUMORS OF THE TESTIS
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Most common neoplasm in men aged 20–35 years. Patient typically discovers a painless nodule. Orchiectomy necessary for diagnosis.
``General Considerations Malignant tumors of the testis are rare, with approximately five to six cases per 100,000 males reported in the United States each year. Ninety to 95 percent of all primary testicular tumors are germ cell tumors and can be divided into two major categories: nonseminomas, including embryonal cell carcinoma (20%), teratoma (5%), choriocarcinoma (< 1%), and mixed cell types (40%); and seminomas (35%). The remainder of primary testicular tumors are nongerminal neoplasms (Leydig cell, Sertoli cell, gonadoblastoma). The lifetime probability of developing testicular cancer is 0.3% for an American male. For the purposes of this review, only germ cell tumors will be considered. Approximately 5% of testicular tumors develop in a patient with a history of cryptorchism, with seminoma being the most common. However, 5–10% of these tumors occur in the contralateral, normally descended testis. The relative risk of development of malignancy is highest for the intra-abdominal testis (1:20) and lower for the inguinal testis (1:80). Placement of the cryptorchid testis into the scrotum (orchidopexy) does not alter the malignant potential of the cryptorchid testis but does facilitate routine examination and tumor detection. Testicular cancer is slightly more common on the right than the left, paralleling the increased incidence of cryptorchidism on the right side. One to 2 percent of primary testicular tumors are bilateral and up to 50% of these men have a history of unilateral or bilateral cryptorchidism. Primary bilateral testicular tumors may occur synchronously or asynchronously but tend to be of the same histology. Seminoma is the most common histologic finding in bilateral primary testicular tumors, while malignant lymphoma is the most common bilateral testicular tumor overall. In animal models, exogenous estrogen administration during pregnancy has been associated with an increased development of testicular tumors with relative risk ranging from 2.8 to 5.3. Other acquired factors such as trauma and infection-related testicular atrophy have been associated with testicular tumors; however, a causal relationship has not been established.
``Clinical Findings A. Symptoms and Signs The most common symptom of testicular cancer is painless enlargement of the testis. Sensations of heaviness are
Cancer not unusual. Patients are usually the first to recognize an abnormality, yet the typical delay in seeking medical attention ranges from 3 to 6 months. Acute testicular pain resulting from intratesticular hemorrhage occurs in approximately 10% of cases. Ten percent of patients are asymptomatic at presentation, and 10% manifest symptoms relating to metastatic disease such as back pain (retroperitoneal metastases), cough (pulmonary metastases), or lower extremity edema (vena cava obstruction). A discrete mass or diffuse testicular enlargement is noted in most cases. Secondary hydroceles may be present in 5–10% of cases. In advanced disease, supraclavicular adenopathy may be present, and abdominal examination may reveal a mass. Gynecomastia is seen in 5% of germ cell tumors.
B. Laboratory Findings Several serum markers are important in the diagnosis and monitoring of testicular carcinoma, including human chorionic gonadotropin (hCG), α-fetoprotein, and lactate dehydrogenase. α-Fetoprotein is never elevated with pure seminomas, and while hCG is occasionally elevated in seminomas, levels tend to be lower than those seen with nonseminomas. Lactate dehydrogenase may be elevated with either type of tumor. Liver function tests may be elevated in the presence of hepatic metastases, and anemia may be present in advanced disease.
C. Imaging Scrotal ultrasound can readily determine whether a mass is intratesticular or extratesticular. Once the diagnosis of testicular cancer has been established by inguinal orchiectomy, clinical staging of the disease is accomplished by chest, abdominal, and pelvic CT scanning.
``Staging In a commonly used staging system for nonseminoma germ cell tumors, a stage A lesion is confined to the testis; stage B demonstrates regional lymph node involvement in the retroperitoneum; and stage C indicates distant metastasis. For seminoma, the M.D. Anderson system is commonly used. In this system, a stage I lesion is confined to the testis, a stage II lesion has spread to the retroperitoneal lymph nodes, and a stage III lesion has supradiaphragmatic nodal or visceral involvement.
``Differential Diagnosis An incorrect diagnosis is made at the initial examination in up to 25% of patients with testicular tumors. Scrotal ultrasonography should be performed if any uncertainty exists with respect to the diagnosis. Although most intratesticular masses are malignant, a benign lesion—epidermoid cyst— may rarely be seen. Epidermoid cysts are usually very small benign nodules located just underneath the tunica albuginea; occasionally, however, they can be large.
``Treatment Inguinal exploration with early vascular control of the spermatic cord structures is the initial intervention. If cancer
cannot be excluded by examination of the testis, radical orchiectomy is warranted. Scrotal approaches and open testicular biopsies should be avoided. Further therapy depends on the histology of the tumor as well as the clinical stage. Up to 75% of clinical stage I nonseminomas are cured by orchiectomy alone. Selected patients who meet specific criteria may be offered surveillance after orchiectomy. These criteria are as follows: (1) tumor is confined within the tunica albuginea; (2) tumor does not demonstrate vascular invasion; (3) tumor markers normalize after orchiectomy; (4) radiographic imaging of the chest and abdomen shows no evidence of disease; and (5) the patient is reliable. Patients most likely to experience relapse on a surveillance regimen include those with predominantly embryonal cancer and those with vascular or lymphatic invasion identified in the orchiectomy specimen. Stage I and IIa/b seminomas (retroperitoneal disease < 2 cm/2–5 cm in diameter) are treated by radical orchiectomy and retroperitoneal irradiation. Patients with clinical stage I disease may be candidates for surveillance or singleagent carboplatin. Seminomas of stage IIc (> 5 cm retroperitoneal involvement) and stage III receive primary chemotherapy (etoposide and cisplatin or cisplatin, etoposide, and bleomycin) (Table 39–4). Surgical resection of residual retroperitoneal masses is warranted if the mass is > 3 cm in diameter, under which circumstances 40% will harbor residual carcinoma. Surveillance needs to be considered an active process both by the clinician and by the patient. Patients are followed monthly for the first 2 years and bimonthly in the third year. Tumor markers are obtained at each visit, and chest radiographs and CT scans are obtained every 3 months. Follow-up continues beyond the initial 3 years; however, 80% of relapses will occur within the first 2 years. With rare exceptions, patients who relapse can be cured by chemotherapy or surgery. Alternatives to surveillance for clinical stage I nonseminoma include adjuvant chemotherapy (bleomycin, etoposide, cisplatin) (see Table 39–4) or retroperitoneal lymph nodes dissection. Patients with bulky retroperitoneal disease (> 5 cm nodes) or metastatic nonseminomas are treated with primary cisplatin-based combination chemotherapy following orchiectomy (etoposide and cisplatin or cisplatin, etoposide, and bleomycin). If tumor markers normalize and a residual mass > 1 cm persists on imaging studies, the mass is resected because 15–20% of the time it will harbor viable cancer and 40% of the time it will harbor teratoma. Even if patients have a complete response to chemotherapy, some clinicians advocate retroperitoneal lymphadenectomy since 10% of patients may harbor residual carcinoma and 10% may have teratoma in the retroperitoneum. If tumor markers fail to normalize following primary chemotherapy, salvage chemotherapy is required (cisplatin, etoposide, ifosfamide).
``Prognosis The 5-year disease-free survival rate for patients with stage A nonseminomas (includes all treatments) ranges from 96% to 100%. For low-volume stage B disease, 90% 5-year
disease-free survival is expected. The 5-year disease-free survival rates for stage I and IIa seminomas (retroperitoneal disease < 10 cm in diameter) treated by radical orchiectomy and retroperitoneal irradiation are 98% and 92–94%, respectively. Ninety-five percent of patients with stage III disease attain a complete response following orchiectomy and chemotherapy. Patients with bulky retroperitoneal or disseminated disease treated with primary chemotherapy followed by surgery have a 5-year diseasefree survival rate of 55–80%.
SPINAL CORD COMPRESSION
Patients with solid masses of the testis should be referred to a urologist. Albers P et al. Randomized phase III trial comparing retroperitoneal lymph node dissection with one course of bleomycin and etoposide plus cisplatin chemotherapy in the adjuvant treatment of clinical stage I nonseminomatous testicular germ cell tumors: AUO trial AH 01/94 by the German Testicular Cancer Study Group. J Clin Oncol. 2008 Jun 20;26(18):2966–72. [PMID: 18458040] Albers P et al; European Association of Urology. EAU guidelines on testicular cancer: 2011 update. Eur Urol. 2011 Aug;60(2): 304–19. [PMID: 21632173] Aparicio J et al. Risk-adapted treatment in clinical stage I testicular seminoma: the third Spanish Germ Cell Cancer Study Group. J Clin Oncol. 2011 Dec 10;29(35):4677–81. [PMID: 22042940] Einhorn LH et al. High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med. 2007 Jul 26; 357(4):340–8. [PMID: 17652649] Oliver RT et al. Randomized trial of carboplatin versus radiotherapy for stage I seminoma: mature results on relapse and contralateral testis cancer rates in MRC TE19/EORTC 30982 study (ISRCTN27163214). J Clin Oncol. 2011 Mar 10;29(8):957–62. [PMID: 21282539] Pettersson A et al. Age at surgery for undescended testis and risk of testicular cancer. N Engl J Med. 2007 May 3;356(18):1835–41. [PMID: 17476009] Tandstad T et al. Risk-adapted treatment in clinical stage I nonseminomatous germ cell testicular cancer: the SWENOTECA management program. J Clin Oncol. 2009 May 1;27(13): 2122–8. [PMID: 19307506] Torpy JM et al. JAMA patient page. Testicular cancer. JAMA. 2008 Feb 13;299(6):718. [PMID: 18270362]
SECONDARY TUMORS OF THE TESTIS Secondary tumors of the testis are rare. In men over the age of 50 years, lymphoma is the most common testis tumor, and overall it is the most common secondary neoplasm of the testis, accounting for 5% of all testicular tumors. It may be seen in three clinical settings: (1) late manifestation of widespread lymphoma, (2) the initial presentation of clinically occult disease, and (3) primary extranodal disease. Radical orchiectomy is indicated to make the diagnosis. Prognosis is related to the stage of disease. Metastasis to the testis is rare. The most common primary site of origin is the prostate, followed by the lung, gastrointestinal tract, melanoma, and kidney.
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Complication of metastatic solid tumor, lymphoma, or multiple myeloma. Back pain is most common presenting symptom. Prompt diagnosis is essential because once a severe neurologic deficit develops, it is often irreversible. Emergent treatment may prevent or potentially reverse paresis and urinary and bowel incontinence.
``When to Refer
CANCER COMPLICATIONS & EMERGENCIES
``General Considerations Cancers that cause spinal cord compression most commonly metastasize to the vertebral bodies, resulting in physical damage to the spinal cord from edema, hemorrhage, and pressure-induced ischemia to the vasculature of the spinal cord. Persistent compression can result in irreversible changes to the myelin sheaths resulting in permanent neurologic impairment. Prompt diagnosis and therapeutic intervention are essential, since the probability of reversing neurologic symptoms largely depends on the duration of symptoms. Patients who are treated promptly after symptoms appear may have partial or complete return of function and, depending on tumor sensitivity to specific treatment, may respond favorably to subsequent anticancer therapy.
``Clinical Findings A. Symptoms and Signs Back pain at the level of the tumor mass occurs in over 80% of cases and may be aggravated by lying down, weight bearing, sneezing, or coughing; it usually precedes the development of neurologic symptoms or signs. Since involvement is usually epidural, a mixture of nerve root and spinal cord symptoms often develops. Progressive weakness and sensory changes commonly occur. Bowel and bladder symptoms progressing to incontinence are late findings. The initial findings of impending cord compression may be quite subtle, and there should be a high index of suspicion when back pain or weakness of the lower extremities develops in cancer patients.
B. Imaging MRI is usually the initial imaging procedure of choice in a cancer patient with new-onset back pain. When there are neurologic findings suggesting spinal cord compression, an emergent MRI should be obtained; the MRI should include a survey of the entire spine in order to define all areas of tumor involvement for treatment planning purposes.
Cancer Bone radiographs, if done, may show evidence of vertebral body or pedicle destruction by the cancer. However, bone radiographs are neither sensitive nor specific and therefore are not helpful in diagnosis or treatment planning. If the back pain symptoms are nonspecific, bone scan imaging may be useful as a screening procedure.
``Treatment Patients found to have epidural impingement of the spinal cord should be given corticosteroids immediately. The initial dexamethasone dose is 10–100 mg intravenously followed by 4–6 mg every 6 hours intravenously or orally. Patients without a known diagnosis of cancer should have emergent surgery to relieve the impingement and obtain a pathologic specimen. Patients with a single area of compression due to solid tumors are best treated with surgical decompression followed by radiation therapy. A randomized trial comparing surgery followed by radiation therapy with radiation therapy alone showed better outcomes (ie, improved ability to ambulate and improved bladder and bowel functions) in persons who had surgery followed by radiation therapy. If multiple vertebral body levels are involved with cancer, radiation therapy is the preferred treatment option. Corticosteroids are generally tapered toward the end of radiation therapy.
George R et al. Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD006716. [PMID: 18843728] Walji N et al. Common acute oncological emergencies: diagnosis, investigation and management. Postgrad Med J. 2008 Aug;84(994):418–27. [PMID: 18832403] White BD et al. Diagnosis and management of patients at risk of or with metastatic spinal cord compression: summary of NICE guidance. BMJ. 2008 Nov 27;337:a2538. [PMID: 19039017]
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Occur in pleural, pericardial, and peritoneal spaces. Caused by direct neoplastic involvement of serous surface or obstruction of lymphatic drainage. Half of undiagnosed effusions in patients not known to have cancer are malignant.
``General Considerations The development of an effusion in the pleural, pericardial, or peritoneal space may be the initial finding in a patient with cancer, or an effusion may appear during the course of disease progression. Direct involvement of the serous surface with tumor is the most frequent initiating cause of the accumulation of fluid. The most common malignancies
causing pleural and pericardial effusions are lung and breast cancers; the most common malignancies associated with malignant ascites are ovarian, colorectal, stomach, and pancreatic cancers.
``Clinical Findings A. Symptoms and Signs Patients with pleural and pericardial effusions complain of shortness of breath and orthopnea. Patients with ascites complain of abdominal distention and discomfort. Cardiac tamponade causing pressure equalization in the chambers impairing both filling and cardiac output can be a lifethreatening event. Signs of tamponade include tachycardia, pulsus paradoxus, and hypotension. Signs of pleural effusions include decreased breath sounds, egophony, and percussion dullness.
B. Laboratory Findings Malignancy is confirmed as the cause of an effusion when analysis of the fluid specimen shows malignant cells in either the cytology or cell block specimen.
C. Imaging The presence of effusions can be confirmed with radiographic studies or ultrasonography.
``Differential Diagnosis The differential diagnosis of a malignant exudative pleural or pericardial effusion includes nonmalignant processes, such as infection, pulmonary embolism, congestive heart failure, and trauma. Malignant effusions are rarely transudative. The differential diagnosis of malignant ascites includes similar benign processes, such as congestive heart failure and infections; cirrhosis and pancreatic disease also cause ascites. Bloody effusions are usually due to cancer, but a bloody pleural effusion can also be due to pulmonary embolism, trauma and, occasionally, infection. Chylous pleural or ascitic fluid is generally associated with obstruction of lymphatic drainage as might occur in lymphomas.
``Treatment In some cases, treatment of the underlying cancer with chemotherapy can cause regression of the effusions; however, not uncommonly, the presence of an effusion is an end-stage manifestation of the disease. In this situation, decisions regarding management are in large part dictated by the patient’s symptoms and goals of care.
A. Pleural Effusion A pleural effusion that is symptomatic may be managed initially with a large volume thoracentesis. With some patients, the effusion slowly reaccumulates, which allows
for periodic thoracentesis when the patient becomes symptomatic. However, in many patients, the effusion reaccumulates quickly, causing rapid return of symptoms of shortness of breath. For those patients, several options exist for management. Chest tube drainage followed by pleurodesis is the preferred option for patients with a reasonable life expectancy. The procedure involves placement of a chest tube that is connected to closed water seal drainage. After lung expansion is confirmed on a chest radiograph, a sclerosing agent (such as talc slurry or doxycycline) is injected into the catheter. Patients should be premedicated with analgesics and placed in a variety of positions in order to distribute the drug through the pleural spaces. Previously, injection of the sclerosing agent was done only after drainage had decreased to < 100 mL/d; but it is now clear that effective sclerosis can be achieved after 24 hours of drainage regardless of the amount of the residual fluid. Pleurodesis will not be successful if the lung cannot be reexpanded; these patients may be treated with the placement of a shunt or an indwelling catheter. Placement of an indwelling catheter that can be drained by a family member or a visiting nurse may also be preferable for patients with short life expectancies or for those who do not respond to pleurodesis.
B. Pericardial Effusion Fluid may be removed by a needle aspiration or by placement of a catheter for more thorough drainage. As with pleural effusions, most pericardial effusions will reaccumulate. Management options for recurrent, symptomatic effusions include catheter drainage followed by sclerosis with such agents as doxycycline or bleomycin or by pericardiectomy.
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Usually symptomatic and severe ( ≥ 15 mg/dL [> 3.75 mmol/L]). Most common paraneoplastic endocrine syndrome; accounts for most inpatients with hypercalcemia. The neoplasm is clinically apparent in nearly all cases when hypercalcemia is detected.
``General Considerations Hypercalcemia affects 20–30% of cancer patients at some point during their illness. The most common cancers causing hypercalcemia are myeloma, breast carcinoma, and non–small cell lung cancer. The presence of bone metastases is not an essential feature of the syndrome, since hypercalcemia can be caused by systemic effects of tumor-released proteins (see The Paraneoplastic Syndromes above).
``Clinical Findings A. Symptoms and Signs Symptoms and signs of hypercalcemia can be subtle; more severe symptoms occur with higher levels of hypercalcemia and with a rapid rate at which the calcium level rises. Early symptoms typically include anorexia, nausea, fatigue, constipation, and polyuria; later findings may include muscular weakness and hyporeflexia, confusion, psychosis, tremor, and lethargy.
B. Laboratory Findings C. Malignant Ascites Patients with malignant ascites not responsive to chemotherapy are generally treated with repeated large volume paracenteses. As the frequency of drainage to maintain comfort can compromise the patient’s quality of life, other alternatives include placement of a catheter or port so that the patient, family member, or visiting nurse can drain fluid as needed at home. Another option is placement of a peritoneovenous shunt; this can be considered for a select group of patients with life expectancy > 3 months and fluid that is nonviscous, nonbloody, and nonloculated. Becker G et al. Malignant ascites: systematic review and guideline for treatment. Eur J Cancer. 2006 Mar;42(5):589–97. [PMID: 16434188] Maisch B et al; Task Force on the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology. Guidelines on the diagnosis and management of pericardial diseases executive summary. Eur Heart J. 2004 Apr;25(7): 587–610. [PMID: 15120056] Roberts ME et al. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline, 2010. Thorax. 2010 Aug;65(Suppl 2):ii32–40. [PMID: 20696691]
Symptoms and signs are caused by free calcium; as calcium is bound by protein in the serum, the measured serum calcium will underestimate the free or ionized calcium in patients with low albumin levels. In the setting of hypo albuminemia, the corrected serum calcium should be calculated by one of several available formulas (eg, corrected calcium = measured calcium – measured albumin + 4). Alternatively, the free calcium can be measured. When the corrected serum calcium rises above 12 mg/dL (3 mmol/L), sudden death due to cardiac arrhythmia or asystole may occur. The presence of hypercalcemia does not invariably indicate a dismal prognosis, especially in patients with breast cancer, myeloma, or lymphoma. In the absence of signs or symptoms of hypercalcemia, a laboratory finding of elevated serum calcium should be retested immediately to exclude the possibility of error.
C. ECG Electrocardiography often shows a shortening of the QT interval.
``Treatment Emergency management should begin with the initiation of intravenous fluids with 0.9% saline at 100–200 mL/h to
Cancer ensure rehydration with brisk urinary output of the often volume-depleted patient. If kidney function is normal or only marginally impaired, a bisphosphonate should be given. Choices include pamidronate, 60–90 mg intravenously over 2–4 hours, or zoledronic acid, 4 mg intravenously over several minutes. Zoledronic acid is more potent than pamidronate and has the advantage of a shorter administration time as well as a longer duration of effect but is more associated with the uncommon but serious side effect of osteonecrosis of the jaw. Once hypercalcemia is controlled, treatment directed at the cancer should be initiated if possible. Commonly, though, hypercalcemia occurs in patients with cancers that are unresponsive to treatment. In the event that the hypercalcemia becomes refractory to repeated doses of bisphosphonates, other agents that can help control hypercalcemia (at least temporarily) include gallium nitrate, calcitonin, and mithra mycin; corticosteroids can be useful in patients with myeloma and lymphoma. Salmon calcitonin, 4–8 international units/kg given subcutaneously or intramuscularly every 12 hours, can be useful in patients with kidney disease; its onset of action is within hours but its hypocalcemic effect will wane in 2–3 days. Drake MT et al. Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc. 2008 Sep;83(9):1032–45. [PMID: 18775204] Mundy GR et al. PTH-related peptide (PTHrP) in hypercalcemia. J Am Soc Nephrol. 2008 Apr;19(4):672–5. [PMID: 18256357] Pelosof LC et al. Paraneoplastic syndromes: an approach to diagnosis and treatment. Mayo Clin Proc. 2010 Sep;85(9):838–54. [PMID: 20810794] Walji N et al. Common acute oncological emergencies: diagnosis, investigation and management. Postgrad Med J. 2008 Aug; 84(994):418–27. [PMID: 18832403]
HYPERURICEMIA & TUMOR LYSIS SYNDROME
E ssent i a l s o f d i a g nos i s
Complication of treatment-associated tumor lysis of hematologic and rapidly proliferating malignancies. May be worsened by thiazide diuretics. Rapid increase in serum uric acid can cause acute urate nephropathy from uric acid crystallization. Reducing pre-chemotherapy serum uric acid is fundamental to preventing urate nephropathy.
``General Considerations Tumor lysis syndrome (TLS) is seen most commonly following treatment of hematologic malignancies, such as acute lymphoblastic leukemia and Burkitt lymphoma. However, TLS can develop from any tumor highly sensitive to chemotherapy. TLS is caused by the massive release
of cellular material including nucleic acids, proteins, phosphorus, and potassium. If both the metabolism and excretion of these breakdown products are impaired, hyperuricemia, hyperphosphatemia, and hyperkalemia will develop abruptly. Acute kidney injury may then develop from the crystallization and deposition of uric acid and calcium phosphate within the renal tubules further exacerbating the hyperphosphatemia and hyperkalemia.
``Clinical Findings Symptoms of hyperphosphatemia include nausea and vomiting as well as seizures. Also, with high levels of phosphorus, co-precipitation with calcium can cause renal tubule blockage further exacerbating the kidney injury. Hyperkalemia, due to release of intracellular potassium and impaired kidney excretion, can cause arrhythmias and sudden death.
``Treatment Prevention is the most important factor in the management of TLS. Published guidelines for TLS management include aggressive hydration prior to initiation of chemotherapy as well as during and after completion of the chemotherapy. Administration of fluid helps keep urine flowing and facilitates excretion of uric acid and phosphorus. For the patients with moderate risk of developing TLS, for instance, those with intermediate grade lymphomas and acute leukemias, allopurinol (which blocks the enzyme xanthine oxidase and therefore the formation of uric acid from purine breakdown) should be given before starting chemotherapy at an oral dose of 100 mg/m2 every 8 hours (maximum 800 mg/d) with dose reductions for impaired kidney function. For patients at high risk for developing TLS, for instance, patients with high-grade lymphomas or patients with acute leukemias and markedly elevated white blood cell counts (with acute myeloid leukemia, white blood cell count > 50,000/mcL [> 50,000/109/L]; with acute lymphoblastic leukemia, white blood cell count > 100,000/mcL [> 100,000/109/L]) or in whom hyperuricemia develops despite treatment with allopurinol, rasburicase 0.1–0.2 mg/ kg/d is given intravenously for 1–7 days. Rasburicase is a recombinant urate oxidase that converts uric acid into the more soluble form resulting in rapid decline in uric acid levels. Rasburicase cannot be given to patients with known glucose 6-phosphate dehydrogenase (G6PD) deficiency nor can it be given to pregnant or lactating women. One of the mainstays of TLS management, systemic bicarbonate infusions to alkalinize the urine, is no longer routinely recommended. Laboratory values should be monitored following initiation of chemotherapy; elevated potassium or phosphorus levels need to be promptly managed.
``When to Refer Should urinary output drop, creatinine level rise, or hyperphosphatemia persist, a nephrologist should be immediately consulted to evaluate the need for dialysis.
Cairo MS et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010 May;149(4):578–86. [PMID: 20331465] Howard SC et al. The tumor lysis syndrome. N Engl J Med. 2011 May 12;364(19):1844–54. [PMID: 21561350]
INFECTIONS Chapter 30 provides a more detailed discussion of infections in the immunocompromised patient.
E ssent i a l s o f d i a g nos i s
In patients with neutropenia, infection is a medical emergency. The presence of fever, although sometimes attributable to other causes, must be assumed to be due to an infection.
``General Considerations Many patients with disseminated neoplasms have increased susceptibility to infection. In some patients, this results from impaired defense mechanisms (eg, acute leukemia, Hodgkin disease, multiple myeloma, chronic lymphocytic leukemia); in others, it results from the myelosuppressive and immunosuppressive effects of cancer chemotherapy or a combination of these factors. Complicating impaired defense mechanisms are the frequent presence of indwelling catheters, impaired mucosal surfaces, and colonization with more virulent hospital-acquired pathogens. The source of a neutropenic febrile episode is determined in about 30% of cases through blood, urine, or sputum cultures. The bacterial organisms accounting for the majority of infections in cancer patients include gramnegative bacteria (Escherichia coli, Klebsiella, Pseudomonas, Enterobacter) and gram-positive bacteria (coagulasenegative Staphylococcus, Staphylococcus aureus, Streptococcus pneumoniae, Corynebacterium, and streptococci). There has been a trend over the last few decades of an increasing percentage of gram-positive organisms. The risk of bacterial infections rises when the neutrophil count is below 1000/mcL (1.0 × 109/L); the risk dramatically increases when the count falls below 100/mcL (0.1 × 109/L).
``Clinical Findings A thorough physical examination should be performed. Routine DREs are generally avoided unless symptoms suggest a rectal abscess or prostatitis. If a rectal examination is necessary, antibiotics should be administered first. Appropriate cultures (eg, blood, sputum, urine and, if indicated, cerebrospinal fluid) should always be obtained before starting therapy. Two sets of blood cultures should be drawn; if the patient has an indwelling catheter, one of the cultures should be drawn from the line. A chest radiograph should also be obtained.
``Treatment Empiric antibiotic therapy needs to be initiated immediately in the febrile, neutropenic patient. The choice of antibiotics depends on a number of different factors including the patient’s clinical status and any localizing source of infection. If the patient is clinically well, monotherapy with an intravenous β-lactam with anti-Pseudomonas activity (cefepime, ceftazidime, imipenem/cilastatin, piperacillin/tazobactam) should be started (see Infections in the Immunocompromised Patient, Chapter 30). If the patient is clinically ill with hypotension or hypoxia, an aminoglycoside or fluoroquinolone should be added for “double” gram-negative bacteria coverage. If there is a strong suspicion of a gram-positive organism, such as from S aureus catheter infection, vancomycin can be given empirically. In some instances, patients may be treated with oral antibiotics and potentially in the outpatient setting. The Infectious Disease Society of America (IDSA) has published recommendations for antibiotic use in these low-risk patients. These patients must have an expected neutropenic timeframe of 7 days or less and not have comorbidities or signs of hemodynamic instability, gastrointestinal symptoms, altered mental status, pulmonary issues (an infiltrate, hypoxia, or underlying chronic obstructive pulmonary disease) and their liver and kidney function must not be impaired. If a patient is to be treated as an outpatient, he or she must also have good support at home and easy access to returning to the hospital if the clinical status worsens. Antibiotics should be continued until the neutrophil count is rising and > 500/mcL (> 0.5 × 109/L) for at least 1 day and the patient has been afebrile for 2 days. If an organism is identified through the cultures, the antibiotics should be adjusted to the antibiotic sensitivities of the isolate; treatment should be continued for the appropriate period of time and at least until the neutrophil count recovers. For the neutropenic patient who is persistently febrile despite broad-spectrum antibiotics, an empiric antifungal drug should be added (amphotericin B, caspofungin, itraconazole, voriconazole, or liposomal amphotericin B). Freifeld AG et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2011 Feb 15;52(4):427–31. [PMID: 21205990] cc
PRIMARY CANCER TREATMENT
SYSTEMIC CANCER THERAPY Detailed guidelines from the NCCN for cancer treatment can be found at www.nccn.org. Use of cytotoxic drugs, hormones, antihormones, and biologic agents has become a highly specialized and increasingly effective means of treating cancer, with therapy usually administered by a medical oncologist. Selection of specific drugs or protocols for various types of cancer has traditionally been based on results of prior clinical trials; however, many patients have drug-resistant
Cancer tumors. Molecular mechanisms of drug resistance continue to be the subject of intense study. Described mechanisms of drug resistance include impaired membrane transport of drugs, enhanced drug metabolism, mutated target proteins, and blockage of apoptosis due to mutations in cell cycle -proteins. Cancer cells may initially be resistant to chemotherapy or acquire resistance when exposed to drugs.
TOXICITY & DOSE MODIFICATION OF CHEMOTHERAPEUTIC AGENTS Use of chemotherapy to treat cancer is generally guided by results from clinical trials in individual tumor types. The complexity of treating cancer has increased over the last decade as more drugs, including those with novel mechanisms of action, have been approved by the Food and Drug Administration and introduced into general practice. Drug side effects and toxicities must be anticipated and carefully monitored. The short- and long-term toxicities of individual drugs are listed in Tables 39–11 and 39–12. Decisions on dose modifications for toxicities should be guided by the intent of therapy. In the palliative setting where the aim of therapy is to improve symptoms and quality of life, lowering doses to minimize toxicity is commonly done. However, when the goal of treatment is cure, dosing frequency and intensity should be maintained whenever possible. Cancer chemotherapy should be given and monitored by a medical oncologist or hematologist. A complete blood count consisting of a differential count with particular attention to the absolute neutrophil count and platelet count as well as tests of liver and kidney function should be obtained before the initiation of chemotherapy. In patients with normal blood counts as well as normal liver and kidney function, drugs are started at their full dose. When the intent of chemotherapy is cure, including treatment in the adjuvant setting, every attempt should be made to schedule chemotherapy on time and at full dose. A complete blood count with differential should be checked at mid cycle to determine the nadir of the absolute neutrophil and platelet counts as well as immediately before the next cycle of chemotherapy is due. Dose reductions may be necessary for patients with impaired kidney or liver function depending on the clearance mechanism of the drug. For patients receivingchemotherapy for palliation, bone marrow toxicity can be managed with dose reductions or delaying the next treatment cycle. A schema for dose modification is shown in Table 39–13.
1. Bone Marrow Toxicity A. Neutropenia Granulocyte colony-stimulating factor (G-CSF), given as either daily subcutaneous injections (filgrastim, 300 mcg or 480 mcg) or as a one-time dose (pegfilgrastim, 6 mg) beginning 24–72 hours after cytotoxic chemotherapy is completed, has been shown to reduce the duration and severity of granulocytopenia following cytotoxic chemotherapy
(Table 39–12). The American Society of Clinical Oncology and NCCN guidelines recommend primary prophylaxis with a G-CSF when there is 20% risk of febrile neutropenia or when the patient’s age, medical history, and disease characteristics make the patient at high risk for complications related to myelosuppression.
B. Anemia Erythropoiesis-stimulating agents (ESAs) ameliorate the anemia and associated symptoms caused by cancer chemotherapy but these drugs have untoward effects, including an increased risk of thromboembolism, and even more concerning, potentially decreased survival due to cancerrelated deaths. These findings have prompted the US Food and Drug Administration and other organizations (American Society of Hematology, American Society of Clinical Oncology, and NCCN) to issue advisories and guidelines limiting their use. The NCCN recommendation that these drugs should not be used when the intent of chemotherapy is curative is based on evidence that survival can be affected by the administration of ESAs. Studies done in patients with potentially curable head and neck, breast, and cervical cancers have shown inferior outcomes when ESAs were used. It is important to point out that the target hemoglobin used in these studies was higher than is currently recommended. Nonetheless, ESAs cannot be currently recommended when the intent of therapy is cure. The alternative to managing symptomatic anemia in these patients receiving curative chemotherapy is administration of red blood cell transfusions. When using ESAs, treatment should not be initiated until the hemoglobin is < 10 g/dL (< 100 g/L) with the medication held when the hemoglobin is > 12 g/dL (> 120 g/L). Epoetin alfa can be given subcutaneously as a weekly dose of 30,000–40,000 units with a target hemoglobin of 11–12 g/ dL (110–120 g/L) (see Table 39–12). Darbepoetin alfa is given subcutaneously every 2–3 weeks at a dose of 200–300 mcg with the same target hemoglobin. Patients need to be iron replete to have maximum therapeutic effect. Uncontrolled hypertension is a contraindication to the use of ESAs; blood pressure must be controlled prior to initiation of this therapy. The FDA mandates that prescribing clinicians receive specific education on use of ESAs, and patients receiving ESAs must be provided written material describing the risks and benefits of the drug.
C. Thrombocytopenia Drug management of chemotherapy-induced thrombocytopenia is more limited. The only available drug, oprelvekin or recombinant interleukin-11, has modest activity in improving thrombocytopenia associated with chemotherapy; however, the side effects of fluid retention, congestive heart failure, and arrhythmias have limited its use. Thrombopoietin, the protein that stimulates megakaryopoiesis in vivo, was isolated in 1994. Despite much work attempting to produce a clinically effective thrombopoietin agent for therapeutic use, no such drug is commercially available for this indication. Two drugs that activate the thrombopoietin receptor and are approved for use in
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. Chemotherapeutic Agent
Usual Adult Dosage
Alkylating Agents—Nitrogen Mustards Bendamustine (Treanda)
100–120 mg/m2 intravenously every 3–4 weeks
Hypersensitivity reaction, nausea, vomiting, skin reaction
Myelosuppression, pyrexia, fatigue
500–1000 mg/m2 intravenously every 3 weeks; 100 mg/m2/d orally for 14 days every 4 weeks
Nausea and vomiting
Myelosuppression, hemorrhagic cystitis, alopecia, cardiotoxicity with high-dose therapy, SIADH
14 mg/kg/d orally in three or four divided doses
Nausea, vomiting, diarrhea
Gynecomastia, thromboembolism, edema
1200 mg/m2 daily for 5 days intravenously every 3 weeks
Nausea and vomiting
Myelosuppression, hemorrhagic cystitis, neurotoxicity, alopecia, SIADH
Mechlorethamine (nitrogen mustard, Mustargen)
0.4 mg/kg intravenously every 3–6 weeks; or 6 mg/m2 intravenously on days 1 and 8 every 4 weeks
Severe nausea and vomiting, severe vesicant
Myelosuppression, increased risk of secondary malignancies
0.25 mg/kg/d or 8–10 mg/m2/d orally for 4 days every 4–6 weeks; 16 mg/m2 intravenously every 2–4 weeks; 200 mg/m2 intravenously for bone marrow transplant
Nausea, vomiting, diarrhea, Myelosuppression, increased risk of secondary malignancies hypersensitivity (IV), mucositis (IV)
Alkylating Agents—Platinum Analogs Carboplatin (Paraplatin)
Area under the curve (AUC)-based dosing use Calvert equation [Dose (mg) = AUC × (GFR + 25)] AUC = 2–7 mg/mL/min every 2–4 weeks; or 200–400 mg/m2 intravenously every 4 weeks
Nausea, vomiting, hypersensitivity reaction
Myelosuppression, electrolyte disturbances, peripheral neuropathy, nephrotoxicity (less common than with cisplatin)
50–100 mg/m2 intravenously every 3–4 weeks; 20 mg/m2/d intravenously for 5 days every 3 weeks
Severe nausea and vomiting
Nephrotoxicity, ototoxicity, peripheral neuropathy, myelosuppression, electrolyte disturbances
85–130 mg/m2 intravenously every 2–3 weeks
Peripheral neuropathy triggered or exacerbated by cold, nausea, vomiting, diarrhea, rare anaphylactic reactions
Peripheral neuropathy, myelosuppression
Alkylating Agents—Triazenes Dacarbazine (DTIC-Dome)
375 mg/m2 intravenously on day 1 and 15 every 4 weeks, 250 mg/m2 intravenously for 5 days
Severe nausea and vomiting, anorexia
Myelosuppression, photosensitivity, hepatotoxicity, flu-like syndrome
60–100 mg/m2 orally for 14 days every 4 weeks
Nausea and vomiting
Myelosuppression; disulfiram-like reaction with alcohol; caution with tyramine-containing foods, tricyclic antidepressants, and sympathomimetic agents – MAO inhibition; increased risk of secondary malignancies
75 mg/m2 orally daily during radiation for 42 days 150–200 mg/m2 orally for 5 days every 4 weeks
Nausea, vomiting, headache, constipation
Nausea and vomiting
Myelosuppression, mucositis, hyper-pigmentation of skin, rare pulmonary fibrosis, hepatic venoocclusive disease with high doses (> 16 mg/d in transplant patients)
Alkylating Agents—Miscellaneous Busulfan (Myleran)
1–8 mg daily orally
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
0.1–0.2 mg/kg/d orally for 3–6 weeks; or 0.4 mg/kg pulse every 4 weeks
Myelosuppression, rare pulmonary toxicity, skin reaction, increased risk of secondary malignancies with prolonged use
100–130 mg/m2 orally every 6 weeks
Nausea and vomiting
Myelosuppression, pulmonary toxicity
Antimetabolites—Folate Antagonists Methotrexate (MTX; Trexall)
Intrathecal: 12 mg High dose: 1000–12,000 mg/m2 intravenously every 2–3 weeks
Nausea, vomiting, mucositis
Myelosuppression, nephrotoxicity, hepatotoxicity, neurotoxicity (with intrathecal administration and high-dose therapy), photosensitivity, pulmonary toxicity, caution multiple drug interactions which may enhance toxicities (avoid aspirin, penicillins, NSAIDs, omeprazole, TMP-SMZ)
500 mg/m2 intravenously every 3 weeks
Fatigue, nausea, vomiting, diarrhea, rash
Myelosuppression, mucositis Avoid NSAIDs which may decrease pemetrexed clearance and enhance toxicities
30 mg/m2 intravenous bolus once weekly for 6 weeks in 7-week cycle
Myelosuppression, edema, fever, fatigue, liver function test abnormalities, renal impairment
Myelosuppression, immunosuppression, fever
Antimetabolites—Purine Analogs Cladribine (Leustatin)
0.14 mg/kg/d intravenously or subcutaneously daily for 5 days or 0.09 mg/kg/d intravenously via continuous infusion for 7 days
Mild nausea, fatigue, injection site reaction, rash
52 mg/m2 intravenously daily for 5 days every 2–6 weeks (for patients < 21 years of age)
Nausea, vomiting, diarrhea, Myelosuppression, hepatotoxicity, nephrotoxicity, capillary leak syndrome, immunosuppression dermatitis, pruritus, headache, rigor
25 mg/m2 intravenously for 5 days every 4 weeks
Asthenia, fever, myalgias, rare hypersensitivity reaction
Myelosuppression, immunosuppression, neurotoxicity, visual disturbances
Mercaptopurine (6-MP; Purinethol)
Induction: 2.5–5 mg/kg/d orally Maintenance: 1.5–2.5 mg/kg/d orally
Diarrhea, hyperpigmentation of skin, rash
Myelosuppression, immunosuppression, hepatotoxicity, mucositis
4 mg/m2 intravenously every other week
Nausea, vomiting, rash
Myelosuppression, immunosuppression, hepatotoxicity
Antimetabolites—Pyrimidine Analogs Azacitidine (Vidaza)
75 mg/m2 subcutaneously or intravenously for 7 days every 4 weeks, may increase to 100 mg/m2 after two cycles if no response
Injection site reaction, nausea, constipation, fever
Myelosuppression, hepatotoxicity, and nephrotoxicity (rare)
625–1250 mg/m2 orally twice a day for 14 days every 3 weeks
Nausea, vomiting, diarrhea
Hand-foot syndrome, mucositis, hyperbilirubinemia, myelosuppression
Cytarabine (Ara-C, Cytosar U)
Standard dose: 100 mg/m2/d intravenously via continuous infusion for 7 days High dose: 1000–3000 mg/m2 intravenously every 12 hours on days 1, 3, 5
Nausea, vomiting, rash, flu-like syndrome
Myelosuppression High-dose therapy: neurotoxicity (cerebellar ataxia, lethargy, confusion), ocular toxicities (conjunctivitis and keratitis), hepatotoxicity, pancreatitis, pulmonary toxicity
Cytarabine Liposome (DepoCyt)
50 mg intrathecally every 14 or 28 days
Chemical arachnoiditis (continued )
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
15 mg/m2 intravenously every 8 hours for 3 days, repeat every 8 weeks
Nausea, fatigue, hyper glycemia
Fluorouracil (5-FU; Adrucil)
500–600 mg/m2 intravenous bolus weekly for 6 weeks, repeat every 8 weeks; in combination with oxaliplatin: 400 mg/m2 intravenous bolus followed immediately by 600 mg/m2 intravenously over 22 hours on days 1 and 2 or 400 mg/m2 intravenous bolus followed immediately by 2400 mg/m2 intravenously over 46 hours; 1000 mg/m2 intravenously via continuous infusion for 4–5 days every 3–4 weeks
Myelosuppression (intravenous bolus), hand-foot syndrome, mucositis, neurotoxicity, ocular toxicity, photosensitivity, cardiotoxicity (rare)
1000–1250 mg/m2 intravenously on days 1, 8, 15 every 4 weeks
Nausea, rash, flu-like symptoms, fever, diarrhea
Myelosuppression, edema, hepatotoxicity (rare), hemolytic uremic syndrome (rare), pulmonary toxicity (rare)
Antimicrotubules—Vinca Alkaloids Vinblastine (Velban)
6 mg/m2 intravenously on days 1 and 15 every 4 weeks; 0.11 mg/kg on days 1 and 2
Vesicant, bronchospasm and dyspnea (rare)
Myelosuppression, peripheral neuropathy, constipation, mucositis, alopecia, SIADH (rare)
0.5–1.4 mg/m2 intravenously every 3 weeks; 0.4 mg/m2 intravenously via continuous infusion for 4 days; maximum single dose usually limited to 2 mg
Peripheral neuropathy, constipation, alopecia, SIADH (rare)
30 mg/m2 intravenously on days 1 and 8 every 3 weeks
Vesicant, nausea, vomiting, bronchospasm and dyspnea (rare)
Myelosuppression, peripheral neuropathy, constipation, alopecia, SIADH (rare)
Antimicrotubules—Taxanes Cabazitaxel (Jevtana)
25 mg/m2 intravenously every 3 weeks
Hypersensitivity reaction, nausea, vomiting
Myelosuppression, peripheral neuropathy, fatigue, diarrhea, renal failure
60–100 mg/m2 intravenously every 3 weeks; 35–40 mg/m2 intravenously weekly for 3 weeks with 1 week rest
Hypersensitivity reaction, nausea, vomiting
Myelosuppression, peripheral neuropathy, alopecia, edema, fatigue, mucositis, diarrhea
135–175 mg/m2 intravenously every 3 weeks; 50–80 mg/m2 intravenously weekly
Hypersensitivity reaction, nausea, vomiting, bradycardia and hypotension during infusion
Myelosuppression, peripheral neuropathy, alopecia, mucositis, diarrhea, arthralgias/ myalgias
Paclitaxel proteinbound (Abraxane)
260 mg/m2 intravenously every 3 weeks
Nausea, vomiting, diarrhea, Myelosuppression, peripheral neuropathy, alopecia, mucositis, arthralgias/myalgias hypersensitivity reaction (less than paclitaxel)
Antimicrotubules—Epothilone Ixabepilone (Ixempra)
40 mg/m2 intravenously every 3 weeks
Hypersensitivity reaction, nausea, vomiting
Peripheral neuropathy, myelosuppression, alopecia, fatigue, mucositis, diarrhea, arthralgias/ myalgias (continued )
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
30–60 mg/m2 intravenously for 3 days
Liposomal Daunorubicin (Daunoxome)
40 mg/m2 intravenously every 2 weeks
Myelosuppression, cardiotoxicity (cardio myopathy with congestive heart failure–dose related), alopecia. Liposomal Doxorubicin can also cause hand-foot syndrome
15–20 mg/m2 intravenously weekly; 45–60 mg/m2 intravenously every 3 weeks
Nausea, vomiting, mucositis, diarrhea, red/orange discoloration of urine, cardiotoxicity (ECG changes). All anthracyclines except for liposomal doxorubicin are potent vesicants.
Liposomal Doxorubicin (Doxil)
20–50 mg/m2 intravenously every 3–4 weeks
35 mg/m2 intravenously every 2 weeks; 60–120 mg/m2 intravenously every 3–4 weeks
12 mg/m2 intravenously for 3 days
Liposomal daunorubicin and liposomal doxorubicin may cause infusionrelated reactions
Enzyme Inhibitors—Topoisomerase Inhibitors Etoposide (Vepesid)
50–100 mg/m2 intravenously for 3–5 days every 3 weeks, oral dose is twice the intravenous dose
Etoposide Phosphate (Etopophos)
100 mg/m2 intravenously for 3–5 days every 3 weeks
Nausea, vomiting, hypersensitivity reaction, fever, hypotension
Myelosuppression, alopecia, fatigue
60 mg/m2 intravenously on days 1, 8, and 15 every 4 weeks; 125 mg/m2 intravenously weekly for 4 weeks every 6 weeks; 180 mg/m2 intravenously every other week; 350 mg/m2 intravenously every 3 weeks
Diarrhea and cholinergic syndrome, nausea, vomiting
1.5 mg/m2 intravenously for 5 days every 3 weeks; 2.3 mg/m2 orally for 5 days every 3 weeks
Nausea, vomiting, diarrhea
Myelosuppression, alopecia, asthenia
Targeted Therapy—Monoclonal Antibodies Alemtuzumab (Campath)
30 mg/m2 intravenously three times weekly
Infusion-related reaction, nausea, vomiting, hypotension
5–15 mg/kg intravenously every 2–3 weeks
Arterial thromboembolism, wound healing complications, gastro-intestinal perforation or fistula, hemorrhage, hypertension, proteinuria
Brentuximab Vedotin (Adcetris)
1.8 mg/kg intravenously every 3 weeks
Infusion-related reaction, nausea, vomiting, diarrhea
Myelosuppression, peripheral neuropathy, tumor lysis syndrome, fatigue, rash
Loading dose 400 mg/m2 intravenously followed by maintenance dose 250 mg/m2 intravenously weekly
Acneiform skin rash, hypomagnesemia, asthenia, paronychial inflammation, pulmonary toxicity (rare)
Ibritumomab tiuxetan (Zevalin)
0.4 mCi/kg intravenously on day 8
Myelosuppression, asthenia, infections, increased risk of secondary malignancies (continued )
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
3 mg/kg intravenously every 3 weeks for a total of four doses
Fatigue, diarrhea, colitis, pruritus, rash, hepatotoxicity, neuropathy, endocrinopathy
450 mg intravenously
Myelosuppression, asthenia, infections, hypothyroidism, increased risk of secondary malignancies
300 mg initial dose (Dose 1), followed 1 week later by 2000 mg weekly for 7 doses (Doses 2 through 8), followed 4 weeks later by 2000 mg every 4 weeks for 4 doses (Doses 9 through 12)
Infusion-related reaction, diarrhea, nausea
Neutropenia, infections, pyrexia, rash, fatigue
6 mg/kg intravenously every 2 weeks
Acneiform skin rash, hypomagnesemia, asthenia, paronychial inflammation, pulmonary toxicity (rare)
375 mg/m2 intravenously weekly for 4 weeks, or every 3 weeks
Rare reactions: Hepatitis B reactivation, pulmonary toxicity, tumor lysis syndrome, StevensJohnson syndrome, progressive multifocal leukoencephalopathy, cardiac arrhythmias, bowel obstruction
Loading dose 4 mg/kg intravenously followed by 2 mg/kg intravenously weekly; or loading dose 8 mg/kg followed by 6 mg/kg intravenously every 3 weeks
Infusion-related reaction, headache, diarrhea
Cardiotoxicity, pulmonary toxicity, myelosuppression in combination with chemotherapy
I Tositumomab (Bexxar)
Targeted Therapy—mTOR Inhibitors Everolimus (Afinitor)
10 mg orally once daily
Mucositis, diarrhea, cough
Myelosuppression, fatigue, edema, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hypophosphatemia, immunosuppression, pneumonitis (rare)
25 mg intravenously weekly
Hypersensitivity reaction, rash, mucositis
Myelosuppression, edema, fatigue, mucositis, hyperglycemia, hyperlipemia, immunosuppression, nephrotoxicity, interstitial lung disease (rare), bowel perforation (rare), abnormal wound healing
Targeted Therapy—Tyrosine Kinase Inhibitors Crizotinib (Xalkori)
250 mg orally twice daily
Nausea, vomiting, diarrhea, Edema, pneumonitis, vision disorder, liver funcconstipation tion test abnormalities, prolonged QT interval
70 mg orally twice daily; 100–140 mg orally once daily
Diarrhea, nausea, vomiting
Myelosuppression, fluid retention, fatigue, musculoskeletal pain, rash, cardiac dysfunction/ congestive heart failure (rare), hemorrhage (rare)
100–150 mg orally once daily
Acneiform skin rash, fatigue, anorexia, conjunctivitis, gastrointestinal hemorrhage (rare), pulmonary toxicity (rare)
250 mg orally once daily
Acneiform skin rash, asthenia, ocular toxicity, myelosuppression, hepatotoxicity (rare), pulmonary toxicity (rare)
100–800 mg orally once daily
Nausea, vomiting, diarrhea
Myelosuppression, edema, myalgias, rash, congestive heart failure, left ventricular dysfunction (rare), hemorrhage (rare), hepatotoxicity (rare) (continued )
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
1250 mg orally once daily in combination with capecitabine
Diarrhea, nausea, vomiting
Hand-foot syndrome, fatigue, hepatotoxicity (rare), left ventricular dysfunction (rare), prolonged QT interval (rare), interstitial lung disease (rare)
400 mg orally twice daily
Nausea, vomiting, headache, diarrhea
Edema, rash, arthralgia, fatigue, myelosuppression, electrolyte abnormalities, elevated serum lipase (rare), hepatotoxicity (rare), prolonged QT interval (rare)
800 mg orally once daily
Nausea, vomiting, diarrhea
Hypertension, hair color changes, hepatotoxicity, hemorrhagic events, hypothyroidism
400 mg orally twice daily
Diarrhea and nausea
Hypertension, hand-foot syndrome, rash, fatigue, gastrointestinal perforation (rare), hemorrhage (rare), cardiac ischemia/infarction (rare)
50 mg orally once daily for 4 weeks followed by 2 weeks rest.
Diarrhea and nausea
Hypertension, hand-foot syndrome, rash, yellow discoloration of skin, fatigue, hypothyroidism, mucositis, myelosuppression, left ventricular dysfunction (rare), prolonged QT interval (rare), hemorrhage (rare)
300 mg orally once daily
Nausea and diarrhea
Acneiform skin rash, hypertension, fatigue, anorexia, abdominal pain, prolonged QT interval, interstitial lung disease (rare)
960 mg orally twice daily
Nausea, hypersensitivity reaction (rare)
Photosensitivity, rash, arthralgia, alopecia, fatigue, prolonged QT interval, cutaneous squamous cell carcinoma
260 mg/m2 orally in 4 divided doses for 14–21 days every 4 weeks
Nausea, vomiting, diarrhea
Neurotoxicity, myelosuppression, flu-like syndrome
Arsenic Trioxide (Trisenox)
0.15 mg/kg intravenously daily
Edema, acute promyelocytic leukemia differentiation syndrome (fever, dyspnea, skin rash, fluid retention, pleural effusions), prolonged QT interval and complete atrioventricular block
6000–10,000 units/m2 intravenously daily on days 17–28; 6000–10,000 units/m2 intramuscularly every 3 days for a total of 9 doses
Hypersensitivity reaction (requires test dose), nausea, vomiting
Coagulation abnormalities (hemorrhagic and/or thrombotic events), hepatotoxicity, pancreatitis, neurotoxicity
10 units/m2 intravenously on days 1 and 15 every 4 weeks; 30 units on day 2, 9, and 16 every 3 weeks
Skin reaction (rash, hyperpigmentation of skin, striae), pulmonary fibrosis
1.3 mg/m2 intravenous bolus on days 1, 4, 8, 11 followed by a 10 day rest every 3 weeks
Orthostatic hypotension, fever
Peripheral neuropathy, fatigue, myelosuppression, hemorrhage (rare), left ventricular dysfunction (rare), pulmonary toxicity (rare), reversible posterior leukoencephalopathy syndrome (rare), hepatotoxicity (rare)
15 mcg/kg intravenously daily for 5 days; 12 mcg/kg intravenously daily for 5 days; 1000 mcg/m2 intravenously
Vesicant, nausea, vomiting
Myelosuppression, mucositis, diarrhea, alopecia, hyperpigmentation of skin, hepatotoxicity, hepato-veno-occlusive disease (rare)
Denileukin diftitox (Ontak)
9 or 18 mcg/kg intravenously daily for 5 days every 3 weeks
Flu-like syndrome, hypersensitivity reaction, nausea, vomiting
Diarrhea, decreased visual acuity, fever, increased risk for infection, hypoalbuminemia, capillary leak syndrome (rare)
20–30 mg/kg orally once daily
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
5–25 mg orally once daily for 21 days every 4 weeks
Diarrhea, itching, rash
Myelosuppression, potential for birth defects, thromboembolic events, fatigue
20 mg/m2 intravenously every 6–8 weeks; 20–40 mg intravesically weekly
Vesicant, local irritation (cystitis when given intravesically)
Myelosuppression, mucositis, hemolytic uremic syndrome (rare), pulmonary toxicity (rare)
12–14 mg/m2 intravenously every 3 weeks; induction chemotherapy for leukemia 12 mg/m2 intravenously for 2–3 days
Blue-green discoloration of urine, nausea, vomiting, diarrhea, intravenous irritant
Myelosuppression, cardiotoxicity, alopecia, mucositis, increased risk of secondary malignancies (rare)
14 mg/m2 intravenously on days 1, 8, 15 of a 28-day cycle
Myelosuppression, fatigue, anorexia, ECG changes, QT prolongation
One dose (minimum of 50 million autologous CD54+ cells) intravenously every 2 weeks for three doses
Infusion-related reaction, nausea, vomiting
Fatigue, back pain, joint ache, headache, stroke
50–800 mg orally once daily
Sedation, constipation, fatigue
Potential for birth defects, thromboembolic events, peripheral neuropathy, edema
Tretinoin (All-TransRetinoic Acid, ATRA, Vesanoid)
45 mg/m2 orally divided twice daily for 45–90 days or 30 days past complete remission
Headache, vitamin A toxicity, retinoic acid-acute promyelocytic leukemia syndrome, ototoxicity
Antiandrogens Bicalutamide (Casodex)
50 mg orally once daily
Hot flashes, decreased libido, erectile dysfunction, gynecomastia, breast tenderness, fatigue
250 mg orally every 8 hours
Diarrhea, yellow-green discoloration of urine
Hot flashes, decreased libido, erectile dysfunction, gynecomastia, breast tenderness, hepatotoxicity (rare)
300 mg orally for 30 days then 150 mg orally once daily
Visual disturbances (impaired adaptation to dark), hot flashes, decreased libido, erectile dysfunction, gynecomastia, breast tenderness, disulfiram reaction with alcohol, interstitial pneumonitis (rare), hepatotoxicity (rare)
Selective Estrogen Receptor Modulators Tamoxifen (Nolvadex)
20–40 mg orally once daily
Hot flashes, vaginal discharge or bleeding, menstrual irregularities, thromboembolic events (rare), endometrial hyperplasia, cataracts, hepatotoxicity, tumor flare
60 mg orally once daily
Hot flashes, vaginal discharge, thromboembolic events (rare), tumor flare, endometrial hyperplasia, cataracts, hepatotoxicity
1 mg orally once daily
25 mg orally once daily
Hot flashes, peripheral edema, hypercholesterolemia, arthralgia/myalgia, headache, osteoporosis
2.5 mg orally once daily
Table 39–11. Chemotherapeutic agents: Dosage and toxicity. (continued) Chemotherapeutic Agent
Usual Adult Dosage
Pure Estrogen Receptor Antagonist 250 mg intramuscularly once a month
Injection site reactions, nausea, diarrhea, constipation
Hot flashes, backache, headache
40–320 mg orally once daily or in divided doses (four times a day)
Hot flashes, tumor flare, weight gain, hyperglycemia, thrombotic events (rare), adrenal insufficiency (rare)
Goserelin acetate (Zoladex)
3.6 mg subcutaneously once every month; 10.8 mg subcutaneously once every 3 months
Injection site discomfort
Hot flashes, tumor flare, decreased libido, erectile dysfunction, vaginal bleeding, thromboembolic events (rare), osteoporosis (rare)
7.5 mg intramuscularly once every month; 22.5 mg intramuscularly once every 3 months; 30 mg intramuscularly once every 4 months
Injection site reaction
Hot flashes, tumor flare, edema, erectile dysfunction thromboembolic events (rare), osteoporosis
Triptorelin pamoate (Trelstar)
3.75 mg intramuscularly once every month; 11.25 mg intramuscularly once every 3 months
Hot flashes, tumor flare, skeletal pain, erectile dysfunction
Initial: 240 mg subcutaneously Maintenance: 80 mg subcutaneously every 28 days
Injection site reaction
Hot flashes, weight gain, LFT elevation
1000 mg orally once daily
Adrenocortical insufficiency, hepatotoxicity, joint swelling, hypokalemia, hot flashes
40 mg orally once weekly or 40 mg orally on days 1–4, 9–12, 17–20
Hyperglycemia, weight gain, fluid retention, psychiatric symptoms
400 mg orally three times daily
Nausea and vomiting
5 mg orally twice a day; 100 mg orally daily for 5 days
Hyperglycemia, weight gain, gastritis, fluid retention, psychiatric symptoms
Progestins Megestrol acetate (Megace) LHRH Analogs
LHRH Antagonist Degarelix (Firmagon)
Biologic Response Modifiers Aldesleukin (IL-2, Proleukin)
600,000 international units/kg intravenously every 8 hours for 14 doses, repeat after 9 days rest
Hypotension, nausea, vomiting, diarrhea
Capillary leak syndrome (rare), impaired neutrophil function and increased risk of infection, lethargy or somnolence that may result in coma if therapy is not held
Interferon-α-2b (Intron A)
5 million international units subcutaneously 3 times a week; 2 million international units/m2 intramuscularly/subcutaneously three times a week; 20 million international units/ m2 5 days a week for 4 weeks then 10 million international units/m2 three times a week
Hypersensitivity reaction, injection site reaction, flu-like syndrome, nausea, vomiting, diarrhea
Myelosuppression, fatigue, anorexia, alopecia, depression, hyperthyroidism or hypothyroidism (rare), hepatotoxicity (rare), visual disturbances
GFR, glomerular filtration rate; LFT, liver function tests; LHRH, luteinizing hormone–releasing hormone; MAO, monoamine oxidase; NSAIDs, nonsteroidal anti-inflammatory drugs; SIADH, syndrome of inappropriate antidiuretic hormone; TMP-SMZ, trimethoprimsulfamethoxazole.
Table 39–12. Supportive care agents: Dosage and toxicity. Agent
Prevent hyperuricemia from tumor lysis syndrome
300 mg orally once daily
Rash, Stevens-Johnson syndrome (rare), myelosuppression (rare)
Prevent hyperuricemia from tumor lysis syndrome
0.1–0.2 mg/kg intravenously for pediatric patients; 3–6 mg intravenously once
Hypersensitivity reaction in patients with G6PD deficiency, nausea, vomiting, diarrhea, fever, headache
Prevent ifosfamideinduced hemorrhagic cystitis
20% of ifosfamide dose intravenously immediately before ifosfamide and at 4 hours and 8 hours after (total dose is 60% of ifosfamide dose); 100% of ifosfamide dose mixed with ifosfamide in same intravenous bag
Nausea and vomiting
Rescue after high-dose methotrexate; in combination with fluorouracil for colon cancer
10 mg/m2 intravenously or orally every 6 hours until serum methotrexate level is below 0.01 micromolar; 20 mg/m2 or 200–500 mg/m2 intravenously before fluorouracil
Rescue after high-dose methotrexate in osteosarcoma
7.5 mg intravenously every 6 hours for 10 doses (to start 24 hours after the beginning of methotrexate infusion)
Prevent cisplatin nephropathy; prevent radiation-induced xerostomia
910 mg/m2 intravenously before cisplatin; 200 mg/m2 intravenously before radiation
Nausea, vomiting, hypotension, infusion-related reaction
Prevent cardiomyopathy secondary to doxorubicin; anthracyclineinduced injection site extravasation
10 times the doxorubicin dose intravenously before doxorubicin
Prevent mucositis following chemotherapy
60 mcg/kg/d intravenously for 3 days before and 3 days after chemotherapy
Edema, rash, pruritus, erythema, fever, enlargement or discoloration of tongue, altered taste sensation
5 mg orally 1 hour before chemotherapy, then 5 mg once daily for 7 days; 5–10 mg orally three times a day
Flushing, sweating, nausea, dizziness, increased urinary frequency, rhinitis
Pain from bone metastasis
1 milliCurie/kg intravenously
Pain flare, diarrhea, hematuria
Myelosuppression, spinal cord compression
148 megabecquerels (4 milliCuries) intravenously; or 1.5–2.2 megabecquerels/kg (40–60 microcuries/kg)
Flushing, pain flare
120 mg subcutaneously every 4 weeks
Hypocalcemia, hypophosphatemia, fatigue, nausea, osteonecrosis of the jaw
Strontium (Metastron) Pain from bone metastasis
Bone-Modifying Agents Denosumab (Xgeva)
Osteolytic bone metastasis
Table 39–12. Supportive care agents: Dosage and toxicity. (continued) Agent
Osteolytic bone metastasis, hypercalcemia of malignancy
90 mg intravenously every 3–4 weeks; 60–90 mg intravenously, may repeat after 7 days
Injection site reaction
Electrolyte disturbances (hypocalcemia), anemia, arthralgia, bone pain, osteonecrosis of the jaw, nephrotoxicity
Zoledronic acid (Zometa)
Osteolytic bone metastasis, hypercalcemia of malignancy
4 mg intravenously every 3–4 weeks
Injection site reaction
Electrolyte disturbances (hypocalcemia), anemia, arthralgia, bone pain, osteonecrosis of the jaw, nephrotoxicity
Epoetin alfa (Epogen, Procrit)
40,000 units subcutaneously once weekly; 150 units/kg subcutaneously 3 times a week
Injection site reaction
Hypertension, thrombotic events, increased risk of tumor progression or recurrence, seizures, rash
Darbepoetin alfa (Aranesp)
2.25 mcg/kg subcutaneously weekly; 500 mcg subcutaneously every 3 weeks
Injection site reaction
Hypertension, thrombotic events, increased risk of tumor progression or recurrence, seizures, rash
Alternative dosing: 200 mcg subcutaneously every 2 weeks or 300 mcg subcutaneously every 3 weeks Filgrastim (Neupogen)
Febrile neutropenia prophylaxis
5–10 mcg/kg/d subcutaneously or intravenously once daily, treat past nadir
Injection site reaction
Bone pain, enlarged spleen, leukocytosis
Febrile neutropenia prophylaxis
6 mg subcutaneously once per chemotherapy cycle
Injection site reaction
Bone pain, enlarged spleen, leukocytosis
Myeloid reconstitution following bone marrow transplant, febrile neutropenia prophylaxis
250 mcg/m2 intravenously daily until the absolute neutrophil count is > 1500 cells/mcL for 3 consecutive days
Rash, pruritus, injection site reaction, dyspnea, fever
Bone pain, myalgia, fluid retention, supraventricular tachycardia, capillary leak syndrome (rare)
50 mcg/kg subcutaneously every day for 14–21 days or until post-nadir platelet count is > 50,000/mcL
Nausea, vomiting, headache, dizziness, blurred vision, dyspnea, injection site reaction
Candidiasis, rash, fluid retention, arrhythmias, febrile neutropenia
G6PD, glucose 6-phosphate dehydrogenase.
Table 39–13. A common scheme for dose modification of cancer chemotherapeutic agents. Granulocyte Count (cells/mcL)
Platelet Count ( /mcL)
Suggested Drug Dosage (% of Full Dose)
idiopathic thrombocytopenia, romiplostim and eltrombopag, may also benefit patients with chemotherapy-associated thrombocytopenia, although larger trials are needed to establish their use in this setting.
2. Chemotherapy-Induced Nausea & Vomiting A number of cytotoxic anticancer drugs can induce nausea and vomiting, which can be the most anticipated and stressful side effects for patients. Chemotherapy-induced
nausea and vomiting is mediated in part by the stimulation of at least two central nervous system receptors, 5-hydroxytryptamine subtype 3 (5HT3) and neurokinin subtype 1 (NK1). Chemotherapy-induced nausea and vomiting can be acute, occurring within minutes to hours of chemotherapy administration, or delayed until the second day and lasting up to 7 days. Anticipatory nausea and vomiting may even occur before the administration of chemotherapy. Chemotherapy drugs or drug regimens are classified into high, moderate, low, and minimal likelihoods of causing emesis (90%, 30–90%, 10–30%, < 10%, respectively). Highly emetogenic chemotherapy drugs include cisplatin, carmustine, cyclophosphamide at doses over 1.5 g/m2, dacarbazine, mechlorethamine, and streptozocin. Chemotherapy drugs that are moderately emetogenic include doxorubicin, daunomycin, idarubicin, epirubicin, cyclophosphamide, irinotecan, oxaliplatin, ifosfamide, cytarabine, and carboplatin. Drugs with low emetic potential include bortezomib, docetaxel, etoposide, fluorouracil, gemcitabine, methotrexate, mitomycin, mitoxantrone, paclitaxel, pemetrexed, temsirolimus, and topotecan. Drugs with minimal risk of emesis include bevacizumab, bleomycin, cladribine, fludarabine, vinblastine, vincristine, and vinorelbine. By understanding the physiology of chemotherapyinduced nausea and vomiting, major advances have occurred with the development of highly effective antiemetic drugs. Antagonists to the 5HT3-receptor include ondansetron, granisetron, dolasetron, tropisetron, and palonosetron. Each of these drugs has similar efficacy. Ondansetron can be given either intravenously (8 mg or 0.15 mg/kg) or orally (24 mg for highly emetogenic chemotherapy, 8 mg twice daily for moderately emetogenic chemotherapy). Doses of 8 mg can be repeated parenterally or orally every 8 hours. Dosing of granisetron is 1 mg or 0.01 mg/kg intravenously or 1–2 mg orally. Dolasetron is given 1.8 mg/kg or a fixed dose of 100 mg intravenously or 100 mg can be given orally. Tropisetron is given at a dose of 5 mg either orally or intravenously. Palonosetron, a long-acting 5HT3 with high affinity for the 5HT3-receptor given at a dose of 0.25 mg intravenously, is effective for not only acute but also delayed emesis. The efficacy of the 5HT3-blockers is improved by adding 6–10 mg of either oral or intravenous dexamethasone. Aprepitant is an antagonist to the NK1 receptor. When given as a 125-mg oral dose followed by 80 mg on the second and third day with a 5HT3-receptor antagonist (such as ondansetron or granisetron), the immediate and delayed protective effect for highly emetogenic chemotherapy is increased. Standard therapy for highly emetogenic chemotherapy includes a 5HT3-antagonist given on the first day and both dexamethasone and aprepitant given on the first day as well as the second and third days. Moderately emetogenic chemotherapy regimens are best managed with a two-drug regimen of a 5HT3-antagonist and dexamethasone. Doses of the 5HT3 may be given on days 2 and 3 to prevent delayed emesis. Other adjunctive medications that may be helpful include lorazepam, 0.5–1.0 mg given orally every 6–8 hours,
and prochlorperazine, 5–10 mg orally or intravenously every 8 hours. Lorazepam, in addition to antianxiety effects, has an antinausea effect. Prochlorperazine is generally sufficient to treat patients receiving low emetogenic chemotherapy. A suppository form of prochlorperazine, 25 mg, may be used for patients who are unable to swallow oral medications. The importance of treating chemotherapy-induced nausea and vomiting expectantly and aggressively beginning with the first course of chemotherapy cannot be overemphasized. Patients being treated in the clinic setting should always be given antiemetics for home use with written instructions as well as contact numbers to call for advice.
3. Gastrointestinal Toxicity Untoward effects of cancer chemotherapy include damage to the more rapidly growing cells of the body such as the mucosal lining from the mouth through the gastrointestinal tract. Oral symptoms range from mild mouth soreness to frank ulcerations in the mouth. Not uncommonly, mouth ulcerations will have superimposed candida or herpes simplex infections. In addition to receiving cytotoxic chemotherapy, a significant risk factor for development of oral mucositis is poor oral hygiene and existing caries or periodontal disease. Toxicity in the gastrointestinal tract usually manifests as diarrhea. Gastrointestinal symptoms can range from mild symptoms of loose stools to life-threatening diarrhea due to dehydration and electrolyte imbalances. Drugs most commonly associated with causing mucositis in the mouth and the gastrointestinal tract are cytarabine, 5-FU, and methotrexate. Patients undergoing treatment for head and neck cancer with concurrent chemotherapy and radiation therapy have a very high risk of developing severe mucositis. Preventive strategies for managing oral mucositis includes a pretreatment dental examination, particularly for all head and neck cancer patients and any cancer patient with poor dental hygiene who will be receiving chemotherapy. For patients receiving fluorouracil, simple measures such as ice chips in the mouth for 30 minutes during infusion can reduce the incidence and severity of mucositis. Once mucositis is encountered, superimposed fungal infections should be treated with topical anti-fungal medications (oral nystatin mouth suspensions, or clotrimazole troches) or systemic therapy (fluconazole 100–400 mg orally daily). Suspected herpetic infections can be treated with acyclovir (up to 800 mg orally five times daily) or valacyclovir (1 g orally twice daily). Mucositis may also be managed with mouthwashes; it is also important to provide adequate pain medication. Newer strategies for prevention of oral mucositis include the recombinant keratinocyte growth factor inhibitor palifermin. Practice guidelines recommend prophylaxis with intravenous palifermin (60 mcg/kg/d) for patients receiving high-dose chemotherapy in order to reduce the incidence and duration of mucositis. Diarrhea is most associated with fluorouracil, capecitabine, and irinotecan as well as the tyrosine kinase inhibitors
Cancer (sorafenib, sunitinib, imatinib, dasatinib) and epithelial growth factor inhibitors (cetuximab, panitumumab, and erlotinib). Mild to moderate diarrhea can be managed with oral antidiarrheal medication (loperamide, 4 mg initially followed by 2 mg every 2–4 hours until bowel movements are formed). Occasionally, the diarrhea will be overwhelming causing dehydration, electrolyte imbalances, and acute kidney injury. These patients require inpatient management with aggressive intravenous hydration and replacement of electrolytes.
4. Skin Toxicity Dermatologic complications from cancer chemotherapy can include hyperpigmentation (liposomal doxorubicin, busulfan, hydroxyurea) alopecia, photosensitivity, nail changes, acral erythema, and generalized rashes. Acral erythema, otherwise known as hand-foot syndrome and most commonly associated with administration of fluorouracil, capecitabine, and liposomal doxorubicin, manifests as painful palms or soles accompanied by erythema, progressing to blistering desquamation and ulceration in its worst forms. Management can include attempts at prevention with oral pyridoxine, 200 mg daily, and applying cold packs to the extremities while the chemotherapy is being administered. Agents targeting the epidermal growth factor pathway can cause an acne like rash; interestingly, the development of the rash may identify those who will respond to the drug. Inhibitors of the tyrosine kinase pathway are also associated with a high incidence of dermatologic complications, such as rash and acral erythema.
5. Miscellaneous Drug-Specific Toxicities The toxicities of individual drugs have been summarized in Tables 39–11 and 39–12; however, several of these warrant additional mention, since they occur with frequently administered agents, and special measures are often indicated.
A. Hemorrhagic Cystitis Induced by Cyclophosphamide or Ifosfamide Metabolic products of cyclophosphamide that retain cytotoxic activity are excreted into the urine. Some patients appear to metabolize more of the drug to these active excretory products; if their urine is concentrated, severe bladder damage may result. Patients receiving cyclophosphamide must maintain a high fluid intake prior to and following the administration of the drug and be counseled to empty their bladders frequently. Early symptoms suggesting bladder toxicity include dysuria and increased frequency or urination. Should microscopic hematuria develop, it is advisable to stop the drug temporarily or switch to a different alkylating agent, to increase fluid intake, and to administer a urinary analgesic such as phenazopyridine. With severe cystitis, large segments of bladder mucosa may be shed, resulting in prolonged gross hematuria. Such patients should be observed for signs of urinary obstruction and may require cystoscopy for removal of obstructing blood clots. The cyclophosphamide analog ifosfamide can cause severe
hemorrhagic cystitis when used alone. However, when its use is followed by a series of doses of the neutralizing agent mesna, bladder toxicity can be prevented. Mesna can also be used for patients taking cyclophosphamide in whom cystitis develops.
B. Neuropathy Due to Vinca Alkaloids and Other Chemotherapy Drugs Neuropathy is caused by a number of different chemotherapy drugs, the most common being vincristine. The peripheral neuropathy can be sensory, motor, autonomic, or a combination of these effects. In its mildest form, it consists of paresthesias of the fingers and toes. Occasionally, acute jaw or throat pain can develop after vincristine therapy. This may be a form of trigeminal neuralgia. With continued vincristine therapy, the paresthesias extend to the proximal interphalangeal joints, hyporeflexia appears in the lower extremities, and significant weakness can develop. Other drugs in the vinca alkaloid class as well as the taxane drugs (paclitaxel and docetaxel) and agents to treat myeloma (thalidomide and bortezomib) cause similar toxicity. The presence of neurologic symptoms is not in itself a reason to stop therapy; the severity of the symptoms must be balanced against the goals of therapy. Usually though, the presence of moderate to severe paresthesias or the detection of motor impairment would result in the decision to discontinue the drug. Constipation is the most common symptom of autonomic neuropathy associated with the vinca alkaloids. Patients receiving these drugs should be started on stool softeners and mild cathartics when therapy is begun; otherwise, severe impaction may result from an atonic bowel. More serious autonomic involvement can lead to acute intestinal obstruction with signs indistinguishable from those of an acute abdomen. Bladder neuropathies are uncommon but may be severe. These two complications are absolute contraindications to continued vincristine therapy.
C. Methotrexate Toxicity Methotrexate, a folate antagonist, is a commonly used drug and a key component of regimens to treat patients with leptomeningeal disease, acute lymphoblastic leukemia, and sarcomas. The dose used in intrathecal therapy is 12 mg. Methotrexate is almost entirely eliminated by the kidney. The methotrexate toxicity affects cells with rapid turnover, including the bone marrow and mucosa resulting in myelosuppression and mucositis. Methotrexate can also damage the liver and kidney manifesting as elevated liver enzymes and creatinine. High-dose methotrexate, usually defined as a dose of 500 mg/m2 or more given over 4–36 hours, would be lethal without “rescue” of the normal tissues. Leucovorin, a form of folate, will reverse the toxic effects of methotrexate and is given until serum methotrexate levels are in the safe range (< 0.05 mmol/L). It is crucial that high-dose methotrexate and leucovorin are given precisely according to protocol as deviations of the timing of methotrexate delivery or delay in rescue can result in patient death. Lower doses of methotrexate can be problematic in patients with kidney disease who cannot
clear the drug normally or with patients who have effusions. In the latter instance, methotrexate distributes itself in effusions and will leak out continuously, exposing normal tissue to small but cumulatively toxic amounts of the drug. If methotrexate is given to a patient who either has or develops kidney disease or to a patient with an effusion, prolonged rescue with leucovorin will be necessary. Vigorous hydration and bicarbonate loading also appear to be important in preventing crystallization of high-dose methotrexate in the renal tubular epithelium and minimizing the possibility of nephrotoxicity. Daily monitoring of the serum creatinine is mandatory. Drugs impairing methotrexate excretion include aspirin, nonsteroidal antiinflammatory drugs, amiodarone, omeprazole, penicillin, phenytoin, and sulfa compounds; these drugs should be stopped if possible before methotrexate administration.
D. Anthracycline Cardiotoxicity A number of cancer chemotherapy drugs can cause cardiotoxicity. The most common class of drugs associated with cardiotoxicity is the anthracycline antibiotics, including doxorubicin, daunomycin, idarubicin, and epirubicin. They can produce acute (during administration), subacute (days to months following administration), and delayed (years following administration) cardiac toxicity. The most feared complication is the delayed development of congestive heart failure. Risk factors for this debilitating toxicity include the anthracycline cumulative dose, age over 70, previous or concurrent irradiation of the chest, preexisting cardiac disease, and concurrent administration of chemotherapy drugs such as trastuzumab. The problem is greatest with doxorubicin because this drug is the most commonly administered anthracycline due to its major role in the treatment of lymphomas, sarcomas, breast cancer, and certain other solid tumors. Patients receiving anthracyclines should have a baseline multiple-gated radio-nuclide cardiac scan (MUGA) to calculate the left ventricularejection fraction (LVEF). If the LVEF is > 50%, anthracyclines can be administered; if the LVEF is < 30%, these drugs should not be given. For patients with intermediate cardiac function, anthracycline dosing, if necessary, should be cautiously done with LVEF monitoring between doses. Studies of left ventricular function and endomyocardial biopsies indicate that some changes in cardiac dynamics occur in most patients by the time they have received 300 mg/m2 of doxorubicin. In general, patients should not receive a total dose of doxorubicin in excess of 450 mg/m2; the dose should be lower if prior chest radiotherapy has been given. The appearance of a high resting pulse may herald the appearance of overt cardiac toxicity. Unfortunately, toxicity may be irreversible and frequently fatal at dosage levels above 550 mg/m2. At lower doses (eg, 350 mg/m2 of doxorubicin), the symptoms and signs of cardiac failure generally respond well to medical therapy as well as the discontinuation of anthracycline. Laboratory studies suggest that cardiac toxicity may be due to a mechanism involving the formation of intracellular free radicals in cardiac muscle. The iron chelator dexrazoxane has been approved for use as a cardioprotectant for
patients receiving anthracyclines; however, some evidence suggests that the anthracycline anticancer effect may be compromised by the coadministration of dexrazoxane. In general, dexrazoxane should not be used when the goal of chemotherapy is for curative intent either in the settings of adjuvant or definitive treatment. Doxorubicin and daunomycin have been formulated as liposomal products; these drugs, approved for use in patients with Kaposi sarcoma and sometimes used in certain cancers as a substitute for conventional anthracyclines, appear to have minimal potential for cardiac toxicity.
E. Cisplatin Nephrotoxicity and Neurotoxicity Cisplatin is effective in treating a wide range of malignancies, including testicular, bladder, lung, and ovarian cancers. Although nausea and vomiting are the side effects most commonly associated with cisplatin, the more serious side effects of nephrotoxicity and neurotoxicity must also be anticipated and aggressively managed. Patients must be vigorously hydrated prior, during, and after cisplatin administration. Both kidney function and electrolytes must be monitored. Low magnesium and potassium levels as well as hyponatremia can develop. The neurotoxicity is usually manifested as a peripheral neuropathy of mixed sensori足 motor type and may be associated with painful paresthesias. Development of neuropathy typically occurs after cumulative doses of 300 mg/m2. Ototoxicity is a potentially serious manifestation of neurotoxicity and can progress to deafness. Amifostine, developed initially as a radioprotective agent and given intravenously at a dose of 910 mg/m2 over 15 minutes prior to cisplatin, is used to protect against nephrotoxicity and neuropathy. Use of amifostine does not appear to compromise the antineoplastic effect of cisplatin. The second-generation platinum analog carboplatin is non-nephrotoxic, although it is myelosuppressive. In the setting of preexisting kidney disease or neuropathy, carboplatin is occasionally substituted for cisplatin.
F. Bleomycin Toxicity Bleomycin is used for the treatment of testicular cancer, Hodgkin disease, and non-Hodgkin lymphoma. Bleomycin produces edema of the interphalangeal joints and hardening of the palmar and plantar skin. The more serious toxicities include an anaphylactic or serum sickness-like reaction and a serious or fatal pulmonary fibrotic reaction (seen especially in elderly patients receiving a total dose of over 300 units). If nonproductive cough, dyspnea, and pulmonary infiltrates develop, the drug is discontinued, and high-dose corticosteroids are instituted as well as empiric antibiotics pending cultures. Fever alone or with chills is an occasional complication of bleomycin treatment and is not an absolute contraindication to continued treatment. The fever may be avoided by intravenous premedication with hydrocortisone administration. Moreover, fever alone is not predictive of pulmonary toxicity. About 1% of patients (especially those with lymphoma) may have a severe or even fatal hypotensive reaction after the initial dose of bleomycin. In order to identify such patients, a test dose of 5 units of bleomycin is administered first with
Cancer adequate monitoring and emergency facilities available should they be needed. Patients exhibiting a hypotensive reaction should not receive further bleomycin therapy.
PROGNOSIS A valuable sign of clinical improvement is the general well-being of the patient. Although this finding is a combination of subjective and objective factors and may be partly a placebo effect, it nonetheless serves as a sign of clinical improvement in assessing some of the objective observations listed above. Factors included in the
assessment of general well-being are improved appetite and weight gain and increased “performance status” (eg, ambulatory versus bedridden). Evaluation of factors such as activity status enables the clinician to judge whether the net effect of chemotherapy is worthwhile palliation (see Chapter 5). Basch E et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. 2011 Nov 1;29(31):4189–98. [PMID: 21947834] Zeller JL et al. JAMA patient page. Cancer chemotherapy. JAMA. 2008 Jun 11;299(22):2706. [PMID: 18544731]