Steven R. Alberts and Axel Grothey
Cancers of the gastrointestinal (GI) tract account for 19% of all new visceral cancers and 24% of cancer deaths in the United States. The frequency and mortality of cancers of the various GI organs are shown in Table 9.1.
ESOPHAGEAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Epidemiology. The incidence of esophageal cancer is noted in Table 9.1.
1. Squamous cell esophageal cancer is the foremost malignancy in the Bantu of Africa. South Africa, Japan, China, Russia, Scodand, and the Caspian region of Iran also have relatively high incidence rates.
2. Incidence rates of squamous cell esophageal cancer can vary from 100- to 200-fold among different populations living in geographic adjacency.
3. In many Western countries and in some areas of Asia, the incidence of adenocarcinoma of the esophagus (distal esophagus and gastroesophageal junction) is rapidly rising and the incidence of squamous cell cancers is declining. The rise within the United States is now beginning to plateau.
Table 9.1 Occurrence of Digestive Tract Cancers in the United States (2010)a,b
aExtracted from Jemal A. Cancer statistics 2010. Cancer J Clin 2010;60:277.
bGastrointestinal tract malignancies account for about 274,330 new cancers and 139,580 cancer deaths annually.
cDeath rates from colon cancer and rectal cancer are combined.
B. Etiology
1. Carcinogens
a. Long-term use of tobacco and alcohol increases the incidence of both squamous cell carcinoma and adenocarcinoma of the esophagus.
b. Human papillomavirus (HPV) infection is associated with squamous cell carcinoma of the esophagus.
c. Dietary carcinogens relevant to the development of squamous cell esophageal cancers include the following:
(1) Plants growing in soil deficient in molybdenum have reduced vitamin C content and cause hyperplasia of esophageal mucosa, a precursor of cancer.
(2) Elevated nitrates in the drinking water and soup kettles that concentrate the nitrate
(3) Food containing fungi: Geotrichum candidum (pickles, air-dried corn), Fusarium sp., and Aspergillus sp. (com)
(4) Bread that is baked once a week and eaten when moldy (G. candidum)
(5) Dried persimmons, a rough food that injures the esophageal mucosa when eaten (China)
2. Predisposing factors for squamous cell esophageal cancer
a. Howel-Evans syndrome or tylosis (hyperkeratosis of the palms and soles) is a rare genetic disease that is transmitted as a mendelian-dominant trait (nearly 40% develop esophageal cancer).
b. Lye stricture (up to 30%)
c. Esophageal achalasia (30%)
d. Esophageal web (20%)
e. Plummer-Vinson syndrome (iron-deficiency anemia, dysphagia from an esophageal web, and glossitis, 10%)
f. Short esophagus (5%)
g. Peptic esophagitis (1%)
h. Other conditions associated with squamous cell esophageal cancer
(1) Patients with head and neck cancer (field cancerization theory)
(2) Patients with celiac disease
(3) Chronic esophagitis without Barrett esophagus (see Section II.A)
(4) Thermal injury to the esophagus because of drinking boiling hot tea or coffee (Russia, China, and Middle East)
3. Predisposing factors for adenocarcinoma of the esophagus
a. Barrett esophagus is metaplastic replacement of squamous with intestinalized columnar epithelium.
(1) Adenocarcinomas associated with Barrett esophagus constitute the cancer whose incidence is most rapidly increasing worldwide, but particularly in white men.
(2) In the United States, the incidence of adenocarcinoma of the esophagus has increased six- to sevenfold since 1970. Patients with Barrett esophagus have a 30- to 125-fold increased risk for esophageal adenocarcinoma compared with the average US population.
b. Obesity
c. Reflux esophagitis
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. While squamous cell tumors once constituted the majority of esophageal cancers, particularly in the upper and middle esophagus, adenocarcinomas are now the predominant form of esophageal cancer. A small portion of esophageal cancers will be sarcomas, small cell carcinomas, or lymphomas. Adenocarcinoma may arise from esophageal continuation of the gastric mucosa (Barrett esophagus) or may represent extension of a gastric adenocarcinoma.
B. Location of cancer in the esophagus
1. Cervical: 10%
2. Upper thoracic: 40%
3. Lower thoracic: 50%
C. Clinical course. Esophageal cancer is highly lethal; >80% of affected patients die from the disease. About 75% present initially with mediastinal nodal involvement or distant metastasis. Death is usually caused by local disease that results in malnutrition or aspiration pneumonia.
III. DIAGNOSIS
A. Symptoms and signs. Dysphagia is the most common complaint. Patients become unable to swallow solid foods and eventually liquids. Symptoms rarely develop until the esophageal lumen is greatly narrowed and metastasis has occurred. Pain may or may not be present. Physical findings other than cachexia, palpable supraclavicular lymph nodes, or hepatomegaly are rare.
B. Diagnostic studies
1. Preliminary studies include physical examination, CBC, LFT, chest radiograph, esophagoscopy, and barium esophagogram. Brushings can be obtained and lesions can undergo biopsy using endoscopy.
2. CT scan staging predicts invasion or metastases with an accuracy rate of >90% for the aorta, tracheobronchial tree, pericardium, liver, and adrenal glands; 85% for abdominal nodes; and 50% for paraesophageal nodes.
3. Endoscopic ultrasound (EUS) is more accurate than CT in assessing tumor depth and paraesophageal nodes. Transesophageal biopsy to sample enlarged lymph nodes is possible under EUS guidance.
4. Positron emission tomography (PET) is a potentially useful diagnostic tool for the preoperative assessment of patients with esophageal cancer. It has a greater sensitivity for the detection of nodal metastases when compared with CT.
5. Laparoscopy allows assessment of subdiaphragmatic, peritoneal, liver, and lymph node metastases. In patients who are getting chemotherapy and radiation, either preoperatively or in lieu of surgery, placement of a jejunostomy tube for enteral alimentation during laparoscopy is clinically useful. Thoracoscopy can allow patients who are noted to have intrathoracic dissemination to be spared radical resections.
6. Bronchoscopy for tumors of the upper or middle esophagus can diagnose direct tumor extension into the tracheobronchial tree and synchronous primary sites.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A tumor-lymph node-metastasis (TNM) staging classification is available. Stage groupings are different for squamous cell carcinomas and adenocarcinomas of the esophagus with regard to both TNM classification and histologic grades. Patients with earlier disease stage, particularly N0 and M0, have a better prognosis. Readers should consult an up-to-date staging manual because of the frequent revisions of staging systems.
Most patients die from their disease within 10 months of diagnosis. The 5-year survival rate ranges from approximately 35% with localized disease to <10% for distant disease despite all efforts at treatment.
V. SCREENING AND EARLY DETECTION
In high-risk populations, such as in portions of Asia, mass screening using balloon-assisted brushings or endoscopy has been used. Early detection by these methods is of uncertain benefit. In the United States, screening for esophageal cancer is not effective in the general population, but patients such as those with lye-induced strictures or Barrett esophagus, who are at higher risk, should undergo periodic screening via upper endoscopy.
VI. MANAGEMENT
A variety of options exist for the treatment of esophageal cancer depending on its stage.
A. Resection of primary tumor. Results of surgical resection in cancer of the esophagus are poor. The operative mortality rate is about 5% to 10%. In the United States, the 5-year survival rate in patients undergoing R0 (complete) tumor resection is <20%. Aggressive surgery, however, may be justified, particularly for some patients with lesions in the lower half of the esophagus.
B. Palliating an obstructed esophagus can be accomplished by several procedures and permits enteral nutrition.
1. Laser therapy may relieve obstruction and bleeding. Endoscopic laser therapy has a <1% mortality rate but may require prior mechanical dilation. Although successful, laser therapy may require multiple endoscopic sessions, it can be done on an outpatient basis, and its overall cost is still much lower than the cost of palliative surgery. Photosensitization of esophageal tumors using an injectable porphyrin derivative can beneficially increase the laser energy absorbed by the tumor but is associated with generalized dermal photosensitivity to sunlight lasting 4 to 6 weeks.
2. Esophageal stenting. Multiple devices are available for esophageal intubation. About 15% of patients with malignant esophageal obstruction are candidates for tube placement. The tube may be introduced with a pusher tube, which is loaded either onto a bougie or over an endoscope and expands after placement. The latter method permits visualization of the obstructed lumen. The success rate is above 90%.
a. Advantages of tube placement are improved ability to swallow saliva, pleasure of oral alimentation, relief from pulmonary aspiration related to esophagopulmonary fistula, independence from physician or hospital for constant care, and ability to spend time with family and friends in relative comfort.
b. Contraindications to placement of endoprosthesis are carcinoma <2 cm below the upper sphincter, limited life expectancy (<6 weeks), and uncooperativeness.
c. Complications include perforation, dislocation, tumor overgrowth, reflux symptoms with stricturing, pressure necrosis, foreign body impaction with obstruction, bleeding, and failure of intubation. The complication rate (early and late) is 10% to 25%.
3. Feeding gastrostomy is not advisable because it does not palliate dysphagia, which forces patients with complete or nearly complete esophageal obstruction to expectorate saliva and secretions, does not increase life expectancy, and has its own morbidity and mortality.
4. Colonic interposition to bypass the obstructed segment is recommended only for surgical candidates in whom a suitable gastric remnant cannot be fashioned because of prior gastric resection, extent of disease, or underlying esophageal disease. The complication rate of this procedure is high.
5. External-beam irradiation or endoluminal brachytherapy can result in tumor regression with palliation in some cases. Up to 70% to 80% of patients with dysphagia may note improved swallowing after external-beam irradiation. Endoluminal brachytherapy can be useful in previously irradiated patients with local tumor regrowth causing dysphagia.
C. Single-modality treatment
1. Radiotherapy (RT) alone to a dose of 6,000 cGy resulted in 1-, 2-, 3-, and 5-year survival rates of 33%, 12%, 8%, and 7%, respectively, of patients treated on the radiation arm of a randomized trial in which responding patients were permitted to proceed to resection at physician discretion.
2. Surgery alone. The surgical procedures employed in esophagectomy depend on the location and preference of the surgeon and include principally transhiatal esophagectomy or the Ivor-Lewis procedure, which requires both thoracotomy and laparotomy. In the 25% to 30% of patients in whom complete resection is possible, 5-year survival rates are 15% to 20%.
3. Chemotherapy alone is seldom an effective palliative modality of the primary tumor in patients with esophageal cancer. When chemotherapy is employed, it should be coupled with mechanical or radiotherapeutic approaches for palliation of dysphagia. As in gastric cancer, discussed later, multiagent chemotherapy-induced responses tend to be short-lived.
D. Combined-modality therapy
1. Primary combined therapy without surgery. In patients not planning to undergo esophageal surgery because of comorbid disease or patient or physician choice, combined chemotherapy and RT can lead to long-term survival in some, as compared with surgery alone.
a. Currently, the following regimen is most commonly used and is given during the first and fourth weeks of RT:
Cisplatin, 75 mg/m2 IV on day 1 of the cycle, and 5-fluorouracil (5-FU), 1,000 mg/m2/d by continuous IV infusion for 4 days. Several other multiagent regimens have resulted in higher response rates but have increased toxicity without a clear overall survival benefit.
b. In a prospective randomized trial of patients with squamous cell or adenocarcinoma of the thoracic esophagus, combined-modality treatment (5-FU plus cisplatin plus 5,000 cGy) resulted in improved median survival (9 vs. 12.5 months) when compared with RT alone (6,400 cGy). The 2-year survival rate for patients randomized to combined chemotherapy and radiation was 38%, compared with 10% for those randomized to radiation alone. The patients receiving the combined-modality treatment experienced decreased local and distant recurrences but significantly more toxicity, much of which was serious or life-threatening. Only half of these patients received all of the planned cycles of chemotherapy. Currently, this approach should be reserved for patients unable to undergo surgery and for selected patients with squamous cell cancers.
2. Preoperative or postoperative RT alone may reduce the local recurrence rate but has no apparent affect on median survival.
3. Perioperative chemotherapy alone. Similarly, neither preoperative (as reported in six randomized trials) nor postoperative chemotherapy alone has improved outcomes in patients with esophageal cancer, though it may benefit patients with gastroesophageal cancers (see Gastric Cancer, Section IV.B.1.c). Response rate to multiagent neoadjuvant chemotherapy can be as high as 40% to 50%, and up to 25% of treated patients may have apparent pathologic complete remissions. Preoperative chemotherapy using cisplatin and 5-FU, however, did not improve overall survival when compared with surgery alone in a randomized trial of 440 patients with squamous esophageal cancer.
4. Triple-modality therapy. The combination of preoperative chemotherapy and RT has led to an increase in the 3-year survival rates and prolonged median disease-free survival in several randomized studies compared with surgery alone. While older trials have shown mixed results in regard to overall survival, more recent trials with predominantly adenocarcinoma patients have shown significant benefit to the use of neoadjuvant chemoradiotherapy followed by surgery compared to surgery alone. Current options for chemotherapy included (1) carboplatin and paclitaxel, (2) 5-FU and oxaliplatin, and (3) 5-FU and cisplatin. Based on outcomes and level of toxicity, carboplatin and paclitaxel appear to be the best option. Patients with complete pathologic response at surgery have about a 50% likelihood of long-term survival.
E. Advanced disease. The responses using single chemotherapeutic agents (15% to 20%) are usually partial and of brief duration (2 to 5 months). Combination chemotherapy, usually including cisplatin with 5-FU, a taxane, or both, is associated with reported response rates ranging from 15% to 80%, a median duration of response of 7 to 10 months, and many times with substantial toxicity. Higher response rates, however, do not necessarily translate into significant benefit for these patients, and the outcome remains poor. In most situations, the use of a doublet, rather than a triplet, chemotherapy combination will provide meaningful responses with acceptable levels of toxicity. For doublets, choices include FOLFOX, XELOX, as well as carboplatin and paclitaxel.
GASTRIC CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. The prevalence and death rates of gastric carcinoma (particularly distal cancers) have been markedly and significantly decreasing in all regions of the world and in all age groups by about 2% to 7% per year. Deaths due to gastric cancer have decreased to 20% of that seen in the 1930s in the United States, although it remains the second leading cause of cancer death worldwide. However, an increase in cardia and gastroesophageal tumors has been observed in the United States. Currently, one-third of all gastric cancers arise in the proximal stomach, predominantly the cardia and gastroesophageal junction.
Dietary factors and improvement in food storage are believed to be the major factors causing this decline. Improvements include reduction in toxic methods of food preservation (such as smoking and pickling), a decline in salt consumption, greater use of refrigeration, and increased consumption of fruits and vegetables.
Mortality from gastric cancer is highest in Costa Rica (61 deaths per 100,000 population) and East Asia (Hong Kong, Japan, and Singapore) and lowest in the United States (5 deaths per 100,000). Of interest, the Nordic and Western European countries have incidence rates two to three times higher than the United States. The incidence remains high in Japan and is intermediate in Japanese immigrants to the United States; first-generation Japanese Americans have an incidence comparable with other Americans. The average age of onset is 55 years.
B. Etiology. Two gastric cancer entities can be distinguished by their risk factors and histology. Diffuse gastric cancer is associated with hereditary factors and a proximal location and does not appear to occur in the setting of intestinal metaplasia or dysplasia. Intestinal-type gastric cancer is more distal, occurs in younger patients, is more frequently endemic, and is associated with inflammatory changes and with Helicobacter pylori infection.
1. Diet. Gastric cancer has been linked to the ingestion of red meats, cabbage, spices, fish, salt-preserved or smoked foods, a high-carbohydrate diet, and low consumption of fat, protein, and vitamins A, C, and E. Selenium dietary intake may be inversely proportional to the risk of gastric cancer but not to that of colorectal cancer.
2. Helicobacter pylori infection is associated with an increased risk for gastric adenocarcinoma and may be a cofactor in the pathogenesis of noncardiac gastric cancer. The H. pylori organism was identified in the malignant and nearby inflammatory tissue of 89% of patients with intestinal-type cancer, whereas it was present in 32% of tissues taken from patients with diffuse-type cancers. This raises the possibility now under investigation in prospective randomized trials that eradicating H. pylori through antibiotic treatment and bismuth administration may be preventive of both atrophic gastritis and intestinal-type gastric cancer.
3. Heredity and race. African, Asian, and Hispanic Americans have a higher risk for gastric cancer than whites. The diffuse histologic pattern is the predominant pathologic type seen in families with multiple affected members.
4. Pernicious anemia, achlorhydria, and atrophic gastritis. Pernicious anemia carries an increased relative risk for gastric cancer that is said to be 3 to 18 times that of the general population, based on retrospective studies. Although some controversy surrounds this finding, follow-up endoscopy is generally suggested for patients known to have pernicious anemia.
5. Previous gastric resection. Gastric stump adenocarcinomas, which occur with a latency period of 15 to 20 years, are more common in patients after surgical treatment for benign peptic ulcer disease, particularly in those who have hypochlorhydria and reflux of alkaline bile. These cancers are associated with dysplasia of gastric mucosa, elevated gastrin levels, and a poor prognosis. Two meta-analyses have supported this increased risk. Some population-based studies do not support this finding.
6. Mucosal dysplasia is graded from I to III, with grade III showing marked loss in cell differentiation and increased mitosis. The finding of high-grade dysplasia by experienced pathologists in two separate sets of endoscopic biopsies is considered to be a marker for future gastric cancer. Intestinal metaplasia, replacement of gastric glandular epithelium with intestinal mucosa, is associated with intestinal-type gastric cancer. The risk for cancer appears to be proportional to the extent of metaplastic mucosa.
7. Gastric polyps. As many as half of adenomatous polyps show carcinomatous changes in some series. Hyperplastic polyps (>75% of all gastric polyps) do not appear to have malignant potential. Patients with familial adenomatous polyposis (FAP) have a higher incidence of gastric cancer. Patients with adenomatous polyps or FAP should have endoscopic surveillance.
8. Chronic gastritis. In chronic atrophic gastritis of the corpus or antrum, H. pylori infection and environmental and autoimmune (as in pernicious anemia) causes are thought to be associated with an increased risk for gastric cancer. In Ménétrier disease (hypertrophic gastritis), an increase in the incidence of gastric cancer is also observed.
9. Other risk factors. Gastric cancer is more common in men older than 50 years of age and in people with blood group A. Gastric cancer is consistently seen more commonly among those of lower socioeconomic class across the world.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology and classification. About 95% of gastric cancers are adenocarcinomas; 5% are leiomyosarcomas, lymphomas, carcinoids, squamous cancers, or other rare types.
1. Useful characteristics of gastric cancer
a. Histologic classification (Lauren): Diffuse (scattered solitary or small clusters of small cells in the submucosa), intestinal (polarized columnar large cells with inflammatory infiltrates localized in areas of atrophic gastritis or intestinal metaplasia), and mixed types. This classification has proved to be the most useful for adenocarcinomas because the two major types (diffuse and intestinal) represent groups of patients with differing ages, sex ratios, survival rates, epidemiology, and apparent origin. Studies have shown that diffuse histology affects younger patients, with slight predominance among women. Diffuse histology occurred in 50% of all cases and in 55% of unresectable cases. Intestinal type predominates in high-risk regions of the world and among older people, and affects more men than women.
b. Clinical classification (gross anatomy): Superficial (superficial spreading), focal (polypoid, fungate, or ulcerative), and infiltrative (linitis plastica) types
c. Japanese Endoscopic Society (JES) classification: Type I (polypoid or mass-like), type II (flat, minimally elevated, or depressed), and type III (cancer associated with true ulcer)
2. Location of cancers
a. Distal location: 40%
b. Proximal: 35%
c. Body: 25%
B. Clinical course. About 20% of gastric cancer patients are long-term survivors in the United States. Gastric carcinoma spreads by the lymphatic system and blood vessels, by direct extension, and by seeding of peritoneal surfaces. The ulcerative and polypoid types spread through the gastric wall and involve the serosa and draining lymph nodes. The scirrhous type spreads through the submucosa and muscularis, encasing the stomach, and in some instances spreads to the entire bowel. The physical examination is often normal.
Widespread metastatic disease may affect any organ, especially the liver (40%), lung (may be lymphangitic, 40%), peritoneum (10%), supraclavicular lymph nodes (Virchow node), left axillary lymph nodes (Irish node), and umbilicus (Sister Mary Joseph nodule). Sclerotic bone metastases, carcinomatous meningitis, and metastasis to the ovary in women (Krukenberg tumor) or rectal shelf in men (Blumer shelf) may also occur.
C. Associated paraneoplastic syndromes
1. Acanthosis nigricans (55% of cases that occur in malignancy are associated with gastric carcinoma)
2. Polymyositis, dermatomyositis
3. Circinate erythemas, pemphigoid
4. Dementia, cerebellar ataxia
5. Idiopathic venous thrombosis
6. Ectopic Cushing syndrome or carcinoid syndrome (rare)
7. Leser-Trélat sign
III. DIAGNOSIS
A. Symptoms and signs. Gastric cancer often progresses to an advanced stage before symptoms and signs develop. Symptoms of advanced disease include anorexia, early satiety, distaste for meat, weakness, and dysphagia. Abdominal pain is present in about 60% of patients, weight loss in 50%, nausea and vomiting in 40%, anemia in 40%, and a palpable abdominal mass in 30%. The abdominal pain is similar to ulcer pain, is gnawing in nature, and may respond initially to antacid treatment but remains unremitting. Hematemesis or melena occurs in 25% and, when present, is seen more often with gastric sarcomas.
B. Diagnostic studies
1. Preliminary studies include CBC, LFT, esophagogastroduodenoscopy (EGD) or upper GI barium studies, and chest radiographs.
2. CT of the abdomen is useful for assessing the extent of disease. At laparotomy, however, half of patients are found to have more extensive disease than predicted by CT. Laparoscopy can identify patients with regionally advanced or disseminated disease who are not candidates for immediate potentially curative surgical intervention.
3. EUS is up to six times more accurate in staging the primary gastric tumors than CT, but differentiation between benign and malignant changes in the wall is often difficult. EUS is useful in imaging the cardia, which may be difficult to evaluate by CT. Lymph node biopsy can also be obtained by EUS guidance.
4. Endoscopy. The combination of flexible upper GI endoscopy with biopsy of visible lesions, exfoliative cytology, and brush biopsy is able to detect >95% of gastric cancers. Biopsy of a stomach lesion alone is accurate in only 80% of cases. Positive gastric cytology with no endoscopic or radiographic abnormalities indicates superficial spreading gastric cancer.
5. PET. PET has more limited value in the diagnostic workup of patients compared to its use in esophageal cancer. It may help to identify malignant adenopathy not seen by CT. Its use in patients with gastroesophageal junction cancers appears to be more comparable to esophageal cancer.
C. Differential diagnosis and gastric polyps. The differential diagnosis of gastric cancer includes peptic gastric polyps, ulcer, leiomyoma, leiomyoblastoma, glomus tumor, malignant lymphoma (and pseudolymphoma), granulocytic sarcoma, carcinoid tumors, lipoma, fibrous histiocytoma, and metastatic carcinoma. Gastric polyps rarely undergo malignant transformation (3% after 7 years), but many contain independent carcinoma.
1. Inflammatory gastric polyps are not true neoplasms. They are usually located in the pyloroantrum and are associated with hypochlorhydria but not with carcinoma.
2. Hyperplastic gastric polyps (Ménétrier polyadenome polypeux) are the most common polyps (75%). Randomly distributed throughout the stomach, these polyps are usually small and multiple. Coexisting carcinoma is present in 8% of cases.
3. Adenomatous polyps are usually located in the antrum of the stomach and are frequently single and large. Coexisting carcinoma is present in 40% to 60% of patients.
4. Villous adenomas rarely occur in the stomach but are more often malignant.
5. Polyposis syndromes
a. Familial gastric polyposis presents with multiple gastric polyps but no skin or bone tumors. The gastric wall is usually invaded with atypical carcinoma.
b. FAP is associated with gastric involvement in more than half of patients. The gastric polyps are adenomatous, hyperplastic, or of the fundic gland hyperplasia type. Gastric carcinoma and carcinoid tumor may occur.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. The TNM staging system developed for gastric cancer is shown in Table 9.2. The current TNM system does not take into account the location of the tumor within the stomach, the histologic type (Lauren classification), the pattern of growth (linitis plastica), or whether all disease could be resected (and if so, the type of resection).
B. Prognostic factors. Previously, data using three grave prognostic signs (serosal involvement, nodal involvement, and tumor at the line of resection) have shown that if none of these signs is present, the 5-year survival rate is 60%, and if all are present, the 5-year survival rate is <5%.
1. Stage. Multivariate analysis indicates that stage, invasion, and lymph node involvement are the most significant prognostic factors. The most important prognostic determinant appears to be the number of positive lymph nodes. Interestingly, patients with one to three lymph nodes involved with metastasis have as good a prognosis as those without nodal involvement.
Table 9.2 TNM Staging System for Cancers of the Stomacha
aAdapted from the AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; 2010.
bIntramural extension to the duodenum or esophagus is classified by the depth of the greatest invasion in any of these sites, including the stomach.
2. Clinical classification. Survival is better with superficial than with focal cancer and worst with infiltrative types of cancer.
3. JES classification. Survival is better with type II (flat) than with type III (associated with ulcer) tumors and worst with type I (polypoid) tumors.
4. Grade. Tumors with high histologic grade have a poor prognosis.
5. Nature and extent of resection. Survival is better with curative resection (a resection with uninvolved margins, or R0 resection) versus palliative resection, distal gastrectomy versus proximal gastrectomy, and subtotal gastrectomy versus total gastrectomy.
V. SCREENING AND EARLY DETECTION. Early detection of gastric cancers is clearly improved with relentless investigation of persistent upper GI symptoms. In Japan, mobile screening stations equipped with video gastrocameras have resulted in early detection of gastric cancer. Gastric cancer, which was detected in 0.3% of those screened, was associated with a 95% 5-year survival rate (50% of the patients had involvement of mucosa and submucosa only). Despite such screening programs, gastric cancer remains the most common cause of cancer death in Japan. Screening of populations with routine risk factors for gastric cancer is not recommended, however, in the United States.
VI. MANAGEMENT
A. Surgery
1. Curative resection. Subtotal gastrectomy with adequate margins of grossly uninvolved stomach (3 to 4 cm) and regional lymph node dissection is the treatment of choice, and is generally considered the only potentially curative approach for patients with gastric cancer. Total gastrectomy is not superior to subtotal gastrectomy for achieving cures and should be used only when indicated by the local extent of the disease. More extensive lymphatic dissection, known as D-2 resections (e.g., of the celiac lymph nodes), omentectomy, and splenectomy are of uncertain benefit, but do not appear to be advisable outside its use in Japan.
2. Palliative resections are performed to rid patients of infected, bleeding, obstructed, necrotic, or ulcerated polypoid gastric lesions. For these purposes, a limited gastric resection may suffice. Palliative resections succeed in ameliorating symptoms about half the time.
3. Vitamin B12 deficiency develops in all patients who undergo total gastrectomy within 6 years and in 20% of patients who undergo subtotal gastrectomy within 10 years unless parenteral B12 injections are administered.
B. Chemotherapy
1. Neoadjuvant, adjuvant, or perioperative chemotherapy
a. Neoadjuvant chemotherapy. Patients with potentially resectable disease treated in phase II studies with preoperative chemotherapy, RT, or both have shown a high response rate, and some have had pathologically negative resection specimens. There have not been any randomized trials published to help discern whether response translates into resectability, time to progression, or survival advantage over no neoadjuvant therapy.
b. Adjuvant chemotherapy. Individual trials have shown mixed results in regard to the benefit of adjuvant chemotherapy over surgery alone. However, a recent meta-analysis showed that the use of adjuvant therapywith 5-fluorouracil based regimens does reduce the risk of death related to gastric cancer compared to surgery alone. Therefore, adjuvant chemotherapy or chemotherapy and radiation are appropriate options for patients who went directly to surgery without preoperative therapy.
c. Perioperative chemotherapy. In a randomized phase III trial of perioperative ECF chemotherapy (epirubicin, cisplatin, and infusional 5-FU), with three cycles of preoperative and three cycles of postoperative therapy, a significant improvement was seen in overall survival compared with surgery alone. While this trial enrolled primarily patients with stomach cancer, similar benefit appeared to extend to those with adenocarcinoma of the gastroesophageal junction or lower esophagus. Cycles are given every 3 weeks as follows:
Epirubicin 50 mg/m2 IV on day 1
Cisplatin 60 mg/m2 IV on day 1
5-FU 225 mg/m2/d by continuous IV infusion on days 1 to 21
In a separate randomized phase III trial, perioperative chemotherapy with 5-FU and cisplatin provided similar results. In this trial, approximately two-thirds of patients had gastroesophageal junction cancers.
2. Combined-modality therapy. Several clinical trials for potentially resectable gastric cancer have assessed sequential chemotherapy and radiation. A previously completed intergroup trial (Intergroup 0116) involving nearly 600 patients undergoing potentially curative resection randomized patients to either observation alone or to combined-modality therapy. Patients randomized to adjuvant therapy received one cycle of 5-FU and leucovorin followed by a combination of bolus 5-FU and RT. After the RT was completed, two additional cycles of 5-FU and leucovorin were given. Significant 3-year relapse-free and overall survivals were seen in the patients randomized to adjuvant therapy. The benefit of this approach appeared to be in a reduction of locoregional failures. Less benefit was seen with treatment in reducing distant failures.
3. Chemotherapy for advanced disease. Single agents produce low response rates. Combination regimens produce higher response rates but are more toxic and more costly. Cisplatin has been increasingly used in new combinations that also yield higher response rates, but the incidence of important toxic events exceeds 10%. The reported response rates are about 20% for 5-FU alone and 10% to 50% for combination chemotherapy; the median survival times range from 5 to 11 months.
After nearly two decades of using combination chemotherapy, including mitomycin, doxorubicin, epirubicin, etoposide, methotrexate, nitrosoureas, irinotecan, taxanes, or cisplatin, there is no regimen considered standard in the setting of advanced disease.
a. ECF. The chemotherapy regimen of epirubicin, cisplatin, and continuous infusion 5-FU (ECF) was shown to have superior activity over 5-FU, doxorubicin, and methotrexate (FAMtx) in a phase III trial. Dosages for ECF are shown in section VI.B.1.c.
b. EOX. A newer version of ECF, EOX (epirubicin, oxaliplatin, and capecitabine) showed an improvement in overall survival and less toxicity compared with ECF. The dosage schedule for EOX is as follows; cycles are repeated every 3 weeks:
Epirubicin, 50 mg/m2 IV on day 1
Oxaliplatin, 130 mg/m2 IV on day 1
Capecitabine, 625 mg/m2/dose twice daily days 1 to 21
c. DCF. The use of docetaxel (Taxotere) has also been of benefit. As assessed in a trial comparing docetaxel, cisplatin (DCF), and 5-FU versus cisplatin and 5-FU (CF), the combination of DCF provided improved overall survival. However, both DCF and modified DCF may result in significant toxicity. Nearly 30% of patients receiving modified DCF were hospitalized. DCF is given in 3-week cycles as follows:
(1) DCF
Docetaxel 75 mg/m2 IV on day 1
Cisplatin 75 mg/m2 IV on day 1
5-FU 750 mg/m2/d by continuous IV infusion on days 1 to 5
(2) Modified DCF using the following has shown comparable outcomes:
Docetaxel 40 mg/m2 IV on day 1
Cisplatin 40 mg/m2 IV on day 1
5-FU 400 mg/m2/d by continuous IV infusion on days 1 to 5
d. FOLFOX/XELOX. While triplets have generally shown the highest response rates and overall survivals, the toxicity of these combinations can make them difficult to administer. FOLFOX or XELOX may provide similar outcomes with less toxicity.
e. Carboplatin/Paclitaxel. This combination also has meaningful activity with manageable toxicity.
f. Trastuzumab. In patients with gastric or gastroesophageal junction tumors overexpressing Her2/neu, trastuzumab added to chemotherapy significantly enhances outcomes, including overall survival. All patients should be assessed for the use of trastuzumab unless contraindications exist. Overall approximately 25% of gastroesophageal adenocarcinomas will overexpress Her2/neu at a level appropriate for the use of trastuzumab. It is important to work with the pathologist to define the level of expression as the criteria differ from those used in breast cancer. Dosages are given in Chapter 4, Section VII.J.
C. RT
1. Localized disease. RT alone has not proved useful for treating gastric cancer. RT (4,000 cGy in 4 weeks) in combination with 5-FU (15 mg/kg IV on the first 3 days of RT), however, appears to improve survival over RT alone in patients with localized but unresectable cancers. Intraoperative radiation therapy (IORT) allows high doses of radiation to the tumor bed or residual disease while permitting the exclusion of mobile radiosensitive normal tissues from the area irradiated. Trials are limited to single institutional experiences; therefore, generalizing from such trials is difficult. Selected patients may benefit from IORT, particularly when combined with supplemental external-beam radiation and chemotherapy. Long-term survival has been reported in some patients treated in this fashion for residual disease after surgery.
2. Advanced disease. Gastric adenocarcinoma is relatively radioresistant and requires high doses of radiation with attendant toxic effects to surrounding organs. RT may be useful for palliating pain, vomiting due to obstruction, gastric hemorrhage, and metastases to bone and brain.
COLORECTAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Colorectal cancer is the second most common cause of cancer mortality after lung cancer in the United States and ranks third in frequency among primary sites of cancer in both men and women. Nearly one million cases are diagnosed annually worldwide, accounting for 9% to 10% of human cancers. Peak incidence rates are observed in Europe, the United States, Australia, and New Zealand. The lowest incidence rates are noted in India and South America and among Arab Israelis. A 10-fold variability is noted from highest to lowest regional incidence rates. Both the incidence and the mortality rates have declined in the United States since they peaked in 1985, a phenomenon thought to be a consequence of increased screening for and removal of premalignant polyps as well as potentially a more widespread use of aspirin and other nonsteroidal antirheumatic agents. Studies of migrant populations have discerned that the incidence of colorectal cancer reflects country of residence and not the country of origin. This suggests that overall environmental influences outweigh genetic trends for populations in which the experiences of those people with inherited special risk are pooled with those of lesser risk. Rural dwellers have a lower incidence of colorectal cancer than do urbanites. In the United States, cancer of the colon/rectum is more common in the East and the North than in the West and the South.
The risk for colorectal cancer increases with age, but 3% of colorectal cancers occur in patients younger than 40 years of age. The incidence is 19 per 100,000 population for those younger than 65 years of age and 337 per 100,000 among those older than 65 years of age. The median age of diagnosis is around 70 years. It was estimated that, in the United States in 2010, 143,000 new cases of colorectal cancer developed and an estimated 51,400 persons died from the disease. In the United States, a person of average risk has a 5% lifetime risk for developing colorectal cancer.
B. Etiology. Multiple forces drive the transformation of healthy colorectal mucosa to cancer. Inheritance and environmental factors, such as maintaining a low body mass index and exercising regularly, correlate with lower incidence rates, but the extent of the interdependence of these two factors as causative variables remains unknown.
1. Polyps. The main importance of polyps is the well-recognized potential of a subset to evolve into colorectal cancer. The evolution to cancer is a multistage process that proceeds through mucosal cell hyperplasia, adenoma formation, and growth and dysplasia to malignant transformation and invasive cancer. Environmental carcinogens may result in the development of cancer regardless of a patient’s genetic background, but patients with genetically susceptible mucosa inherit a predisposition to abnormal cellular proliferation. Oncogene activation, tumor suppressor gene inactivation, deficient DNA mismatch repair enzymes, and chromosomal deletion may lead to adenoma formation, growth with increasing dysplasia, and invasive carcinoma.
a. Types of polyps. Histologically, polyps are classified as neoplastic or nonneoplastic. Nonneoplastic polyps have no malignant potential and include hyperplastic polyps, mucous retention polyps, hamartomas (juvenile polyps), lymphoid aggregates, and inflammatory polyps. Neoplastic polyps (or adenomatous polyps) have malignant potential and are classified according to the World Health Organization system as tubular (microscopically characterized by networks of complex branching glands), tubulovillous (mixed histology), or villous (microscopically characterized by relatively short, straight glandular structures) adenomas, depending on the presence and volume of villous tissue. Polyps larger than 1 cm in diameter, those with high-grade dysplasia, and those with predominantly villous histology are associated with higher risk for colorectal cancer and are termed screen-relevant neoplasias. Colonoscopic polypectomy and subsequent surveillance can reduce the incidence of colon cancer by 90%, compared with that observed in unscreened controls.
b. Frequency of polyp types. About 70% of polyps removed at colonoscopy are adenomatous, 75% to 85% of which are tubular (no or minimal villous tissue), 10% to 25% are tubulovillous (<75% villous tissue), and fewer than 5% are villous (>75% villous tissue). The incidence of synchronous adenomas in patients with one known adenoma is 40% to 50%.
c. Dysplasia may be classified as low and high grade. About 6% of adenomatous polyps exhibit high-grade dysplasia and 5% contain invasive carcinoma at the time of diagnosis.
d. The malignant potential of adenomas correlates with increasing size, the presence and the degree of dysplasia in a villous component, and the patient’s age. Small colorectal polyps (smaller than 1 cm) are not associated with increased occurrence of colorectal cancer; the incidence of cancer, however, is increased 2.5- to 4-fold if the polyp is larger than 1 cm and 5- to 7-fold in patients who have multiple polyps. The study of the natural history of untreated polyps larger than 1 cm showed that the risk for progression to cancer is 2.5% at 5 years, 8% at 10 years, and 24% at 20 years. The time to malignant progression depends on the severity of dysplasia, averaging 3.5 years for severe dysplasia and 11.5 years for mild atypia.
e. Management of polyps. Because of the adenoma–cancer relationship and the evidence that resecting adenomas prevents cancer, newly detected polyps should be excised and additional polyps should be sought through colonoscopy. There are data to show that the miss rate for polyps that are potentially detectable during colonoscopy is lower when the operator exceeds an endoscope-withdrawal time of 6 minutes. A minority of polyps are flat and lack an easily detectable profile in the absence of special techniques, such as instillation of dye, to accentuate mucosal irregularities during screening.
The accuracy of colonoscopic examinations (94%) exceeds that of barium enema (67%), which is seldom used as a screening tool anymore. Additionally, with colonoscopy, therapeutic polypectomy can be accomplished during the diagnostic examination. CT colonography (virtual colonoscopy) is increasingly sensitive and specific, with refinements in software and radiologist expertise leading to sufficient improvements in the technique such that many centers offer this as a screening option, although a regular bowel preparation is required, and if relevant polyps are found, a colonoscopy will have to be performed. Fecal DNA assays that target genetic abnormalities specific to the malignant transformation of mucosal cells are now commercially available and are continuously being refined to improve their performance. The year 2000 recommendations of the American College of Gastroenterology for the management of colorectal polyps are discussed by Bond and colleagues (see Suggested Reading).
f. Intestinal polyposis syndromes. Table 9.3 summarizes familial polyposis syndromes and their histology distribution, malignant potential, and management (see Section V.B.3 for discussion of the potential benefit of anti-inflammatory drugs).
Table 9.3 Polyp Syndromes and Colorectal Cancer
FOB, fecal occult blood; CC, colorectal cancer; AP, adenomatous polyps; HNPCC, hereditary nonpolyposis colorectal cancer (“cancer family syndrome”); Ac, adenocarcinoma; ES, endoscopic surveillance; FAP, familial adenomatous polyposis; SB, small bowel; JP, juvenile (retention) polyps.
aLynch syndrome I: autosomal-dominant inheritance with susceptibility to early onset of colorectal cancer proximal to the splenic flexure in the absence of diffuse polyps; Lynch syndrome II: contains most of the features of Lynch I with excess incidence of carcinomas of the endometrium, ovary, kidney, ureter, bladde r, bile duct, and small bowel and of lymphoma. (Lynch HT. The surgeon and colorectal cancer genetics. Arch Surg 1990;125:699.)
bEpidermoid cysts, fibromas, desmoids, dental and osseous abnormalities, intraperitoneal and retroperitoneal fibrosis, ampullary carcinoma, and tumors in other glandular structures. Follow with ophthalmoscopy for associated congenital hypertrophy of the retinal pigment epithelium.
cHyperpigmentation, alopecia, and nail dystrophy.
dProphylactic colectomy should be considered if 5 to 10 adenomatous polyps are present or if polyps recur.
eOr, total colectomy with pouch reconstruction. Nonsteroidal anti-inflammatory drugs decrease the number and size of polyps (see “Colorectal Cancer” section V.B.3).
2. Diet. Populations with high intake of fat, higher caloric intakes, and low intake of fiber (fruits, vegetables, and grains) characterized as a westernized diet tend to have increased risk for colorectal cancer in most but not all studies. Higher calcium intake, calcium supplementation, vitamin D supplementation, and regular aspirin use are associated with a lower risk for colorectal polyps and cancer in some studies. Fewer tumors that overexpress Cox-2 occur in individuals who regularly use aspirin, which is known to reduce the incidence of both polyps and cancers. Increased intake of vitamins A, C, and E and β-carotene does not appear to decrease the risk for polyp formation. The higher incidence of rectal and sigmoid cancer in men may be related to their greater consumption of alcohol. Women who have taken postmenopausal estrogen replacement therapy appear to have a lower risk for colorectal cancer than those who have not.
3. Inflammatory bowel disease
a. Ulcerative colitis is a clear risk factor for colon cancer. About 1% of colorectal cancer patients have a history of chronic ulcerative colitis. The risk for the development of cancer in these patients varies inversely with the age of onset of the colitis and directly with the extent of colonic involvement and duration of active disease. The cumulative risk is 2% at 10 years, 8% at 20 years, and 18% at 30 years. Individuals with colon cancers associated with ulcerative colitis have a similar prognosis to sporadic cases.
The recommended approach to the increased risk for colorectal cancer in ulcerative colitis has been annual or semiannual colonoscopy to determine the need for total proctocolectomy in patients with extensive colitis of >8 years’ duration. This strategy is based on the assumption that dysplastic lesions can be detected before invasive cancer has developed. An analysis of prospective studies concluded that immediate colectomy is essential for all patients diagnosed with a dysplasia-associated mass or lesion. Most important, the analysis demonstrated that the diagnosis of dysplasia does not preclude the presence of invasive cancer. The diagnosis of dysplasia has inherent problems with sampling of specimens and with variation in agreement among observers (as low as 60%, even with experts in the field).
b. Crohn disease. Patients with colorectal Crohn disease are at increased risk for colorectal cancer, but the risk is less than that of those with ulcerative colitis. The risk is increased about 1.5 to 2 times.
4. Genetic factors
a. Family history may signify either a genetic abnormality or shared environmental factors or a combination of these factors. About 15% of all colorectal cancers occur in patients with a history of colorectal cancer in first-degree relatives. Individuals with a first-degree relative who has had colorectal cancer are more than twice as likely to develop colon cancer than those individuals with no family history.
b. Gene changes. Specific inherited (adenomatous polyposis coli [APC] gene) and acquired genetic abnormalities (ras gene point mutation; c-myc gene amplification; allele deletion at specific sites of chromosomes 5, 8, 17, and 18) appear to be capable of mediating steps in the progression from normal to malignant colonic mucosa. About half of all carcinomas and large adenomas have associated point mutations, most often in the K-ras gene. Such mutations are rarely present in adenomas smaller than 1 cm. Allelic deletions of 17p– are demonstrated in three-fourths of all colorectal carcinomas, and deletions of 5q– are demonstrated in more than one-third of colonic carcinoma and large adenomas.
Two major syndromes and several variants of these syndromes of inherited predisposition to colorectal cancer have been characterized. The two syndromes, which predispose to colorectal cancer by different mechanisms, are FAP and hereditary nonpolyposis colorectal cancer (Lynch syndrome or HNPCC).
(1) FAP. The genes responsible for FAP, APC genes, are located in the 5q21 chromosome region. Inheritance of defective APC tumor-suppressor gene leads to a virtually 100% likelihood of developing colon cancer by 55 years of age, leading to the recommendation of a total proctocolectomy for affected individuals during their 20s or 30s. Screening for polyps should begin during early teenage years. The FAP syndrome can be associated with the development of gastric and ampullary polyps, desmoid tumors, osteomas, abnormal dentition, and abnormal retinal pigmentation. Variants of FAP include Gardner and Turcot syndromes.
(2) HNPCC. The autosomal-dominant pattern of HNPCC includes Lynch syndromes I and II, both of which are associated with an increased incidence of predominantly right-sided colon cancer. This genetic abnormality in the DNA mismatch repair enzymes leads to defective excision of abnormal repeating sequences of DNA known as microsatellites (microsatellite instability [MSI]). Retention of these sequences leads to expression of a mutator phenotype characterized by frequent DNA replication errors (also called the RER+ phenotype), which predispose affected people to a multitude of primary malignancies, including cancers of the endometrium, ovary, bladder, ureter, stomach, and biliary tract.
(a) Specific mutated genes on chromosomes 2 and 3, known as hMSH2, hMLH1, hPMS1, and hPMS2, have been linked to HNPCC. Patients with the RER+ phenotype may not have a germ line abnormality and may instead have acquired abnormal methylation of DNA as the source of the absence of expression of the genes previously noted. Abnormal methylation, which silences the promoter region of mismatch repair genes preventing protein synthesis, is more common in older patients and women. Germ line testing to determine if the RER+ phenotype is inherited or acquired is necessary as a part of genetic counseling when an individual is found to have a mismatch repair defect. Immunohistochemical stains can be used to determine if a tumor is devoid of the expression of mismatch repair enzymes, and then patients with absent gene expression should undergo germ line testing to enable appropriate counseling of family members.
(b) Patients with HNPCC have a tendency to develop colon cancer at an early age, and screening should begin by 20 years of age or 5 years earlier than the age at diagnosis of the earliest affected family member for relatives of HNPCC patients. The median age of HNPCC patients with colon cancer at diagnosis was 44 years, versus 68 years for control patients in one study.
(c) The prognosis for HNPCC patients is better than for those patients with sporadic colon cancer; the death rate from colon cancer for HNPCC patients is two-thirds that for sporadic cases over 10 years. One study suggests that patients with HNPCC may derive less benefit from adjuvant chemotherapy based on fluorouracil combinations than patients without this abnormality. Correlation with additional data from patients treated in the adjuvant setting and from patients with advanced disease is needed.
(d) It is important to note that apart from the genetic deficiency in mismatch repair enzyme expression, about 15% of colon cancers exhibit the same biologic phenotype as HNPCC-derived tumors via the methylation of the promoter regions of DNA mismatch repair enzyme genes.
c. Tumor location. Proximal tumors have a higher likelihood to exhibit the defective DNA mismatch repair phenotype and MSI. Distal tumors show evidence of greater chromosomal instability and may develop through the same mechanisms that underlie familial polyposis-associated colorectal cancer.
5. Smoking. Men and women smoking during the previous 20 years have three times the relative risk for small adenomas (<1 cm) but not for larger ones. Smoking for >20 years was associated with 2.5 times the relative risk for larger adenomas. It has been estimated that 5,000 to 7,000 colorectal cancer deaths in the United States can be attributed to cigarette use.
6. Other factors. Personal or family history of cancer in other anatomic sites (such as breast, endometrium, and ovary) is associated with increased risk for colorectal cancer. Exposure to asbestos (e.g., in brake mechanics) increases the incidence of colorectal cancer to 1.5 to 2 times that of the average population. Other than this association, there appears to be little relationship between occupational exposures and the incidence of colon cancer. Data indicate that HPV infection of the columnar mucosa of the colon may cause benign and malignant neoplasia.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Ninety-eight percent of colorectal cancers above the anal verge are adenocarcinomas. Cancers of the anal canal are most often squamous cell or basaloid carcinomas. Carcinoid tumors cluster around the rectum and cecum and spare the rest of the colon and are distinguished from undifferentiated small cell neuroendocrine tumors of the colon by their tendency to be both well differentiated and indolent in their behavior.
B. Location. Two-thirds of colorectal cancers occur in the left colon and one-third in the right colon, although women more often develop right-sided tumors. About 20% of colorectal cancers develop in the rectum. Rectal tumors can be detected by digital rectal examination in 75% of cases. Nearly 3% of colorectal adenocarcinomas are multicentric, and the risk for developing a second primary tumor in the colon is estimated to be approximately 1% per year.
C. Clinical presentation. The common clinical complaints of patients with colorectal cancer relate to the size and location of the tumor. Right-sided colonic lesions are often asymptomatic but when symptoms are manifested, these tumors most often result in dull and ill-defined abdominal pain, bleeding, and symptomatic anemia (causing weakness, fatigue, and weight loss), rather than in colonic obstruction. Left-sided lesions lead commonly to changes in bowel habits, bleeding, gas pain, decrease in stool caliber, constipation, increased use of laxatives, and colonic obstruction. Sometimes, distant metastases, in particular liver metastases, can cause the initial clinical symptoms.
D. Clinical course. Metastases to the regional lymph nodes are found in 40% to 70% of cases at the time of resection. Venous or lymphatic invasion is found in up to 60% of cases. Metastases occur most frequently in the liver, peritoneal cavity, and lung, followed by the adrenals, ovaries, and bone. Metastases to the brain, while rare, are noted more commonly as survival with distant disease is extended by better treatments. Rectal cancers are three times more likely to recur locally than are proximal colonic tumors, in part because the anatomic confines of the rectum preclude wide resection margins and in part because the rectum lacks an outer serosal layer through most of its course. Because of the venous and lymphatic drainage of the rectum into the inferior vena cava (as opposed to the venous drainage of the colon into the portal vein and variable lymphatic drainage), rectal cancers have a higher incidence of lung metastasis compared with colon cancers that more frequently recurs first in the liver.
III. DIAGNOSIS
A. Diagnostic studies. After the clinical diagnosis of colorectal cancer is made, several diagnostic and evaluative steps should be taken.
1. Biopsy confirmation of malignancy via colonoscopy or via CT-guided fine-needle aspiration is important.
2. General evaluation includes a complete physical examination with digital rectal examination, CBC, LFT, and chest imaging.
3. Carcinoembryonic antigen (CEA) screening is recommended by the American Society of Clinical Oncology (ASCO) as a means of identifying early recurrence despite the lack of elevation in 40% of individuals with metastatic disease. A preoperative CEA can be useful as a prognostic factor and in determining if the primary tumor is associated with CEA elevation. Preoperative CEA elevation implies that CEA may aid in early identification of metastases because metastatic tumor cells are more likely to result in CEA elevation in this circumstance.
4. CT or MRI with contrast of the chest, abdomen, and pelvis may identify small lung, liver, or intraperitoneal metastases.
5. Endoscopy (or CT colonography) is indicated to assess the entire colonic mucosa because about 3% of patients have synchronous colorectal cancers and a larger percentage have additional premalignant polyps.
6. EUS significantly improves the preoperative assessment of the depth of invasion of large bowel tumors, especially rectal tumors. The accuracy rate is 95% for EUS, 70% for CT, and 60% for digital rectal examination. In rectal cancer, the combination of EUS to assess tumor extent and digital rectal examination to determine mobility should enable precise planning of surgical treatment and definition of those patients who may benefit from pre-operative chemoradiation (T3, 4 and N+). Transrectal biopsy of perirectal lymph nodes can often be accomplished under EUS direction. MRI with rectal coils is comparable to EUS in its sensitivity for staging the primary tumor and might be superior to EUS in the identification of perirectal lymph node metastases.
7. PET scanning is of increasing utility to help distinguish if anatomic lesions of unclear origin are malignant or benign. Such scans are also useful to determine if localized or metastatic disease is potentially resectable.
B. Biological markers
1. CEA is a cell-surface glycoprotein that is shed into the blood and is the best-known serologic marker for monitoring colorectal cancer disease status and for detecting early recurrence and liver metastases. CEA is too insensitive and nonspecific to be useful for screening of colorectal cancer. Elevation of serum CEA levels, however, does correlate with a number of parameters. Higher CEA levels are associated with histologic grade 1 or grade 2 tumors, more advanced stages of the disease, and the presence of visceral metastases. Although serum CEA concentration is an independent prognostic factor, its putative value lies in serial monitoring after surgical resection.
2. Other markers, such as CA 19-9, may be of value in monitoring recurrences and complement CEA. Monoclonal antibodies (anti-CEA, anti-TAG-72) may also be useful in immunohistologic chemical staining of tissues. The presence of an abnormal number of chromosomes in the tumor cells (aneuploidy) confers a worse prognosis than is observed in patients with diploid tumors. Light microscopic features and stage, however, remain the most reliable prognostic measures. Early reports suggest that tumor DNA and circulating tumor cells may also have utility both as initial diagnostic tools and for early diagnosis of recurrent disease.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. Staging using the TNM system has been recommended over the Astler-Coller modification of the Dukes system. Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. The current staging system is delineated in Table 9.4.
Table 9.4 TNM Staging System for Cancers of the Colon and Rectuma
MAC, modified Astler-Coller classification.
aAdapted from the AJCC Cancer Staging Manual. 7th ed. Springer; 2010.
B. Prognostic factors
1. Stage is the most important prognostic factor (see Section IV.A).
2. Histologic grade significantly influences survival regardless of stage. Patients with well-differentiated carcinomas (grades 1 and 2) have a better 5-year survival than those with poorly differentiated carcinomas (grades 3 and 4).
3. The anatomic location of the tumor appears to be an independent prognostic factor. For equal stages, patients with rectal lesions have a worse prognosis than those with colon lesions, and transverse and descending colon lesions result in poorer outcomes than ascending or rectosigmoid lesions.
4. Clinical presentation. Patients who present with bowel obstruction or perforation have a worse prognosis than patients who present with neither of these problems.
5. Chromosome 18. The prognosis of patients with an allelic loss of chromosome 18q is significantly worse than that of patients with no allelic loss. The survival of patients with stage II (B) disease is the same as that for stage I (A) when there is no allelic loss and the same as for stage III (C) when there is allelic loss. Other abnormalities that have been identified and that are of potential value for determining prognosis are located on chromosomes 1, 5, 8, 17, and 22. Identification of these genes or their products is possible using gel electrophoresis or immunohistochemical probes. These observations may ultimately prove to be helpful in selecting patients with stage II (B) disease for adjuvant therapy or stage III (C) patients with better-than-average prognoses who can avoid the potential toxicity and expense of adjuvant therapy.
6. Other tumor characteristics. Investigators have examined a number of tumor characteristics as judged by immunohistochemical or polymerase chain reaction-based assays for use either as factors for predicting prognosis or as characteristics that could potentially predict the likelihood of an individual patient’s response to a specific regimen. These evaluations include levels in the tumor of thymidylate synthetase, dihydropyrimidine dehydrogenase (DPD), proliferation markers (Ki-67 or MIB-1), and tumor-suppressor deletions (such as 18q deletions), among others. Molecular signature assays as prognostic markers have been developed and are commercially available for patients with stage II colon cancer, although their relevance for clinical practice is still unclear.
V. SCREENING AND PREVENTION
A. Screening. The National Cancer Institute, the American College of Surgeons, the American College of Physicians, and the American Cancer Society (ACS) recommend a number of potential screening tests as alternatives for asymptomatic patients who are 50 years of age and older. One option is to have a sigmoidoscopic examination every 3 to 5 years. An annual digital rectal and three-sample fecal occult blood (FOB) test examination are recommended by the ACS, American College of Gastroenterology, and NCI for people 50 years of age and older. Screening colonoscopy has also been recommended for average-risk individuals every 10 years. Screening colonoscopy for high-risk patients with a family history of colorectal cancer in first-degree relatives but no clear evidence of FAP or HNPCC should begin at 40 years of age.
1. Three large randomized trials in which >250,000 patients were tested for FOB or followed according to the usual patterns of care have been reported. In the largest trial and the only one conducted in the United States, annual testing of a rehydrated fecal smear was associated with a 33.4% decrease in risk for death from colorectal cancer in 46,551 adults older than 50 years of age. Better markers for colorectal cancer are being sought because of the high false-positive and false-negative rates associated with FOB.
2. There has been burgeoning interest in the isolation of specific DNA sequences such as those in the APC or p53 genes and long segments of DNA that can be obtained from colonocytes shed into the stool and assayed using techniques for amplifying the amount of DNA present. These markers appear to be sensitive and specific for screening for malignancy in the aerodigestive tract. These technologies continue to undergo refinement and large-scale randomized trials of FOB versus these DNA-based assays are under way.
B. Prevention. The management of patients with ulcerative colitis is discussed in Section I.B.3.a.
1. Periodic sigmoidoscopy or colonoscopy identifies and removes precancerous lesions (polyps) and reduces the incidence of colorectal cancer in patients who undergo colonoscopic polypectomy. However, no prospective randomized clinical trials have yet demonstrated that sigmoidoscopy is effective in the prevention of colorectal cancer death, although trials to test this strategy are in progress. The presence of even small rectosigmoid polyps is associated with polyps beyond the reach of the sigmoidoscope, and their presence should lead to full colonoscopy.
2. Diets that are high in fiber and low in fat or that contain calcium supplements, or both, may deter polyp progression to cancer.
3. Nonsteroidal anti-inflammatory drugs (NSAIDs). In a randomized, double-blind, placebo-controlled study of patients with familial polyposis, the NSAID sulindac at a dose of 150 mg b.i.d. significantly decreased the mean number and mean diameter of polyps as compared with those in patients given placebo. The size and number of the polyps, however, increased 3 months after the treatment was stopped but remained significantly lower than at baseline. Data further suggest that aspirin reduces the formation, number, and size of colorectal polyps and reduces the incidence of colorectal cancer, whether familial or nonfamilial. These protective effects appear to require continuous exposure to at least 325 mg of aspirin per day for years. Selective Cox-2 inhibitors have also been shown to be preventive for colon cancer but have been associated with an increased risk of cardiac events such that these are not routinely recommended outside of clinical trials
VI. MANAGEMENT
A. Surgery is the only universally accepted potentially curative treatment for colorectal cancer. Curative surgery should excise the tumor with wide margins and maximize regional lymphadenectomy such that at least 12 lymph nodes are available for pathologic evaluation. For lesions above the rectum, resection of the tumor with a minimum 5-cm margin of grossly negative colon is considered adequate, although the ligation of vascular trunks required to perform an adequate lymphadenectomy may necessitate larger bowel resections. Laparoscopic colectomy approaches have been developed and appear to be equally effective staging and therapeutic approaches to open colectomy, with modest decreases in hospital stay and pain medication use and improved cosmetic results. Subtotal colectomy and ileoproctostomy may be advisable for patients with potentially curable colon cancer and with adenomas scattered in the colon or for patients with a personal history of prior colorectal cancer or a family history of colorectal cancer in first-degree relatives.
1. Arterial supply. Excision of a tumor in the right colon should include the right branch of the middle colic artery as well as the entire ileocolic and right colic artery. Excision of a tumor at the hepatic or splenic flexure should include the entire distribution of the middle colic artery.
2. Avoidance of permanent colostomy in middle and low rectal cancers has been encouraged by the emergence of new surgical stapling techniques as well as the use of preoperative chemotherapy and radiation to shrink tumors prior to resection.
3. Rectal tumors may be treatable by primary resection and more distal anastomosis, usually without even a temporary (anastomosis-protective) colostomy, if the lower edge is above 5 cm from the anal verge. Treatment options for rectal tumors include the following:
a. Middle and upper rectum (6 to 15 cm): Anterior resection of rectum
b. Lower rectum (0 to 5 cm): Coloanal anastomosis, with or without a pouch, transanal excision, transsphincteric and parasacral approaches, diathermy, primary radiation therapy, or abdominoperineal resection (APR)
c. Total mesorectal excision (TME). The mesorectum is defined as the lymphatic, vascular, fatty, and neural tissues that are circumferentially adherent to the rectum from the level of the sacral promontory to the levator ani muscles. Data from Europe suggest that local recurrence rates may be decreased with en bloc sharp dissection of the entire mesorectum at the time of tumor extirpation, and this procedure has now become standard.
4. Obstructing tumors in the right colon are usually managed by primary resection and primary anastomosis. Obstructing tumors in the left colon may be managed with initial decompression (proximal colostomy) or stent insertion followed by resection of the tumor and deferred closure of the colostomy. Recent trends, however, favor extending resection and primary anastomosis to include obstructing tumors in the transverse, descending, and even sigmoid colon.
5. Perforated colon cancer requires initial excision of the primary tumor and a proximal colostomy, followed later by reanastomosis and closure of the colostomy.
B. Adjuvant chemotherapy for stage III colon cancer (lymph node involvement) with 5-FU plus levamisole (mainly of historical interest) or 5-FU plus leucovorin (FU/L) reduced the incidence of recurrence by 41% (p < 0.001) in a number of large prospective randomized trials. The MOSAIC study in Europe randomized 2,200 patients (40% stage II, 60% stage III) to receive 5-FU infusion and leucovorin without or with oxaliplatin (FOLFOX). The primary end point of this trial was 3-year overall disease-free survival (DFS) rather than the more conventional end point of 5-year overall survival. There was a 73% 3-year DFS for the standard 5-FU/leucovorin arm and a 78% 3-year DFS for the FOLFOX regimen, with a 7.5% statistically significant advantage for stage III disease. Recently presented data have shown a 2.6% benefit in 6-year overall survival for FOLFOX over the two-drug regimen in all patients with a 4.4% difference for stage III disease. The National Surgical Adjuvant Breast Project (NSABP) C-07 study showed a similar outcome for DFS, but a higher rate of diarrhea for the specific regimen that employed a bolus-based 5-FU plus oxaliplatin regimen called FLOX.
The superiority of an oxaliplatin-fluoropyrimidine regimen to fluoropyrimidine alone was confirmed in a phase III trial comparing bolus 5-FU/LV to a combination of capecitabine plus oxaliplatin (XELOX) with increased DFS, comparable to the results found with FOLFOX and FLOX.
Three randomized trials have failed to show an advantage to irinotecan-containing regimens in the adjuvant setting. The use of irinotecan alone or in combinations is not recommended in the adjuvant setting.
Similarly, two large randomized phase III trials (NSABP C-08 and AVANT) have failed to show a benefit in terms of DFS and OS for the addition of bevacizumab to FOLFOX as adjuvant therapy in stage II and III colon cancer. In addition, the cetuximab added to FOLFOX as tested in the phase III Intergroup trial N0147 also did not improve outcomes as adjuvant therapy in stage III colon cancer, not even in patients with KRAS wild-type cancers.
As a consequence, the standard treatment for stage III colon cancer is now an oxaliplatin-containing regimen, most commonly FOLFOX or XELOX, unless there are contraindications to its use such as pre-existing sensory neuropathy. In that case, FU/LV or capecitabine is recommended. In a large study known as the X-ACT trial, capecitabine, an oral 5-FU prodrug, was compared with bolus FU/LV and outcomes were essentially equivalent. Adjuvant chemotherapy is begun 3 to 5 weeks after surgery.
1. FU/LV regimens Two bolus 5-FU regimens commonly employed in the United States are as follows:
a. Dosage, Mayo Clinic regimen: Leucovorin, 20 mg/m2 by 30-minute IV infusion, followed by 5-FU, 425 mg/m2 by rapid IV injection, daily for 5 consecutive days for two 4-week cycles and then every 5 weeks thereafter
b. Dosage, Roswell Park Memorial Institute (RPMI) regimen: Leucovorin, 500 mg/m2 by 30-minute IV infusion, followed by 5-FU, 500 mg/m2 by rapid IV injection, weekly for 6 of every 8 weeks
c. The side effects of the Mayo and RPMI regimens and capecitabine are different. Toxicity of grade III or more is based on the NCI common toxicity criteria (see Appendix B-2). The principal difference in toxicity between the two regimens relates to rates of severe stomatitis and diarrhea. The Mayo regimen is associated with more grade III neutropenia and stomatitis, the RPMI regimen with a higher rate of grade III diarrhea. Nausea and vomiting are generally not severe. Dermatologic side effects are generally limited to erythema and desquamation of sun-damaged skin.
Capecitabine is able to be administered orally and is associated with less GI toxicity and neutropenia than bolus FU regimens. However, it does cause hand–foot syndrome in which the skin of the palms and soles can become tender, erythematous, and if the drug is continued, exfoliation of the overlying skin may follow.
d. Dihydropyrimidine (DPD) is the rate-limiting enzyme in the breakdown of 5-FU. Less than 1% of the US population has a deficiency of DPD. Such patients have severe toxicity and often die after exposure to standard doses because of profound and prolonged neutropenia and mucositis. Cerebellar toxicity occurs relatively commonly in DPD-deficient patients. An assay for DPD levels is commercially available and can be selectively ordered if DPD deficiency is suspected based on history or clinical parameters.
2. FOLFOX and XELOX are the preferred regimens
a. Dosage, FOLFOX4. Leucovorin, 200 mg/m2, is given preceding a bolus of 5-FU of 400 mg/m2. A 22-hour infusion of 600 mg/m2 is then administered via infusion pump. The FU/L infusion is given on 2 consecutive days. Oxaliplatin is given at a dose of 85 mg/m2 on day 1. The cycle is repeated every 2 weeks. Other FOLFOX regimens including FOLFOX 6, modified FOLFOX 6, and FOLFOX 7 explore variations on the oxaliplatin dose and have eliminated the 5-FU bolus.
b. Dosage, XELOX. Capecitabine 1,000 mg/m2 b.i.d. PO days 1 to 14, oxaliplatin 130 mg/m2 IV on day 1 of a 3-week cycle. Planned duration of eight cycles. Commonly, capecitabine has to be reduced to 850 mg/m2b.i.d. due to hand–foot syndrome and diarrhea.
c. Dosage, FLOX. Leucovorin 500 mg/m2 is given preceding a bolus of 5-FU of 500 mg/m2 weekly for 6 weeks in three 8-week cycles. Oxaliplatin, 85 mg/m2, is given on weeks 1, 3, and 5 of each 8-week cycle. No pumps or prolonged infusions are used. Grade 3/4 diarrhea occurs in 40% of patients.
d. The side effects of FOLFOX4. This regimen is commonly associated with grade 3 to 4 neutropenia (41% in the MOSAIC trial) but seldom causes neutropenic fever (1.8%). GI tract toxicity is less problematic than in the bolus-based 5-FU regimens, with 2.7% having stomatitis, 5.9% vomiting, and 10.8% diarrhea. Alopecia is relatively rare at 5%. Chronic sensory neuropathy, which is often aggravated by cold exposure and can limit the amount of oxaliplatin that can be administered over time, afflicted 12.3% of patients, but most patients with grade 3 neuropathy had recovered 1 year after the agent was stopped.
e. The side effects of XELOX. Hand–foot syndrome, diarrhea, and sensory neuropathy as described above for FOLFOX are common. Myelosuppression is less common than with FOLFOX4.
C. Adjuvant chemotherapy for stage II colon cancer (no lymph node involvement) is controversial. Investigators from the NSABP advocate for adjuvant therapy in this setting because it has produced a small but consistent benefit in patients with stage II disease in serial NSABP trials. Conversely, a meta-analysis of five trials involving about 1,000 patients showed a statistically insignificant difference in 5-year survival rates of 82% versus 80%, treated versus untreated, respectively, for patients with stage II disease. The QUASAR group did show a 3% survival advantage at 5 years for FU/L over observation in a trial that enrolled >3,200 patients. There was no survival advantage for the 40% of stage II patients enrolled in the MOSAIC trial. The ASCO recommends against the routine use of chemotherapy in stage II colon cancer.
Intense efforts have focused on differentiating stage II patients with higher risk for recurrence from those with lower risk through examination of molecular markers such as tumor ploidy (number of chromosomes), p53 status, levels of thymidylate synthesis, presence or absence of individual chromosomal mutations, and other parameters. Although none of these is accepted as a standard prognostic determinant, in one trial, patients with aneuploid tumors had a 5-year survival rate of 54%, compared with patients with diploid tumors who had a 74% 5-year survival rate.
Several attempts have been made to characterize a population of stage II patients at high risk for tumor recurrence and metastases. The best validated high-risk factors are T4 tumor stage and the retrieval of <12 lymph nodes in the resected specimen. In contrast, obstruction, perforation, lymphovascular invasion, and undifferentiated histology have been found to be of lesser value in multivariate analysis. High-risk stage II colon cancers are commonly treated with oxaliplatin-containing regimens as adjuvant therapy. Patients with tumor expressing the defective mismatch repair phenotype (dMMR or high microsatellite instability—MSI-H) are at low risk of recurrence and should not be subjected to any adjuvant chemotherapy unless high-risk factors are present. For the group of patients with intermediate risk of recurrence, commercial molecular signature stets are available that can help to refine the prognosis, although the utility of these tests in clinical practice has yet to be established.
D. Neoadjuvant therapy for rectal cancer. Because of the anatomic confines of the pelvic bones and sacrum, surgeons often cannot achieve wide, tumor-free margins during the resection of rectal cancer. Almost half of recurrences in rectal cancer are in the pelvis. This observation led a German group to compare preoperative chemotherapy with 5-FU and radiation to postoperative therapy in order to determine if the preoperative strategy could improve outcomes and reduce the number of APRs that result in a permanent colostomy. The trial randomized >800 patients and the outcomes favored preoperative therapy, which showed a lower local recurrence rate, less anastomotic stenosis, and fewer APRs. Patients who have a complete pathologic response to preoperative therapy have a favorable long-term prognosis. In general, postoperative adjuvant therapy with FOLFOX or FU/L based on preoperative staging is indicated for patients with known or suspected positive nodes. This trial has led to a widespread shift in practice to embrace preoperative chemotherapy plus RT.
1. Variations in the use of RT alone or combined with chemotherapy and in surgical technique have been investigated in attempts to improve local control rates. Numerous randomized controlled studies of both preoperative and postoperative RT alone have demonstrated no improvement in survival; at best, there has been a small decrease in the rate of local recurrence. In the United States, radiation is generally given over 6 weeks to a dose approaching 50 Gy and surgery is performed 4 to 6 weeks later. In some countries in Europe, it is common to give 25 Gy in five fractions (5 × 5 Gy) without chemotherapy and proceed promptly to surgery. In two randomized, albeit small trials, these two approaches demonstrated similar short-term results in terms of local recurrence rates.
A number of European surgeons have advocated TME and it has now become the standard of care. A Dutch trial showed that TME is associated with a lower local recurrence rate than conventional rectal resection but have also noted that rectal stump devascularization results in a higher rate of postoperative anastomotic site leakage. RT after TME reduces the rate of local recurrence at 2 years from the time of surgery, suggesting that RT is still a valuable tool in reducing local recurrence even after the more extensive en bloc resection done with TME.
2. The current standard therapy for stage III rectal cancer, and sometimes for stage II disease, is preoperative chemotherapy using 5-FU and RT, followed by surgery, and then followed by adjuvant chemotherapy which is modeled after experiences in colon cancer.
E. Postoperative follow-up. About 85% of all recurrences that are destined to occur in colorectal cancer are evident within 3 years after surgical resection, and nearly all recurrences are noted within 5 years. High preoperative CEA levels usually revert to normal within 6 weeks after complete resection.
1. Clinical evaluation. After curative surgical resection, patients with stage II and III colon or rectal cancer are commonly seen more frequently during the first 2 postoperative years and less frequently thereafter. After 5 years, follow-up is mainly targeted at detection of new primary tumors. The primary goal of follow-up is to detect metastatic disease early. Some patients with colorectal cancer develop a single or a few metastatic sites (known as oligometastases) in the liver, in the lungs, or at the anastomotic site from which the primary bowel cancer was removed that can be resected with curative intent (see Section VI.F).
2. Chest CT scanning has largely replaced chest radiographs for detecting recurrence. They are advocated annually or semiannually.
3. Colonoscopy. Patients who presented with obstructing colon lesions that preclude preoperative imaging of the colon should have colonoscopy 3 to 6 months after surgery to ensure the absence of a concurrent neoplastic lesion in the remaining colon. The purpose of endoscopy done thereafter is to detect a metachronous tumor, suture line recurrence, or colorectal adenoma. In the absence of obstruction, colonoscopy is performed annually for 1 to 3 years after surgery and, if negative, at 5-year intervals thereafter.
4. Rising CEA levels call for further studies to identify the site of recurrence and are most often helpful in identifying hepatic recurrences. An elevated CEA calls for further testing using CT of the abdomen, pelvis, and chest as well as other studies as dictated by symptoms. If pelvic recurrence of a rectal cancer is suspected, MRI may be more helpful than CT. The use of hepatic imaging by CT, ultrasound, or MRI at regular intervals is now advocated by ASCO. PET scans may also be of value in identifying early signs of recurrent disease and for quantifying the number of metastatic deposits of disease visible at the time of recurrence.
F. Management of isolated recurrence. Early detection and surgical resection of isolated intrahepatic or pulmonary recurrence may be curative or result in improved survival. Those patients most likely to do well have a single lesion in a single site and a disease-free interval of 3 or more years between the primary diagnosis and evidence of metastatic disease. Resection of an isolated hepatic metastasis that involves one lobe of the liver may result in a 60% 5-year survival rate. Resection of an isolated pulmonary metastasis may result in 5- and 10-year survival rates of 40% and 20%, respectively. Even patients with multiple lesions can be resected and cured, although cure rates decrease with more widespread, albeit resectable, disease. In selected patients, multiple resections may be performed even for disease in lung and liver with favorable outcomes. As more effective chemotherapy and biologic therapy are developed, the possibility of converting patients who were initially unresectable into resection candidates is more and more common. Restaging with an eye toward resection when possible should be done on a frequent basis in patients who may be resection candidates.
G. Management of advanced colorectal cancer: local measures
1. Surgery. About 85% of patients diagnosed with colorectal cancer can undergo surgical resection. Patients with incurable cancer may benefit from palliative resection to prevent obstruction, perforation, bleeding, and invasion of adjacent structures. However, in the absence of symptoms, surgery can often be avoided when metastatic disease is present. It is common with newer CT scans to note the primary tumor on the scan and to observe shrinkage with chemotherapy treatment. The use of colonic stents and laser ablation of intraluminal tumors can often obviate the need for surgery even in symptomatic cases.
2. RT may be used as the primary and only treatment modality for small, mobile rectal tumors or in combination with chemotherapy after resection of rectal tumors (see earlier discussion). RT in palliative doses relieves pain, obstruction, bleeding, and tenesmus in about 80% of cases. In selected cases with locally advanced disease, the use of IORT may provide an advantage. However, no randomized trials of external-beam versus IORT or IORT plus external-beam therapy have been reported.
3. Hepatic arterial infusion takes advantage of the dual nature of hepatic blood supply. Metastases in the liver derive their blood supply predominantly from the hepatic artery, whereas hepatocytes derive blood principally from the hepatic vein. The installation of floxuridine (FUDR) into the hepatic artery has been advocated and appears to improve the response rate over 5-FU administered systemically. Problems with this approach include variable anatomy, which makes placement of a single catheter impossible, catheter migration; biliary sclerosis; and gastric ulceration. Progression of extrahepatic disease is a common pattern of failure with this modality. Randomized trials of systemic versus intrahepatic therapy have shown modest advantages to this approach but the practical difficulties of managing these lines and ever-improving systemic therapies have kept this approach from widespread usage.
H. Management of advanced colorectal cancer: chemotherapy. The most commonly used chemotherapeutic agents are 5-FU (alone or in combination with leucovorin, FU/L), capecitabine (the oral 5-FU prodrug), irinotecan, and oxaliplatin.
1. Biochemical modulation of 5-FU with leucovorin. The combination of 5-FU and leucovorin increases the activity as well as the toxicity of 5-FU, results in significant improvement in regression rate, and according to some studies, culminates in improved survival. The partial response rate is about 25%. The dose-limiting toxicities are diarrhea, mucositis, and myelosuppression. Regimens being used with essentially the same response rate involve.
a. 5-FU plus low-dose or high-dose leucovorin given weekly
b. 5-FU plus low-dose or high-dose leucovorin given for 5 days every 4 to 5 weeks
c. 5-FU plus leucovorin by infusion over 24 to 48 hours or for longer intervals
2. Continuous IV infusion of 5-FU changes the toxicity profile from hematologic to predominantly mucositis and dermatologic (hand–foot syndrome) when compared with bolus administration. Multiple randomized trials, however, have shown that continuous infusion of 5-FU using an ambulatory infusion pump, as compared with rapid injection, results in marginally improved survival, prolonging life on average for <1 month. Because of its favorable toxicity profile, the use of short-term infusion as the backbone of the FOLFOX and FOLFIRI regimens, and improvements in infusion pumps, has become common practice to treat advanced colorectal cancer.
3. Therapy with irinotecan has been shown to improve survival and quality of life in patients with advanced colorectal cancer. In patients with recurrent disease refractory to at least one 5-FU regimen, the survival at 1 year of patients treated with supportive care alone or with 5-FU was about 15%, compared with 36% when patients were treated with irinotecan. In the United States, a commonly used regimen for irinotecan is 125 mg/m2 weekly for 4 of every 6 weeks or 2 of every 3 weeks. Irinotecan can also be administered as 350 mg/m2 every 3 weeks.
About 10% of the population in the United States has an inherited polymorphism of the UGT1A1 gene that results in diminished activity of the enzyme that detoxifies irinotecan. Such patients have a higher risk of neutropenia, especially with the every-3-week higher dose regimen. A test for this abnormality is now commercially available, and testing is recommended in the package insert. In second-line therapy, there are no clear data supporting better outcomes from combinations of irinotecan with FU/L over single-agent irinotecan if a patient has had prior 5-FU exposure.
4. Oxaliplatin is a diaminocyclohexane-containing platinum agent with broad activity in cisplatin-resistant human tumor xenografts. It has been used in Europe for a decade and has been approved in the United States in combination with 5-FU and leucovorin for patients with metastatic colorectal cancer in the first- and second-line settings, as well as the adjuvant setting. It is generally administered in combination with 5-FU and leucovorin using one of a number of regimens called FOLFOX 1 to FOLFOX 7 as data suggest greater efficacy in combination.
5. First-line chemotherapy. A number of randomized studies have compared three-drug regimens to FU/L as first-line therapy.
a. Combination regimens being compared include
(1) IFL: Irinotecan, 125 mg/m2, with 5-FU, 500 mg/m2, and leucovorin, 20 mg/m2
(2) FOLFIRI: Irinotecan, 180 mg/m2, followed by folinic acid (leucovorin), 200 mg/m2, and then 5-FU, 2.4 g/m2 infused over 24 hours. Recent data have shown that the FOLFIRI regimen has advantages in both activity and toxicity over bolus 5-FU or capecitabine-based combinations.
(3) FOLFOX4: Folinic acid (leucovorin), 5-FU (given with a loading dose and 22-hour infusion repeated on consecutive days), and oxaliplatin (dosing schedule is defined in Section VI.B.2)
(4) FOLFOX6: Folinic acid (leucovorin), 5-FU (given with a loading dose and 46-hour infusion), and oxaliplatin
(5) FUFOX: 5-FU given in high dose as a 24-hour infusion, folinic acid (leucovorin), and oxaliplatin
(6) IROX: Irinotecan plus oxaliplatin
b. Results of randomized studies are shown in Table 9.5.
(1) Both the IFL and FOLFIRI regimens have been shown in randomized trials to offer an advantage to patients in median overall survival (OS), median time to tumor progression (TTP), and response rate (RR) over FU/LV regimens.
(2) Several studies have compared oxaliplatin plus FU/LV to FU/LV alone. Both the FOLFOX and FUFOX regimens have been shown in randomized trials to offer a statistically significant advantage to patients with respect to TTP and RR but showed no statistically significant difference in OS over FU/LV regimens.
(3) Studies have compared regimens in which FU/LV is coupled to either irinotecan or oxaliplatin. In one large trial, 795 patients were randomly assigned to IFL versus FOLFOX versus IROX. The FOLFOX regimen was superior to both IFL and IROX with respect to overall MS, MTP, and RR. Toxicity also favored the FOLFOX regimen as patients had fewer episodes of severe diarrhea, febrile neutropenia, vomiting, and dehydration.
(4) A comparison of FOLFOX followed by FOLFIRI versus the reverse sequence has shown no significant differences in outcomes with respect to OS (21 months), RR in first-line therapy (55%), or TTP (8 months for first-line and 3 to 4 months for second-line therapy) based on the two sequences. Toxicity patterns were similar between the two regimens.
6. Monoclonal antibodies
a. Bevacizumab (Avastin) is a monoclonal antibody that targets the vascular endothelial growth factor receptor. Bevacizumab plus IFL was compared with IFL alone in a randomized trial involving 815 patients (Table 9.5). The results for IFL alone were very similar to those reported in other phase III studies. The patients receiving IFL plus bevacizumab in this study achieved a better RR and MS compared with those receiving IFL alone. Toxicity was increased only modestly by the addition of bevacizumab, which led to hypertension and rare episodes of bowel perforation. Additional trials of bevacizumab with FOLFIRI and FOLFOX and capecitabine chemotherapy combinations have shown improvements in activity of lesser magnitude than that observed in IFL and bevacizumab study with similar toxicity profiles to the base regimens.
b. Cetuximab (Erbitux) and panitumumab (Vectibix) are two other monoclonal antibodies that target the epidermal growth factor receptor (EGFR) and have been approved for use in advanced, refractory colorectal cancer. Multiple clinical trials have convincingly established that mutations in KRAS render these two antibodies ineffective in colorectal cancer. Consequently, cetuximab and panitumumab should only be used in KRAS wild-type colorectal cancer. Both have single-agent activity resulting in response rates of 10% to 15% in third-line therapy in KRAS wild-type cancers.
In second-line treatment, the combination of either antibody with irinotecan is more active than irinotecan alone. Combinations of both agents with FOLFOX and FOLFIRI in first- and second-line therapy increase the efficacy of therapy with increases in RR and PFS in KRAS wild-type cancer in most, but not all phase III trials. When compared with FOLFIRI alone, the combination of FOLFIRI + cetuximab increased overall survival in an unplanned subgroup analysis in KRAS wild-type colorectal cancer.
Table 9.5 Randomized Trials of Combination Chemotherapy Regimens in Advanced Colorectal Cancer
aRegimens are defined in “Colorectal Cancer,” Section VI.H.5. FU/L (5-fluorouracil/leucovorin) regimen is defined in “Colorectal Cancer,” Section VI.B.1.a.
bStudy compared IROX versus IFL versus FOLFOX for 795 patients.
cBev, bevacizumab (Avastin); study involved 815 patients.
Cetuximab and panitumumab should not be combined with bevacizumab since two independent phase III trials demonstrated inferior outcomes when both antibody classes were combined in addition to chemotherapy.
Cetuximab is a chimeric monoclonal antibody and panitumumab is fully humanized. Both agents commonly cause an acne-like skin rash and paronychia in some patients, and development of this rash seems to correlate with benefit from the agents. Anaphylactic reactions are more common with cetuximab than with panitumumab.
7. FOLFOXIRI. A study comparing a 5-FU plus irinotecan regimen to all three chemotherapy agents given together has shown an advantage for the FOLFOXIRI regimen, including a median survival for patients enrolled in the multidrug arm of 23 months and a high rate of liver resections among patients initially judged to be unresectable.
8. Serial sequential single agents versus combined chemotherapy. Two trials done in Europe, the FOCUS study and the CAIRO study, have compared serial single agents with combinations. While trends favored combination therapies, neither study showed a significant advantage for combinations over serial single agents. However, median survivals were 15 to 17 months in all arms of both studies, which does not compare to the nearly 2-year median survivals seen with combinations. In addition, exposure to all three chemotherapy agents over the entire course of treatment for advanced disease is associated with better outcomes than less-intensive therapy.
9. Summary of chemotherapy recommendations for patients with advanced disease. It appears that combination therapy with either irinotecan or oxaliplatin coupled to FU/LV is better than serial single-agent treatment with respect to overall survival. There are no clear data to favor FOLFOX, FOLFIRI, or FOLFOXIRI as the best first-line therapy. However, the protracted infusion of 5-FU seems to be better tolerated than bolus 5-FU, and use of the IFL regimen is not generally recommended. The toxicity profiles of the two regimens do differ, with FOLFOX causing more neutropenia and neuropathy and FOLFIRI more GI toxicity and alopecia; the side effect profiles should be considered when choosing therapy on a patient-by-patient basis. Capecitabine can be substituted for 5-FU infusion in combination with oxaliplatin with similar outcomes. The overlapping GI toxicity of capecitabine and irinotecan limits the combination of these two drugs.
Most oncologists tend to begin patients on FOLFOX or FOLFIRI plus bevacizumab as first-line therapy in the United States. If FOLFOX is used as chemotherapy backbone, oxaliplatin should be discontinued as soon as (or even before) neurotoxicity emerges. Treatment can then be continued with 5-FU/LV (or capecitabine) plus bevacizumab until progression. The use of bevacizumab beyond progression cannot be considered standard of care and is the subject of ongoing clinical trials.
In select patients, who require an anatomical tumor shrinkage as prerequisite for resection of liver metastases, FOLFOXIRI or a combination of FOLFOX + cetuximab (in KRAS wild-type cancers) can be considered.
Recent pooled analyses have suggested that patients older than 70 years and those with a performance status of 2 can tolerate and benefit from combination therapy similar to younger and asymptomatic patients.
ANAL CARCINOMA
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Anal cancers constitute 1% to 2% of large bowel cancers, and 4,000 new cases are diagnosed annually in the United States. Anal canal cancer most commonly develops in patients 50 to 60 years of age and is more frequent in women than in men (female-to-male ratio, 2:1). Cancer of the anal margin is more frequent in men. During the 1990s, however, the incidence of anal canal cancer in men younger than 35 years of age increased, and the gender ratio is reversed in this age group. Anal cancer more frequently afflicts urban than rural populations.
B. Etiology. In most patients with carcinoma of the anus, HPV appears to play a causal role.
1. Infectious agents. HPV, particularly types 16 and 18, is a prime suspect as a causative agent for anal cancer (see Chapter 36, Sections V and VI). More than 70% of tumor tissues show HPV DNA by polymerase chain reaction techniques. An HPV-produced protein, E6, inactivates the tumor-suppressor gene p53. The presence of genital warts increases the relative risk by a factor of 30.
Although human immunodeficiency virus (HIV) has been suggested as a causative agent, anal tumors are extremely rare in IV drug abusers. The relative risk for homosexuals with acquired immunodeficiency syndrome (AIDS) is 84 and for heterosexuals with AIDS is 38. Other associated infections include herpes simplex virus type 2, Chlamydia trachomatis infection in women, and gonorrhea in men.
2. Diseases associated with anal cancer include AIDS, prior irradiation, anal fistulas, fissures, chronic local inflammation, hemorrhoids, Crohn disease, lymphogranuloma venereum, condylomata acuminata, carcinoma of cervix, and carcinoma of the vulva. The relative risk for anal cancer development after a diagnosis of AIDS is 63. Sexual activity, particularly anal intercourse with multiple partners, is associated with an increased risk for anal canal cancer.
3. Immune suppression. Kidney transplant recipients have a 100-fold increase in anogenital tumors.
4. Cigarette smoking is associated with an eightfold increase in the risk for anal cancer.
5. Anal-receptive intercourse in men but not in women is strongly associated with anal cancer at a risk ratio of 33. Studies have shown that the incidence of anal cancer (squamous and transitional cell carcinomas) is six times greater in single men than in married men. Single women are not at an increased risk.
II. PATHOLOGY AND NATURAL HISTORY
A. Anatomy. The anal canal is a tubular structure 3 to 4 cm in length. The junction between the anal canal and perineal skin is known as the anal verge (Hilton line). The pectinate (or dentate) line is located at the center of the anal canal.
The lining of the anal canal is composed of columnar epithelium in its upper portion and keratinized and nonkeratinized squamous epithelium in its lower portion. Intermediate epithelium (also known as transitional or cloacogenic epithelium, which resembles bladder epithelium) lines a middle zone (0.5 to 1 cm in length) that corresponds to the pectinate line. Anal tumors appear to originate near the mucocutaneous junction and grow either upward into the rectum and surrounding tissue or downward into the perineal tissue.
B. Lymphatics. Some of the upper lymphatics of the anus communicate with those of the rectal ampulla that lead to the sacral, upper mesocolic, and para-aortic lymph nodes. The lower lymphatics communicate with those of the perineum that lead to the superficial inguinal lymph nodes. Of patients undergoing abdominal perineal (AP) resection, 25% to 35% manifest pelvic lymph node metastases.
C. Histology. Squamous cell carcinoma accounts for 63% of cases; transitional cell (cloacogenic) carcinoma, 23%; and mucinous adenocarcinoma, 7% (often with multiple fistulous tracts). Basal cell carcinoma (2%) is curable either by local excision or by irradiation. Paget disease (2%) is a malignant neoplasm of the intraepidermal portion of the apocrine glands. Malignant melanoma (2%) usually begins at the pectinate line and progresses as single or multiple polypoid masses; the prognosis is poor and depends on tumor size and depth of invasion. Other forms include small cell carcinoma (rare but extremely aggressive), verrucous carcinoma (a polypoid neoplasm closely related to giant condyloma acuminata), Bowen disease, embryonal rhabdomyosarcoma (infants and children), and malignant lymphoma (in patients with AIDS).
III. DIAGNOSIS
A. Symptoms. Bleeding occurs in 50% of patients, pain in 40%, sensation of a mass in 25%, and pruritus in 15%. About 25% of patients do not have symptoms.
B. Physical examination should include digital anorectal examination, anoscopy, proctoscopy, endoscopic ultrasound if available, and palpation of inguinal lymph nodes. Anorectal examination may have to be performed under sedation or general anesthesia in patients with severe pain and anal spasm.
C. Biopsy. An incisional biopsy is necessary and preferable to confirm the diagnosis. Excisional biopsy should be avoided. Suspicious inguinal lymph nodes should undergo biopsy to differentiate inflammatory from metastatic disease. Needle aspiration of these nodes may establish the diagnosis; if aspiration is negative, surgical biopsy should be performed. Sentinal node biopsy is advocated by some surgeons in order to improve staging accuracy.
D. Staging evaluation should include physical examination, chest radiograph, and LFT. Pelvic CT and EUS of the anal canal may be useful. HIV testing is appropriate when warranted by individual patient risk factors.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. The TNM staging system may be used. Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. Anal margin tumors are staged as for skin cancer. The T stage of anal canal tumors is determined by size and by invasion into adjacent organs, as follows:
B. Prognostic factors
1. TNM stage. Patients with Tis have a propensity to progress to higher T stages and to have widespread superficial spread of disease, particularly among those that are HIV-positive. Patients with T1 cancer (lesions smaller than 2 cm in diameter) have a significantly better prognosis than those with larger lesions. Five-year survival rates are >80% for patients with T1 and T2 cancers and <20% for those with T3 and T4 cancers. The survival is poor even with aggressive therapy for lesions larger than 6 to 10 cm in diameter. In a multivariate analysis, T stage was the only significant independent prognostic factor for anal cancers. Metastasis to lymph nodes also results in a poor outcome. Anal canal cancers tend to remain regionally localized, with distant metastases noted in <10% of cases.
2. Other factors
a. Histology. The histologic type (i.e., cloacogenic vs. epidermoid) has not been found to be prognostically relevant. Keratinizing carcinoma is associated with a better outcome than nonkeratinizing cancers. Patients with mucoepidermoid carcinoma and small cell anaplastic carcinoma have a worse prognosis.
b. Symptoms. Patients without symptoms do better than those with symptoms. Symptoms are usually directly related to the size of the tumor.
c. Tumor grade. Patients with low-grade tumors have a better 5-year survival rate than patients with high-grade tumors (75% vs. 25%, respectively).
V. PREVENTION AND EARLY DETECTION. Early detection depends on the patient’s and physician’s awareness of the disease, the presence of risk factors, and the histologic examination of all surgical specimens, even those removed from minor anorectal surgery. Yearly anoscopy may be indicated in high-risk patients. Anal examination should be performed routinely in patients with cervical and vulvar cancer.
VI. MANAGEMENT. Small tumors of the anal verge or the anal canal (<2 cm) can be cured in 80% of cases by simple excision with 1-cm margins, and cure by repeat local excision may be possible after local recurrence. An approach derived from Mohs surgery in which involved tissue is shaved and examined by a pathologist at the bedside until negative margins have been obtained is commonly done for Tis lesions. Combined chemotherapy and RT are the primary therapeutic modalities for more advanced anal verge or anal canal carcinoma. AP resection is now used as salvage treatment for chemoradiation-resistant disease (i.e., patients who fail to respond or who relapse after a complete response) and for patients who have fecal incontinence at presentation. considering the rarity of anal canal cancer, randomized trials have led to considerable advances, shifting the standard of therapy from surgery, in which colostomy was routinely necessary as a first approach, to combined-modality chemoradiotherapy, leaving surgery as a last resort.
A. Combined chemoradiation therapy is the primary treatment of choice for anal carcinoma. This combination resulted in higher rates of both local control and survival (82%) and preserved anal function when compared with surgery. The administration of high-dose RT reduced the incidence of persistent carcinoma and eliminated the need for surgical lymphadenectomy. The radiation dose, the number of chemotherapy cycles required to improve the local control rate, and the role (if any) of invasive restaging after completion of therapy remain controversial.
1. Primary therapy. External-beam RT appears to be superior to interstitial implants. RT doses of >5,000 cGy do not appear to be necessary. Using mitomycin C plus 5-FU with RT is superior to using 5-FU alone with RT at 4 years of median follow-up with respect to colostomy-free survival (71% vs. 59%), locoregional control (82% vs. 64%), and DFS (73% vs. 51%). The combination of these two drugs when administered concurrently with RT is superior to RT alone. RT regimens vary among institutions; 5-FU is given by continuous IV infusion in each case. Two useful regimens are as follows:
a. Radiation Therapy Oncology Group (RTOG)
Mitomycin C: 10 mg/m2 IV bolus (day 2)
5-FU: 1,000 mg/m2/24 hours by continuous IV infusion (days 2 to 4 and days 28 to 32)
RT: 170 cGy/d between days 1 and 28
Total RT dose: 4,500 to 5,000 cGy
b. National Tumor Institute (Milan)
Mitomycin C: 15 mg/m2 IV bolus (day 1)
5-FU: 750 mg/m2/24 hours by continuous IV infusion (days 1 to 5)
RT: 180 cGy/d for 4 weeks with a 2-week rest
Total RT dose: 5,400 cGy (in patients with locally advanced disease, the boost dose is increased but the total dose does not exceed 6,000 cGy)
2. Follow-up therapy. Additional 6-week cycles of chemotherapy with mitomycin C and 5-FU are given depending on tumor control or treatment toxicity. Full-thickness biopsy at the original tumor site is often performed 6 to 8 weeks after the completion of therapy. Patients are examined via digital examination and anoscopy at 3-month intervals for the first year and at 6-month intervals thereafter. AP resection is performed for biopsy-proven carcinoma during the follow-up period. Second-line chemotherapy with 5-FU plus cisplatin and AP resection are potentially curative salvage approaches after relapse.
B. Surgery alone. Wide, full-thickness excision is sufficient treatment for discrete, superficial, anal margin tumors and results in an 80% 5-year survival rate unless the tumor is large and deep. AP resection of the anorectum as the exclusive treatment for anal canal tumors and large anal margin tumors results in only a 55% 5-year survival rate.
C. Follow-up of patients with anal cancer every 3 months with digital rectal examination, anoscopy or proctoscopy, and biopsy of suspicious lesions is especially important during the first 3 years after initial treatment because salvage therapy may be curative.
PANCREATIC CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. In the United States, the incidence of pancreatic cancer has remained stable for several decades. There are approximately 31,000 new cases diagnosed annually in the United States and 30,000 deaths from pancreatic cancer, making it the fifth leading cause of US cancer deaths. The disease has a male-to-female ratio of 1:1 and is rare before the age of 45 years; the peak incidence occurs between the ages of 65 and 79 years.
In India, Kuwait, and Singapore, the rate is <2 per 100,000 population. In Japan, the incidence has risen sharply from 2 to 5 per 100,000 since the early 1980s.
B. Etiology and risk factors. The cause of pancreatic adenocarcinoma remains unknown, but several factors show a modest association with its occurrence.
1. Cigarette smoking is a consistently noted risk factor for pancreatic cancer, with a relative risk of at least 1.5. The risk increases with increasing duration and amount of cigarette smoking. The excess risk levels off 10 to 15 years after cessation of smoking. The risk is ascribed to tobacco-specific nitrosamines.
2. Diet. A high intake of fat, meat, or both is associated with increased risk, whereas the intake of fresh fruits and vegetables appears to have a protective effect.
3. Partial gastrectomy appears to correlate with a 2 to 5 times higher than expected incidence of pancreatic cancer 15 to 20 years later. The increased formation of N-nitroso compounds by bacteria that produce nitrate reductase and proliferate in the hypoacidic stomach has been proposed to account for the increased occurrence of gastric and pancreatic cancer after partial gastrectomy.
4. Cholecystokinin is the primary hormone that causes growth of exocrine pancreatic cells; others include epidermal growth factor and insulin-like growth factors. Pancreatic cancer has been induced experimentally by long-term duodenogastric reflux, which is associated with increased cholecystokinin levels. Some clinical evidence suggests that cholecystectomy, which also increases the circulating cholecystokinin, may increase the risk for pancreatic cancer.
5. Diabetes mellitus may be an early manifestation of pancreatic cancer or a predisposing factor. It is found in 13% of patients with pancreatic cancer and in only 2% of controls. Diabetes mellitus that occurs in patients with pancreatic cancer may be characterized by marked insulin resistance, which moderates after tumor resection. Islet amyloid polypeptide, a hormonal factor secreted by pancreatic β cells, reduces insulin sensitivity in vivo and glycogen synthesis in vitro and may be present in elevated concentrations in patients with pancreatic cancer who have diabetes.
6. Chronic and hereditary pancreatitis is associated with pancreatic cancer. Chronic pancreatitis is associated with a 15-fold increase in the risk for pancreatic cancer.
7. Toxic substances. Occupational exposure to 2-naphthylamine, benzidine, and gasoline derivatives is associated with a fivefold increased risk for pancreatic cancer. Prolonged exposure to DDT and two DDT derivatives (ethylan and DDD) is associated with a fourfold to sevenfold increased risk for pancreatic cancer.
8. Socioeconomic status. Pancreatic cancer occurs in a slightly higher frequency in populations of lower socioeconomic status.
9. Coffee. Analysis of 30 epidemiologic studies showed that only one case-control study and none of the prospective studies confirmed a statistically significant association between coffee consumption and pancreatic cancer.
10. Idiopathic deep-vein thrombosis is statistically correlated with the subsequent development of mucinous carcinomas (including pancreatic cancer), especially among patients in whom venous thrombosis recurs during follow-up.
11. Dermatomyositis and polymyositis are paraneoplastic syndromes associated with pancreatic cancer and other cancers.
12. Tonsillectomy has been shown to be a protective factor against the development of pancreatic cancer, an observation that has been described for other cancers as well.
13. Familial pancreatic cancer. It is estimated that 3% of pancreatic cancers are linked to inherited predisposition to the disease.
II. PATHOLOGY
A. Primary malignant tumors of the pancreas involve either the exocrine parenchyma or the endocrine islet cells (the latter are discussed in Chapter 15, Section VI). Nonepithelial tumors (sarcomas and lymphomas) are rare. Ductal adenocarcinoma makes up 75% to 90% of malignant pancreatic neoplasms: 57% occur in the head of the pancreas, 9% in the body, 8% in the tail, 6% in overlapping sites, and 20% in unknown anatomic subsites. Uncommon but reasonably distinctive variants of pancreatic cancer include adenosquamous, oncocytic, clear cell, giant cell, signet ring, mucinous, and anaplastic carcinoma. Anaplastic carcinomas often involve the body and tail rather than the head of pancreas. Reported cases of pure epidermoid carcinoma (a variant of adenosquamous carcinoma) probably are associated with hypercalcemia. Cystadenocarcinomas have an indolent course and may remain localized for many years. Ampullary cancer (which carries a significantly better prognosis), duodenal cancer, and distal bile duct cancer may be difficult to distinguish from pancreatic adenocarcinoma.
B. Metastatic tumors. Autopsy studies show that for every primary tumor of the pancreas, four metastatic tumors are found. The most common tumors of origin are the breast, lung, cutaneous melanoma, and non-Hodgkin lymphoma.
C. Genetic abnormalities. Mutant c-K-ras genes have been found in approximately 95% of all specimens of human pancreatic carcinoma and their metastases.
III. DIAGNOSIS
A. Symptoms. Most patients with pancreatic cancer have symptoms at the time of diagnosis. Predominant initial symptoms include abdominal pain (80%); anorexia (65%); weight loss (60%); early satiety (60%); xerostomia and sleep problems (55%); jaundice (50%); easy fatigability (45%); weakness, nausea, or constipation (40%); depression (40%); dyspepsia (35%); vomiting (30%); hoarseness (25%); taste change, bloating, or belching (25%); dyspnea, dizziness, or edema (20%); cough, diarrhea because of fat malabsorption, hiccup, or itching (15%); and dysphagia (5%).
B. Clinical findings. At presentation, patients with pancreatic cancer have cachexia (44%), serum albumin concentration of <3.5 g/dL (35%), palpable abdominal mass (35%), ascites (25%), or supraclavicular lymphadenopathy (5%). Metastases are present to at least one major organ in 65% of patients, to the liver in 45%, to the lungs in 30%, and to the bones in 3%. Carcinomas of the distal pancreas do not produce jaundice until they metastasize and may remain painless until the disease is advanced. Occasionally, acute pancreatitis is the first manifestation of pancreatic cancer.
C. Paraneoplastic syndromes. Panniculitis-arthritis-eosinophilia syndrome that occurs with pancreatic cancer appears to be caused by the release of lipase from the tumor. Dermatomyositis, polymyositis, recurrent Trousseau syndrome or idiopathic deep-vein thrombosis, and Cushing syndrome have been reported to be associated with cancer of the pancreas.
D. Diagnostic studies
1. Ultrasonography. Abdominal ultrasound is technically adequate in 60% to 90% of patients and is noninvasive, safe, and inexpensive. Ultrasound can detect pancreatic masses as small as 2 cm, dilation of the pancreatic and bile ducts, hepatic metastases, and extrapancreatic spread. Intraoperative ultra-sound facilitates surgical biopsy and may detect unsuspected liver metastases in 50% of patients.
2. CT is less operator-dependent than ultrasound and is not limited by air-containing abdominal organs, as is ultrasound. CT is favored over ultrasound because of its superior ability to demonstrate retroperitoneal invasion and lymphadenopathy. A pancreatic tumor must be at least 2 cm in diameter to become visible. Dynamic CT with continuous infusion of IV contrast is the best test for assessing the size of the tumor and its extension. At least 20% of pancreatic tumors believed to be resectable may not be detectable by CT.
3. MRI has no demonstrated advantage over CT in the diagnosis and staging of pancreatic cancer.
4. Endoscopic retrograde cholangiopancreaticography (ERCP) is the mainstay in the differential diagnosis of the tumors of the pancreatobiliary junction, 85% of which originate in the pancreas (about 5% each in the distal common bile duct, ampulla, and duodenum). Ampullary and duodenal carcinomas can usually be visualized and biopsy performed with ERCP. The pancreatogram typically shows the pancreatic duct to be encased or obstructed by carcinoma in 97% of cases.
It may be difficult to distinguish between pancreatic cancer and chronic pancreatitis because both diseases share clinical and radiologic characteristics. Pancreatic duct stricture usually does not exceed 5 mm in chronic pancreatitis; strictures longer than 10 mm (especially if irregular) indicate pancreatic cancer. Cytologic examination of cells in samples of pancreatic juice obtained during ERCP with secretin stimulation has been reported to be highly specific for the diagnosis of carcinoma and 85% sensitive. Brush biopsy of the pancreatic stricture (when possible) increases the diagnostic yield.
5. EUS. Prospective studies showed that EUS is more accurate than standard ultra-sound, CT, and ERCP for diagnosis, staging, and predicting resectability of pancreatic tumors. EUS detected 100% of malignant lesions <3 cm, whereas angiography, CT, and ultrasound were of limited value for these small lesions. EUS can detect tumors smaller than 2 cm; ERCP cannot. The additional information obtained from EUS has been reported to result in a major change in the clinical management in one-third of patients and to aid in the clinical decision in three-fourths of patients.
The current limitations of EUS include a short optimal focal range of only 4 cm, inability to differentiate focal chronic pancreatitis from carcinoma reliably, and inability to differentiate chronic lymphadenitis from metastatic lymph node involvement. The ability to biopsy lymph nodes using EUS does allow assessment of lymph nodes for malignancy in some cases.
6. Percutaneous fine-needle aspiration cytology is safe and reliable, with a reported sensitivity of 55% to 95% and no false-positive results for the diagnosis of pancreatic cancer. This procedure should be performed for histologic confirmation on all patients with unresectable or metastatic disease unless a palliative surgical procedure is planned. Needle aspiration cytology distinguishes adenocarcinoma from islet cell tumors, lymphomas, and cystic neoplasms of the pancreas, permitting therapy to be tailored to the specific diagnosis in each case.
The drawbacks to percutaneous aspiration biopsy include potential tumor seeding along the needle tract, potential to enhance intraperitoneal spread, and negative biopsy results that do not exclude the diagnosis of malignancy. Furthermore, the diagnosis of early and smaller tumors is most likely to be missed by this technique.
7. Angiography is excellent for assessing major vascular involvement but is not useful in determining the size and location of tumor (pancreatic cancer is hypovascular). In most cases, spiral CT scanning with proper administration of IV contrast allows resectability to be judged preoperatively.
8. Laparoscopy can demonstrate extrapancreatic involvement in 40% of patients without demonstrable lesions on CT.
9. Tumor markers. No available serum marker is sufficiently sensitive or specific to be considered reliable for screening of pancreatic cancer.
a. CA 19-9 is widely used for the diagnosis and follow-up of patients with pancreatic cancer but is not specific for pancreatic cancer.
b. CEA is of minimal value in pancreatic cancer.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. The TNM system is most commonly used. Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. T1 and T2 tumors are potentially resectable tumors. T1 tumors are localized to the pancreas, and T1a tumors are <2 cm in diameter. T2 indicates that there is a limited direct extension into the duodenum, bile duct, or stomach. T3 indicates advanced direct extension that is incompatible with surgical resection.
B. Preoperative evaluation. Identifying patients with unresectable pancreatic tumor or with metastasis or vessel involvement would spare many patients a major operation. Operative mortality and morbidity for pancreatic surgery remain high, except in specialized centers. Modern diagnostic methods have reduced unnecessary laparotomies from 30% to 5% and have increased the resectability rate on patients judged to be potentially resectable on the basis of preoperative imaging from 5% to 20%. Accuracy in determining resectability before exploration has become even more important because of the availability of effective decompression of biliary obstruction endoscopically for palliation of obstructive jaundice without the need for laparotomy.
CT, angiography, and laparoscopy assess different aspects of resectability and are complementary. In general, if one of these studies indicates vascular invasion or local or regional spread, the resectability rate is about 5%, whereas if all are negative, the resectability rate is 78%. Gross nodal involvement is usually associated with other signs of unresectability and may be identified by CT or EUS.
C. Prognostic factors. Fewer than 20% of patients with adenocarcinoma of the pancreas survive the first year, and only 3% are alive 5 years after the diagnosis.
1. Resectable disease. The 5-year survival rate of patients whose tumors were resected is poor; the reported range is 3% to 25%. The 5-year survival is 30% for patients with small tumors (≤2 cm in diameter), 35% for patients with no residual tumor or for patients in whom the tumor did not require dissection from major vessels, and 55% for patients without lymph node metastasis.
2. Nonresectable or metastatic disease. The median survival of patients with such disease is 2 to 6 months. Performance status and the presence of four symptoms (dyspnea, anorexia, weight loss, and xerostomia) appear to influence survival; patients with the higher performance status and the least number of these symptoms lived the longest.
V. MANAGEMENT
A. Surgery. Only 5% to 20% of patients with pancreatic cancer have resectable tumors at the time of presentation.
1. Surgical procedures
a. Pancreaticoduodenal resection (Whipple procedure or a modification) is the standard operation. This implies that only cancer involving the head of the pancreas is resectable.
b. A pylorus-preserving variation of Whipple procedure is a commonly used operation in the United States, in part because it has resulted in a significant reduction of postgastrectomy syndrome with no decrease in survival.
c. An extended Whipple procedure, with a more extensive lymph node dissection, is used commonly in Japan but has not been widely accepted in the United States because of higher morbidity and lack of data from randomized trials to suggest that the procedure results in better survival.
d. Regional pancreatectomy confers no survival advantage over conventional Whipple procedure.
e. Total pancreatectomy produces exocrine insufficiency and brittle diabetes mellitus and should be performed only when necessary to achieve clear surgical margins.
2. Surgical mortality and morbidity. The perioperative mortality rate from pancreatic resection is <5% when the operation is performed by expert surgeons. Nationally, however, the surgical mortality rate is about 18%. The major complication rate is 20% to 35% and includes sepsis, abscess formation, hemorrhage, and pancreatic and biliary fistulae.
3. Relief of obstructive jaundice by surgical biliary bypass (cholecystojejunostomy or choledochojejunostomy) is effective, but the average survival time is 5 months, and the postoperative mortality rate in large collected series is 20%. Jaundice can be relieved endoscopically by the placement of stents with a success rate of up to 85%, a procedure-related mortality rate of 1% to 2%, and significant reduction in the length of hospitalization and recovery compared with palliative surgery. Randomized trials showed no difference in survival between endoscopic stent placement and surgical bypass, but patients treated with stents had more frequent readmissions for stent obstruction, recurrent jaundice, and cholangitis.
B. Adjuvant therapy appears to be a reasonable approach to the patient who has undergone curative resection.
1. Chemotherapy. Prior trials assessing the potential benefit of adjuvant chemotherapy have shown mixed results. However, in a phase III trial, 368 patients were randomized to either observation alone or six cycles of gemcitabine following gross complete resection. Significant improvement was noted in DFS, but only a trend toward benefit in overall survival.
2. Combined-modality therapy. There is one prospective randomized study of 43 patients (completed by the Gastrointestinal Study Group in the 1980s) that showed that adjuvant RT and 5-FU after a curative Whipple procedure improved survival. In that study, the median survival was 20 months for patients treated, and 3 of 21 patients survived 5 years or more. For patients not treated, the median survival was 11 months, and only 1 of 22 patients survived 5 years. The 5-year survival rate was 40% for patients with no lymph node involvement and <5% for patients with lymph node metastasis.
A RTOG trial randomized patients to either gemcitabine or infusional 5-FU after surgery. Both groups also received radiation. The results of this trial showed a nonsignificant improvement in survival for patients receiving gemcitabine, primarily in those with cancer arising from the head of the pancreas.
C. Therapy for locally advanced disease
1. External-beam RT combined with 5-FU (15 mg/kg IV on the first 3 and last 3 days of RT) significantly improves survival as compared with RT alone (10 vs. 5.5 months, respectively) in an older trial. Consideration should be given to the use of continuous-infusion 5-FU, capecitabine, or gemcitabine during irradiation, although there are no randomized trials to suggest incremental benefit of these options over bolus 5-FU in pancreatic cancer. The main benefit is in decreased toxicity.
2. Intraoperative electron-beam RT delivered to a surgically exposed tumor from which radiosensitive bowel has been excluded by insertion of a field-limiting cone increased the median survival compared with historical controls in selected patients to 13 months, with excellent local control (5% of patients have lived 3 to 8 years). Intraoperative RT relieves pain in 50% to 90% of patients.
D. Chemotherapy for metastatic disease.
1. 5-FU. 5-FU has a response rate of 0% to 20% in pancreatic cancer. Given its low response rate and poor impact on overall survival, 5-FU used alone is not an option for most patients.
2. Gemcitabine. Weekly gemcitabine at a dose of 1,000 mg/m2 for 3 of every 4 weeks has been shown to have activity and to provide palliative benefit exceeding that of 5-FU in a randomized trial of 126 patients with advanced disease. The median survival times were 5.6 versus 4.4 months (p = 0.002) for gemcitabine versus 5-FU, respectively. A potentially promising alternative schedule for the administration of gemcitabine using fixed-dose rate infusion compared with the standard 30-minute infusion did not show benefit in a phase III trial. The administration of multiagent chemotherapy has generally not resulted in better outcomes than single-agent therapy. Several phase III trials comparing gemcitabine alone with gemcitabine and either oxaliplatin, bevacizumab, or cetuximab have all failed to show benefit. However, a significant improvement was seen in overall survival (6.2 vs. 5.9 months) when erlotinib was added to gemcitabine. The addition of capecitabine has also improved outcome when added to gemcitabine based on the preliminary presentation of a recently completed phase III trial.
3. FOLFIRINOX. In a randomized phase III trial, the combination of 5-FU, irinotecan, and oxaliplatin provided significantly better outcomes compared to gemcitabine. Overall survival improved from approximately 7 months with gemcitabine to 11 months with FOLFIRINOX. In good performance status patients, FOLFIRINOX should be considered as an option.
Oxaliplatin 85 mg/m2 over 2 hours, day 1
Leucovorin 400 mg/m2 over 2 hours, day 1
Irinotecan 180 mg/m2 in 90 mn infusion, day 1
5-FU 400 mg/m2 bolus, day 1
5-FU 2,400 mg/m2 on 46-h infusion, days 1 to 2
E. Neuroablation for pain control. The relentless, boring, posterior abdominal and back pain caused when the celiac nerve plexus becomes invaded by pancreatic cancer can be extremely distressing and frequently requires the use of large doses of narcotics, particularly sustained-release morphine. Chemical splanchnicectomy (celiac axis nerve block) should be performed at the time of operation in nonresectable cases. Either 6% phenol or 50% alcohol (25 mL is injected on each side of the celiac axis) is used. This procedure results in relief of pancreatic cancer-related pain in >80% of patients. Percutaneous chemical neurolysis of the celiac ganglion, which may be attempted in patients who did not have an intraoperative splanchnicectomy or were not explored, is reported to be equally effective. Transient postural hypotension may occur. Celiac plexus block may be repeated if initially unsuccessful or if pain recurs.
F. Other supportive measures. Appetite suppression, decreased caloric intake, and malabsorption can all lead to cancer cachexia in patients with pancreatic cancer. Megestrol acetate (Megace) suspension in doses up to 800 mg/d can be an effective appetite stimulant for treatment of anorexia. Calorie supplements are also potentially valuable. Fat malabsorption resulting from loss of the exocrine function of the pancreas responds to pancreatic enzyme replacement. Ascites can be managed with diuretics when possible and paracentesis when necessary. Removal of protein-rich ascitic fluid, however, can become an additional contributor to the negative protein balance in these already malnourished patients.
LIVER CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Liver cancer is among the most common neoplasms and causes of cancer death in the world, occurring most commonly in Africa and Asia. Up to one million deaths due to hepatocellular carcinoma (HCC) occur each year worldwide. In the United States, 17,000 new cases of cancer of the liver and biliary passages develop annually. Incidence throughout the world varies dramatically, with 115 cases per 100,000 people noted in China and Thailand, compared with 1 to 2 cases per 100,000 in Britain. In countries with high incidence rates, there are often subpopulations also with high incidence rates living nearby lower risk subpopulations. For example, the incidence rates in black South Africans and Alaska Natives far exceed those of nearby white populations. HCC is four to nine times more common in men than in women.
B. Conditions predisposing to HCC
1. Hepatitis B virus (HBV). High titers of hepatitis B surface antigen (HBsAg) and core antibody (HBcAb) are frequently found in patients with HCC. HBsAg was found in the serum of 50% to 60% of patients with HCC and in 5% to 10% of the general population. In the United States, HCC is increased by 140-fold in HBsAg carriers. Anti-HBcAb was found in 90% of black South African and 75% of Japanese patients with HCC, as compared with 35% and 30% of matched controls, respectively. When HCC develops, the patient usually has had chronic HBV infection for three to four decades. The risk factors for the development of HCC in HBsAg carriers are the presence of cirrhosis, family history of HCC, increasing age, male sex, Asian or African race, cofactors (such as alcohol, aflatoxin, and perhaps smoking), and the duration of the carrier state. In Asia, HBV is transmitted vertically from mother to infant in the first few months of life; in Africa, HBV is transmitted horizontally.
2. Cirrhosis. HCC often develops in a cirrhotic liver. Autopsy studies showed that 60% to 90% of HBsAg-positive subjects have associated cirrhosis and 20% to 40% of patients with cirrhosis have HCC. Studies show that in Taiwan, the annual estimated incidence of HCC is 0.005% in HBsAg-negative patients, 0.25% in HBsAg-positive patients, and 2.5% in HBsAg-positive patients with liver cirrhosis (500 times higher than in HBsAg-negative patients). In France, the development of HCC in the presence of alcoholic cirrhosis was nearly always associated with HBV infection, and alcoholism was thought to hasten the development of HCC. In Italy, the prevalence of HCC in patients with cirrhosis was nearly 7%, with a yearly crude incidence of 3%; hepatitis C virus (HCV) chronic infection was the cause of cirrhosis in 45% of these patients. A clear association between alcohol-induced cirrhosis and HCC exists; associations between alcohol and HCC in the absence of cirrhosis are less clear.
3. HCV infection is a risk factor for the development of HCC. Apparently, HCV induces cirrhosis and to a lesser extent increases the risks for HCC in patients with cirrhosis. HCV infection acts independently of HBV infection, alcohol abuse, age, and gender. The ratios for HCC risk factors in patients with chronic liver disease, adjusted for age, sex, and other factors are as follows:
a. Risk ratio six- to sevenfold: age, 60 to 69 years; HBsAg-positive
b. Risk ratio fourfold: high-titer anti-HBcAb, anti-HCV positivity
c. Risk ratio twofold: presence of liver cirrhosis, currently smoking
4. Aflatoxins are produced by the ubiquitous fungi Aspergillus flavus or Aspergillus parasiticus, which commonly colonize peanuts, corn, and cassava in all except extremely cold climates. Aflatoxin B1 has been proved to be a potent hepatocarcinogen in experimental animals, and the amount of exposure is correlated with increased HCC risk in humans. For example, the daily intake of aflatoxin in Mozambique is four times greater than in Kenya, and the incidence of HCC is eight times greater.
5. Mutations of tumor-suppressor gene p53 have been reported in half of patients with HCC. These mutations, specifically of 249ser p53, are correlated both with geographic areas where the ingestion of aflatoxin is common and with the prevalence of HBV infection.
6. Sex hormones. The risk for liver cell adenomas and HCC is increased in women who have used oral contraceptives for 8 or more years. Although liver cell adenomas regress with discontinuation of oral contraceptives in most cases, adenomas must be considered premalignant. Close and prolonged follow-up is necessary for women with adenomas who continue to use oral contraceptives. HCC has also been observed in people with a history of anabolic steroid use.
7. Cigarette smoking, alcohol intake, diabetes, and insulin intake. A study performed in Los Angeles showed that in non-Asian populations that have a low risk for HCC, cigarette smoking, heavy alcohol consumption, and diabetes mellitus, especially with insulin administration, appear to be significant risk factors for HCC.
8. Nonalcoholic steatohepatitis (NASH). It is becoming an increasingly important risk factor, accounting for approximately 10% of all risk factors for HCC. It is associated with fatty infiltration in the liver and is most commonly seen in obese patients.
9. Other factors. A relatively small number of HCCs develop in patients with various other diseases. The most common of these are α1-antitrypsin deficiency, tyrosinemia, and hemochromatosis. Phlebotomy therapy can deplete hepatic iron and induce regression of hepatic fibrosis but does not prevent the development of HCC in hemochromatosis. Clonorchiasis, vinyl chloride exposure, and administration of thorium dioxide (an x-ray contrast agent used between 1930 and 1955) or methotrexate are also associated with the development of HCC.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology
1. Liver cell adenoma has low malignant potential. True adenomas of the liver are rare and occur mostly in women taking oral contraceptives. Most adenomas are solitary; occasionally multiple (10 or more) tumors develop in a condition known as liver cell adenomatosis. These tumors are smooth, encapsulated masses and do not contain Kupffer cells. Patients usually have symptoms; hemoperitoneum occurs in 25% of cases.
2. Focal nodular hyperplasia (FNH) has no malignant potential. FNH occurs with a female-to-male ratio of 2:1. The relationship of oral contraceptives to FNH is not as clear as for hepatic adenoma; only half of patients with FNH take oral contraceptives. FNH tumors are nodular, are not encapsulated, but do contain Kupffer cells. Patients usually do not have symptoms; hemoperitoneum rarely occurs.
3. HCC may present grossly as a single mass, as multiple nodules, or as diffuse liver involvement; these are referred to as massive, nodular, and diffuse forms. The growth pattern microscopically is trabecular, solid, or tubular, and the stroma, in contrast to bile duct carcinoma, is scanty. A rare sclerosing or fibrosing form has been associated with hypercalcemia. Fibrolamellar carcinoma, another variant, occurs predominantly in young patients without cirrhosis, has a favorable prognosis, and is not associated with elevation of serum α-fetoprotein (FP) levels. In the United States, almost half of HCCs in patients younger than 35 years of age are fibrolamellar, and more than half of them are resectable.
Table 9.6 depicts the clinical and pathologic differences between HCC, bile duct carcinoma, and metastatic adenocarcinoma. Appendix C-4.IV shows immunohistochemical phenotypes of HCC and bile duct carcinomas as well as other adenocarcinomas.
Table 9.6 Differential Diagnosis of Hepatocellular Carcinoma (HCC) Versus Adenocarcinoma
Occ, occasionally; CEA, carcinoembryonic antigen.
aAdenocarcinoma, cholangiocarcinoma, and metastatic adenocarcinoma.
bThe fibrolamellar and sclerosing variants of HCC are exceptions because they contain prominently fibrous stroma.
Adapted from Sternberg SS, eds. Diagnostic Surgical Pathology. 2nd ed. New York: Raven Press; 1994:1543, and other sources.
B. Natural history. Most patients die from hepatic failure and not from distant metastases. The disease is contained within the liver in only 20% of cases. HCC invades the portal vein in 35% of cases, hepatic vein in 15%, contiguous abdominal organs in 15%, and vena cava and right atrium in 5%. HCC metastasizes to the lung in 35% of cases, abdominal lymph nodes in 20%, thoracic or cervical lymph nodes in 5%, vertebrae in 5%, and kidney or adrenal gland in 5%.
C. Associated paraneoplastic syndromes include fever, erythrocytosis, hypercholesterolemia, gynecomastia, hypercalcemia, hypoglycemia, and virilization (precocious puberty).
III. DIAGNOSIS
A. Symptoms and signs. Pain in the right subcostal area or on top of the shoulder from phrenic irritation is common (95%). Severe symptoms of fatigue (31%), anorexia (27%), weight loss (35%), and unexplained fever (30% to 40%) are not uncommon. Many patients have vague abdominal pain, fever, and anorexia for up to 2 years before the diagnosis of carcinoma is made. Hemorrhage into the peritoneal cavity is often seen in patients with HCC and may be fatal. Ascites or the presence of an upper abdominal mass noticeable by the patient is an ominous prognostic sign. Any sudden deterioration in a patient with known liver disease or with positive HbsAg or hepatitis C serology should raise the suspicion of HCC. Physical findings include hepatomegaly (90%), splenomegaly (65%), ascites (52%), fever (38%), jaundice (41%), hepatic bruit (28%), and cachexia (15%).
B. Diagnostic studies
1. LFTs may be normal or elevated and are affected by liver cirrhosis. Elevated serum bilirubin and lactate dehydrogenase values and lowered serum albumin are associated with poor survival. Serum g-glutamyl transferase (GGT) isoenzyme II (of 11 isoenzymes) was positive in 90% of patients with HCC. GGT-II was negative in most patients with acute and chronic viral hepatitis or extrahepatic tumors, in pregnant women, and in healthy controls. GGT-II was found to be valuable for the detection of small or subclinical HCC.
2. Biopsy of liver nodules. Some authors believe that percutaneous liver biopsy carries a high risk and has little or no role in the workup of liver tumors, whereas others believe that it can be performed without any significant risk. Nevertheless, liver biopsy is needed to establish the diagnosis and may be obtained either at operation or percutaneously.
3. Serum tumor markers. Serum a-FP is often elevated in patients with HCC but can also be elevated in patients with benign chronic liver disease. In patients with liver cirrhosis and no HCC, serum a-FP may be normal or elevated, with values ranging from 30 to 460 ng/mL (median, 30 to 70 ng/mL). In patients with HCC, the serum a-FP concentrations may range from 30 to 7,000 ng/mL (median, 275 ng/mL). Measurement of a-FP fractions L3, P4, and P5 (different sugar-chain structures) may allow the differentiation of HCC from cirrhosis in some cases. It may also be predictive for the development of HCC during follow-up of patients with cirrhosis. Serum ferritin levels are also frequently elevated in patients with HCC.
4. Radiologic studies
a. Ultrasound. HCC is usually well circumscribed, hyperechogenic, and associated with diffuse distortion of the normal hepatic parenchyma. Metastatic deposits are usually hyperechogenic but may be hypoechogenic.
b. CT. HCC typically appears as an area of low attenuation on CT. Lesions may occasionally be isodense with normal hepatic parenchyma, however. Metastatic tumors with low attenuation (close to the density of water) include mucin-producing tumors of the ovary, pancreas, colon, and stomach and tumors with necrotic centers, such as sarcomas. Mucin-producing metastases may have nearly normal attenuation values because of diffuse microscopic calcifications within the tumor.
c. MRI has been reported to be superior to CT scanning and ultrasound for the detection of liver tumors.
d. Selective hepatic, celiac, and superior mesenteric angiography can confirm portal vein involvement, define the arterial supply, and identify vascular lesions that are as small as 3 mm in diameter. Intra-arterialepinephrine injection can differentiate normal hepatic arteries from tumor vessels, which do not constrict because of the absence of smooth muscles in their walls.
e. Radionuclide scans
(1) Liver–spleen scan. All primary and metastatic liver tumors, except for FNH and regenerating nodules, are devoid of Kupffer cells and appear as “cold” areas in liver scans. However, the liver–spleen scan has now been replaced by MRI, ultrasound, and CT.
(2) Gallium scan of liver may be able to differentiate primary hepatic tumors from metastatic carcinoma because gallium is taken up by the HCC.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging. The initial step is to establish whether the HCC is resectable. Indications of unresectability may be determined either at exploratory laparotomy, by laparoscopy, or by CT, MRI, or angiography. Unresectable disease includes bilobar or four-segment hepatic parenchymal involvement, portal vein thrombus, and vena caval involvement with tumor or tumor thrombus. Metastatic disease includes involvement of regional lymph nodes, which is proved by biopsy at surgery. Liver failure or portal hypertension alone does not contraindicate surgery. Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. While a variety of staging systems exist, the Barcelona Clinic Liver Cancer (BCLC) staging system has commonly been used to help direct therapeutic options. The BCLC staging system, the Child-Pugh and Okuda classification systems for underlying liver disease, as well as other clinical characteristics of the HCC help guide clinical decision making about treatment options such as resection, transplantation, ablation, embolization, or systemic therapy.
B. Prognostic factors. The number of liver lesions and the presence of vascular involvement are the most significant prognostic determinants in patients with disease limited to the liver. Neither the presence nor the degree of a-FP elevation has any prognostic importance. The prognostic factors that relate to survival in patients with resectable HCC are as follows:
1. Number, size, and location of liver lesions. The 5-year survival rate for patients with a solitary tumor is 45%, and it is 15% to 25% for those with multiple liver lesions. The 5-year survival rate is 40% to 45% for patients with small tumors (2 to 5 cm) and 10% for patients with tumors larger than 5 cm. Patients without cirrhosis with tumors located in the left lobe of the liver or in the right inferior segments (anteriorly or posteriorly) have the best prognosis.
2. Vein involvement. All patients with gross tumor thrombi involving the portal vein or the hepatic vein die within 3 years, whereas the 5-year survival rate for patients with no vascular involvement of any kind is 30%.
3. Extent and type of resection. The 5-year survival rate for patients undergoing curative resection is 55%, compared with 5% for those undergoing noncurative resections. The 5-year survival rate is 85% for hepatic lobectomy, 50% for subsegmentectomy, and 20% for wedge enucleation. In patients with resected HCC, the liver is the site of disease recurrence in 90% of cases.
4. Hepatic reserve. Determining underlying liver function is important in providing a prognosis as well as determining the ability of patients to tolerate therapy. The Child-Pugh classification of severity of liver disease (Table 9.7) provides a simple clinical scoring system to estimate liver function and is commonly employed in HCC staging systems.
Table 9.7 Child-Pugh Classification of Severity of Liver Disease
Modified Child-Pugh classification of the severity of liver disease. A total score of 5 to 6 is considered grade A (well-compensated disease), 7 to 9 is grade B (significant functional compromise), and 10 to 15 is grade C (decompensated disease). The 1- and 2-year survivals are 100% and 85% for grade A, 80% and 60% for grade B, and 45% and 35% for grade C.
V. PREVENTION AND EARLY DETECTION
A. Prevention. Avoidance of the risk factors for HCC is difficult in those parts of the world where socioeconomic conditions are poor and where HBV infection is endemic. The widespread use of HBV vaccine may affect the incidence of HCC, but with a considerable lag time.
1. Almost four billion people (75% of the world population) live in areas of intermediate or higher prevalence of HBV. Infections with HBV and HCV can be treated with interferons, although prevention of initial infection is preferable. Protection against HBV, if attempted, is best done in infancy. In the United States, vaccination with recombinant HBsAg is recommended for health workers in contact with blood, for people residing for >6 months in areas that are highly endemic for HBV, and for all others at risk. Interferon-a treatment of patients with chronic active hepatitis and cirrhosis lowered the rate of progression to hepatocellular carcinoma twofold in one trial.
2. Steps should be taken to reduce the high levels of aflatoxin food contaminations that occur in many areas of Asia and southern Africa, as has been done in the Western world.
B. Early detection. Two recent reports describe attempts for early detection of HCC in patients with liver cirrhosis. A study from Italy shows that patients with persistently elevated serum a-FP have a higher incidence of HCC (3% per year) than those with fluctuating levels. This screening program did not appreciably increase the rate of detection of potentially curable liver tumors, however. In a study from Japan, higher percentages of a-FP L3, P4, and P5 fractions allowed the differentiation of HCC in some cases.
VI. MANAGEMENT
A. Liver anatomy. The liver is anatomically divided into four lobes: a larger right lobe, which is separated from a smaller left lobe by the attachment of the falciform ligament, and two small lobes (the quadrate lobe on the anterior inferior aspect and the caudate lobe). Practical surgical anatomy divides the liver into nearly equal halves, and each half is divided into two segments. The right half is divided into anterior (ventrocranial) and posterior (dorsocaudal) segments. The left half is divided into medial and lateral segments by a visible left sagittal accessory fissure. Each of the four segments is subdivided into superior and inferior subsegments. The French literature labels the eight liver subsegments with Roman numerals.
B. Localized and resectable HCC. Only 10% of HCCs are resectable with solitary or unilobar hepatic lesions at the time of diagnosis. The survival in resectable lesions depends on the prognostic factors discussed in Section IV.B. In the United States, the median survival after surgical resection is about 22 months for patients with cirrhotic livers and 32 months for patients with normal livers (range, 2 months to 15 years). The perioperative morbidity is minimal and is slightly higher in the cirrhotic group. Morbidity includes subphrenic abscess, subhepatic abscess, pneumothorax, and wound infection. Total hepatectomy with orthotoptic liver transplantation may be of benefit in patients with unresectable nonmetastatic fibrolamellar HCC, intrahepatic bile duct cancers, or hemangiosarcoma and is under investigation as a strategy for patients with poor underlying hepatic function or bilobar disease limited to the liver.
C. Localized and nonresectable disease
1. Preoperative multimodality treatment followed by surgery. There are no current preoperative approaches that have been shown to be of benefit.
2. Transcatheter arterial chemoembolization (TACE) of unresectable HCC using a mixture of Gelfoam powder, Lipiodol, and contrast media with chemotherapeutic drugs has been used with some success. TACE may also be used preoperatively to reduce intraoperative bleeding or as a palliative measure in patients with far advanced HCC. Recent trials with TACE suggest that there may be a survival advantage with its use.
3. Transcatheter arterial radioembolization (TARE) is a newer modality that uses tumor ablation by transarterial injection of Y90 radioactive microspheres following the principles of transarterial chemoembolization. TARE has not been as rigorously studied as TACE. Early uncontrolled studies suggest that there is a risk of progressive long-term liver decompensation in patients with more advanced liver disease at the time of treatment initiation.
4. Other treatments. Percutaneous intralesional installation of absolute ethanol under ultrasound guidance has resulted in a reported 5-year survival rate of nearly 80% in highly selected patients, particularly those with small tumors who are not surgical candidates. The use of radiofrequency ablation has become a common alternative to ethanol ablation. Radiofrequency ablation is performed by applying a high-frequency electrical current through a treatment probe that is inserted into the HCC. Cryosurgery has been reported to have similar efficacy in highly selected patients.
D. Nonresectable and metastatic disease
1. Targeted and antiangiogenic therapy has shown early evidence of promise. In a randomized phase III trial comparing sorafenib with best supportive care, a significant increase in overall survival of approximately 2.5 months was seen with the use of sorafenib in patients with Child-Pugh A liver disease. A number of trials are underway to better assess this drug and other similar drugs when used alone or in combination with other agents.
2. Hormonal therapy. About 40% of patients with HCC have estrogen receptor protein in the cell cytosol. Large tumors are commonly estrogen receptor-negative. In a prospective, randomized study of tamoxifen (40 mg/d) plus best supportive care versus best supportive care alone, there was no difference in median survival (16 vs. 15 months). Similar negative results have been observed in trials with flutamide, megestrol acetate, and octreotide.
3. Systemic chemotherapy has a response rate of 10% or less and does not affect median survival (3 to 6 months). Doxorubicin as a single agent or in combination with other drugs has been used. Other than in highly selected circumstances, the use of chemotherapy is generally not recommended.
GALLBLADDER CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Primary gallbladder carcinoma (GBC) is the most common malignant tumor of the biliary tract and the fifth most common cancer of the digestive tract. There are 6,000 to 7,000 cases annually in the United States. GBCs were found in 1% to 2% of operations on the biliary tract.
B. Risk factors. The cause of GBC remains unknown. Reported risk factors include the following:
1. Sex. The female-to-male ratio is 3:1 to 4:1. Acalculous carcinoma is also more common in women.
2. Race. The incidence of GBC is doubled in southwestern American Indians, who also have a twofold to threefold greater incidence of cholelithiasis. The incidence of GBC is also high in Peru and Ecuador among populations with Native American genealogy.
3. Older age. The mean age for the occurrence of GBC is 65 years; the disease is rare before 40 years of age.
4. Chronic cholecystitis and cholelithiasis are associated with the development of GBC in 50% and 75% of cases, respectively. Latency periods are lengthy; 1% of patients known to have gallstones for >20 years develop GBC. Those with larger stones are more prone to GBC than those with stones smaller than 1 cm. The incidence of GBC is decreasing among populations in the world where cholecystectomy is becoming more common. Calcification of the wall of the gallbladder (porcelain gallbladder) increases the risk for GBC by 10% to 60%. Cholecystitis associated with liver flukes and in chronic typhoid carriers is linked to the increased incidence of GBC.
5. Benign neoplasms. Both inflammatory and cholesterol polyps are associated with appreciable risk. Papillary and nonpapillary adenomas of the gallbladder may contain carcinoma in situ. Malignant transformation is rare, however.
6. Ulcerative colitis increases the risk for extrahepatic biliary cancer by a factor of 5 to 10; 15% of these cancers occur in the gallbladder.
7. Carcinogens. Rubber industry employees have a higher incidence and earlier onset of GBC.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology. Most GBCs are adenocarcinomas (80%) showing varying degrees of differentiation. The mucus secreted by this cancer is typically of the sialomucin type, in contrast to the sulfomucin type secreted by the normal or inflamed mucus-secreting glands. Other types of GBC include adenoacanthoma, adenosquamous carcinomas, and undifferentiated (anaplastic, pleomorphic, sarcomatoid) carcinomas. Some adenocarcinomas have choriocarcinoma-like elements, and others have morphology equivalent to small cell carcinoma.
B. Natural history. GBC has a propensity to involve the liver, stomach, and duodenum by direct extension. The common sites of metastasis are the liver (60%), adjacent organs (55%), regional lymph nodes (35%), peritoneum (25%), and distant visceral organs (30%).
C. Clinical presentation. GBC may present as one of the following clinical syndromes:
1. Acute cholecystitis (15% of patients). These patients appear to have less advanced carcinoma, a higher rate of resectability, and longer survival.
2. Chronic cholecystitis (45%)
3. Symptoms suggestive of malignant disease (e.g., jaundice, weight loss, generalized weakness, anorexia, or persistent right upper quadrant pain; 35%)
4. Benign nonbiliary manifestations (e.g., GI bleeding or obstruction; 5%)
III. DIAGNOSIS
A. Symptoms. The lack of specific symptoms prevents detection of GBC at an early stage. Consequently, the diagnosis is usually made unexpectedly at the time of surgery because the clinical signs commonly mimic benign gallbladder disease. Pain is present in 79% of patients; jaundice, anorexia, or nausea and vomiting in 45% to 55%; weight loss or fatigue in 30%; and pruritus or abdominal mass in 15%.
B. Physical examination. Certain combinations of symptoms and signs may suggest the diagnosis, such as an elderly woman with a history of chronic biliary symptoms that have changed in frequency or severity. A right upper quadrant mass or hepatomegaly and constitutional symptoms suggest GBC.
C. Laboratory examination. Elevated serum alkaline phosphatase is present in 65% of patients, anemia in 55%, elevated bilirubin in 40%, leukocytosis in 40%, and leukemoid reaction in 1% of patients with GBC. The association of elevated alkaline phosphatase without elevated bilirubin is consistent with GBC; about 40% of these patients have resectable lesions.
D. Radiologic examination
1. Abdominal ultrasound is abnormal in about 98% of patients. Cholelithiasis, thickened gallbladder wall, a mass in the gallbladder, or a combination of these constitutes the most common finding. Ultrasound is diagnostic of GBC in only 20% of cases, however.
2. CT of the abdomen may be diagnostic in half of patients.
3. MRI can differentiate gallbladder tumors from adjacent liver. Use of magnetic resonance cholangiography can help determine whether biliary tract encasement is present, and vascular enhancement techniques often permit preoperative diagnosis of portal vein involvement.
4. Percutaneous transhepatic cholangiography (PTHC) is abnormal in 80% of cases and diagnostic in 40%.
5. ERCP is abnormal in about 75% of cases and yields a tissue diagnosis in 25%.
6. Laparoscopic exploration may allow assessment of the peritoneal surfaces, liver, and tissues adjacent to the gallbladder to determine potential resectability.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging. There are two commonly used staging systems: the American Joint Commission on Cancer Staging system (AJCC, stages 0 to IV) and the Nevin system (stages 1 to 5). Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. The following stage groupings are defined by the AJCC 7th edition in 2010.
Stage I: Tumor invades lamina propria (T1a) or muscle layer (T1b).
Stage II: Tumor invades perimuscular connective tissue, but does not extend beyond serosa or into liver (T2).
Stage IIIA: Tumor perforates visceral peritoneum and/or directly invades the liver or other adjacent structures.
Stage IIIB: Lymph node involvement
Stage IV: Tumor invades main portal vein or hepatic artery or two or more extrahepatic structures.
B. Prognostic factors. The overall median survival of patients with GBC is 6 months. After surgical resection, only 27% are alive at 1 year, 19% at 3 years, and 13% at 5 years. Disease stage is the most significant prognostic factor. The 5-year survival rate after surgical resection is 65% to 100% for stage I, 30% for stage II treated with simple cholecystectomy, <15% for stage III, and 0% for stage IV disease. Poorly differentiated (higher grade) tumors and the presence of jaundice are associated with poorer survival. Ploidy patterns do not correlate with survival.
V. PREVENTION. Cholecystectomy has been recommended to prevent GBC. For every 100 gallbladders removed, there is one patient with GBC. However, the overall mortality rate of cholecystectomy is also about 1% (including patients with diabetes and gangrenous gallbladder as well as patients with cholangitis or gallstone pancreatitis).
VI. MANAGEMENT. Despite the improvement of diagnostic capabilities, better perioperative care, and a more aggressive surgical approach, GBC remains a fatal illness in most patients.
A. Cholecystectomy. The best chance for long-term survival is the serendipitous discovery of an early cancer at the time of cholecystectomy. Simple cholecystectomy is curative for T1a tumors. Repeat resection with “extended cholecystectomy” (en bloc resection of the gallbladder bed, segments IVB and V of the liver, and regional lymph nodes) after the discovery of a GBC during cholecystectomy is recommended for stage T1b or stage II disease and is associated with a 5-year survival of 70% to 80%. Radical surgery for more advanced disease has not resulted in better survival.
B. RT appears to have no added benefit in the adjuvant setting, although the only reports of such therapy have been small retrospective series. Intraoperative RT has been reported to be of benefit in several small series of highly selected patients. RT may be useful as a primary treatment (without surgical resection) using either external-beam RT alone or external-beam RT plus 192Ir implants. RT may relieve pain in a small number of patients.
C. Chemotherapy. The data on adjuvant systemic chemotherapy are anecdotal. 5-FU-based combinations are most commonly used, but the response rates are poor. Phase II trials have shown potential benefit to the use of gemcitabine.
For patients with metastatic disease, the combination of gemcitabine and cisplatin should be considered, based on the results of a randomized phase III trial as discussed in the next section. Alternative options include gemcitabine and oxaliplatin or gemcitabine and capecitabine.
BILIARY TRACT (INTRAHEPATIC AND EXTRAHEPATIC) CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Epidemiology. Biliary tract carcinomas (BTCs, cholangiocarcinomas) are rare and occur with equal frequency in men and women at the average age of 60 years. In American Indians, Israelis, and Japanese, the incidence of BTC is 6 to 7 per 100,000 population, compared with 1 per 100,000 among the US population. However, cancer of the intrahepatic bile ducts appears to be increasing in incidence in both the United States and elsewhere. In a review of incidence data for intrahepatic cholangiocarcinoma from the Surveillance, Epidemiology, and End Results Program of the NCI, there was a 165% increase in incidence between 1975 and 1999. This increase is likely partly a result of more accurate diagnosis causing a shift from a classification of “unknown primary” to cholangiocarcinoma. Despite this possible shift, there appears to be a meaningful increase in the incidence of cholangiocarcinoma. The reasons for the observed increase have not been identified.
Extrahepatic bile duct cancers accounts for less than one-third of BTCs. When BTC is combined with GBC, GBC accounts for two-thirds of all BTCs. Half of patients with BTC have undergone cholecystectomy for cholelithiasis.
B. Etiology and risk factors. An increased incidence of BTC has been reported in patients with Crohn disease, choledocholithiasis, cystic fibrosis, chronic long-term ulcerative colitis, primary sclerosing cholangitis, and Clonorchis sinensis infestation. The incidence is also reportedly increased in patients with congenital anomalies of the intrahepatic and extrahepatic bile ducts (e.g., cysts, congenital dilation of the bile ducts, choledochal cyst, Caroli disease [congenital cystic dilation of multiple sections of the biliary tree], congenital hepatic fibrosis, polycystic disease, abnormal pancreaticocholedochal junction). Conditions that cause chronic bile duct stasis and infection are linked to increased risk for BTC. A history of exposure to the outmoded contrast agent Thorotrast has also been associated with BTC.
II. PATHOLOGY
A. Histology
1. Malignant tumors of the bile ducts are adenocarcinoma in 95% of cases. Microscopically, BTCs generally extend to 1 to 4 cm beyond the gross margin of the tumor. Multiple foci of carcinoma in situ may be noted. Malignant tumors of intrahepatic bile ducts are less common than HCC and have no relation to cirrhosis. Mixed hepatic tumors with elements of both HCC and cholangiocarcinoma do occur; most of these cases are actually HCC with focal ductal differentiation. Table 9.6 depicts the clinical and pathologic differences between HCC, bile duct carcinoma, and metastatic adenocarcinoma. Appendix C-4.IV shows immunohistochemical phenotypes of HCC and bile duct carcinomas as well as other adenocarcinomas.
Other malignant tumors that involve the bile ducts include anaplastic and squamous carcinomas, cystadenocarcinomas, primary malignant melanoma, leiomyosarcoma, carcinosarcoma, and metastatic tumors (particularly breast cancer, myelomas, and lymphomas).
2. Biliary tract adenomas are solitary in 80% of cases and may grossly resemble metastatic carcinoma. Most are <1 cm in diameter and are located under the capsule.
3. Biliary tract cystadenoma and cystadenocarcinoma. Benign and malignant cystic tumors of biliary origin arise in the liver more frequently than in the extrahepatic biliary system.
4. Biliary tract carcinoma (cholangiocarcinoma; see Extrahepatic Bile Duct Cancer, later). Malignant tumors of intrahepatic bile ducts are less common than HCC and have no relation to cirrhosis. Mixed hepatic tumors with elements of both HCC and cholangiocarcinoma do occur; most of these cases are actually HCC with focal ductal differentiation.
B. Location. BTCs are divided anatomically into those that arise from the intrahepatic upper third of the biliary tract, including the hilum (50% to 70% of all tumors); the middle third (10% to 25%); the lower third (10% to 20%); and the cystic duct (<1%). Tumors found near the junction of the right and left hepatic duct (Klatskin tumors) are usually small and may be inconspicuous at laparotomy. Adenocarcinomas located in the right and left hepatic ducts or common hepatic duct are frequently scirrhous, constricting, diffusely infiltrating, or nodular and may mimic sclerosing cholangitis or stricture. Adenocarcinomas of the common bile duct or cystic duct are more often fungating and may have a better prognosis. Carcinoma of the cystic duct is rare, and distention of the gallbladder occurs before jaundice becomes apparent.
III. DIAGNOSIS
A. Symptoms. Jaundice is present in the majority of patients. Abdominal pain, weight loss, fever, malaise, or hepatomegaly occurs in half of cases, but generally in patients with advanced BTC. Patients with proximal tumors in the upper third of the biliary tract usually have symptoms for twice as long as those with tumors in the lower third.
B. Laboratory studies
1. Serum chemistries. Serum bilirubin levels >7.5 mg/dL are found in 60% of cases, alkaline phosphatase greater than twice normal in 80%, and increased transaminase level and prothrombin time in 25%.
2. Tumor marker. Serum CA 19-9 is elevated in 90% of patients.
3. Radiologic examination
a. Abdominal ultrasound shows dilation of the common bile duct or intrahepatic biliary ducts.
b. CT or MRI may reveal a mass and suggest the site or origin of carcinoma.
c. PTHC is the most specific test for proximal bile duct lesions.
d. ERCP is the best diagnostic test for distal bile duct tumors.
e. Angiography and portovenography are useful in determining the extent of the disease for the preoperative evaluation of resectability.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging. Readers should consult an up-to-date staging manual because of frequent revisions of staging systems. All patients should be initially staged so that those with unresectable tumors are not subjected to needless surgery. If PTHC shows that the tumor extends into the parenchyma of both the right and left lobes of the liver, the tumor is unresectable and no surgery is performed. If angiography shows encasement of the main portal vein or hepatic artery, the tumor is also unresectable. If, however, the tumor extends into only one lobe, or if there is involvement of one branch of the portal vein or hepatic artery, surgical exploration is considered with the possibility of adding hepatic lobectomy to the hepatic duct resection. The criteria (Blumgart) for unresectability are as follows:
1. Bilateral intrahepatic duct involvement
2. Entrapment of the main trunk of the portal vein
3. Bilateral invasion of the branches of the portal vein or hepatic artery
4. Ductal involvement in the contralateral lobe
B. Prognostic factors. The poor prognostic variables with statistical significance are mass lesion, cachexia, poor performance status, serum bilirubin 9 mg/dL or greater, multicentric disease, hilar or proximal sites, high tumor grade, sclerotic histology, liver invasion, lymph node involvement, and advanced stage.
V. MANAGEMENT
A. Surgical resection is the only treatment that may result in long-term survival. In specialized medical centers, about 45% of patients who undergo exploratory surgery also undergo complete resection with no gross tumor left behind, 10% undergo incomplete resection, and 45% have tumors that are not resectable. Tumors in the middle and distal ducts have a higher resectability rate than tumors in the proximal ducts, which have a maximal resectability rate of 20%. The median survival of patients with intrahepatic tumors following resection is 18 to 30 months, while that for patients with extrahepatic tumors is 12 to 24 months. The 5-year survival rate is about 10% to 45%. The 30-day operative mortality rate may be as high as 25%. The high postoperative complication rate includes wound infection, cholangitis, liver abscess, subphrenic abscess, pancreatitis, and biliary fistulas.
B. Adjuvant therapy has been advocated to reduce the high incidence of local recurrence (up to 100%), but it does not appear to improve survival after curative resection. The role of adjuvant RT remains unclear. Cholangiocarcinoma is radiosensitive, but bile duct tolerance to radiation is limited. The complications of RT include biliary and duodenal stenosis. The results of small series of selected patients treated with 5-FU combined with RT have led some authors to advocate this as an adjuvant to surgery or in cases with locally advanced and unresectable disease.
C. Biliary tract bypass
1. Surgical biliary tract bypass is carried out predominantly in those patients whose tumors are found to be unresectable at operation. Biliary-enteric anastomosis is usually performed using a Roux-en-Y jejunal loop. The operative mortality rate ranges from 0% to 30%, and the median survival varies from 11 to 16 months. The theoretical advantage of operative drainage is the decreased potential for recurrent cholangitis.
2. Surgical stenting. T-tube or U-tube catheters can be passed through the obstruction. A T-tube is hard to replace when it becomes clogged. The advantage of a U-tube is that both of its ends are externalized separately, easing replacement when the tube becomes obstructed. The 30-day mortality rate for operative stenting varies from 10% to 20%.
3. Endoscopic stenting has two advantages: a decreased morbidity and no creation of external fistulization. This method is more successful with distal bile duct tumors and is associated with a 30-day mortality rate of 10% to 20%.
4. Percutaneous stenting to provide drainage, either as an externalized stent or as an endoprosthesis, is associated with a 30-day mortality rate of 15% to 35%.
D. Other methods of treatment
1. Liver transplantation is generally not considered appropriate because of the high incidence of local recurrence. With orthoptic liver transplantation used alone, long-term survival is only 20% of highly selected patients with disease limited to the liver. The use of pretransplant chemotherapy and radiation has increased 5-year survival to 70% to 80%, making transplant a more meaningful option in selected patients.
2. RT appears to have some effect on the tumor size and may relieve jaundice in patients without biliary stenting. RT may be used (usually with biliary stenting) either as primary treatment or as adjuvant therapy. Conventional external-beam RT has the advantage of giving a moderately high dose of radiation (5,000 to 6,000 cGy) to a relatively large volume of tissue and is more effective in treating bulky tumor masses. Implantation with 192Ir seeds (effective radius of 1 cm from the seeds) delivers high-dose RT to localized residual disease after surgical resection or may provide palliation to patients with bile ducts obstructed by tumor. The typical dose with 192Ir seeds is 2,000 cGy.
3. Chemotherapy is of potential benefit. 5-FU has a response rate of 15%. Gemcitabine has been shown to have meaningful activity with an approximately 20% to 40% response rate and improved overall survival of 8 to 14 months. Building on this observation, a variety of trials have looked at gemcitabine combined with other chemotherapy drugs including either oxaliplatin, capecitabine, or low-dose cisplatin. In a phase III trial, the addition of low-dose cisplatin to gemcitabine compared to gemcitabine alone improved the response rate from approximately 15% to 25% and significantly improved both progression-free and overall survival. The combination was well tolerated compared to gemcitabine alone. Based on this finding, the use of a gemcitabine doublet does appear to be warranted in patients with biliary tract or gallbladder cancer.
CANCER OF THE AMPULLA OF VATER
I. PATHOLOGY
Carcinoma of the ampulla of Vater is a papillary neoplasm arising in the last part of the common bile duct where it passes through the duodenum. Distinction between true ampullary tumor and periampullary tumors originating in the duodenal mucosa or pancreatic ducts is important because the periampullary cancers have a poor prognosis compared with ampullary cancers. The differentiation may be made by examination of the mucins they produce. Ampullary cancer produces sialomucins, whereas periampullary cancers produce sulfated mucins.
II. STAGING SYSTEM AND PROGNOSTIC FACTORS
The TNM staging system is used to stage ampullary cancer. The prognosis of patients with ampullary carcinoma is better than that of patients with cancer arising in any other site in the biliary tree. Pancreatic invasion and lymph node metastasis are the two most important prognostic factors. The 5-year survival rate is in excess of 50% when no nodal metastasis and no invasion of the pancreas have occurred. Nodal metastasis occurs much more frequently in patients with tumors larger than 2.5 cm.
III. MANAGEMENT
Surgery is the only curative treatment modality for ampullary carcinoma. Pancreaticoduodenal resection (Whipple procedure or a modification) is the surgical procedure of choice. The 5-year survival rate ranges from 5% to 55% depending on lymph node involvement, invasion of the pancreas, and histologic differentiation. Ampullectomy (local ampullary excision) performed on poor-risk patients with apparently localized disease is associated with a 10% 5-year survival rate.
Suggested Reading
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Anal Cancer
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Pancreatic Cancer
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Liver Cancer
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Cholangiocarcinoma and Gallbladder Cancer
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