Management of Gastrointestinal Cancers

Jeffrey W. Clark

Gastrointestinal malignancies are among the most common tumors found in adults worldwide. The primary treatment of local disease is surgical although increasingly adjuvant or neoadjuvant chemotherapy and radiation therapy play important roles in management of patients with resectable disease. The care of advanced disease is a responsibility often shared by the primary physician in close conjunction with oncologic colleagues. It is important for the primary physician to know the indications, efficacy, side effects, and limitations of available treatment modalities to help counsel the cancer patient and make best use of therapies offered by the surgeon, radiation oncologist, and medical oncologist.

Continued developments in combining chemotherapy and radiation therapy with surgery for treatment of gastrointestinal cancer have added substantially both to palliation and potential for cure. Although overall mortality remains high (50% to 90%), it varies considerably by specific disease and stage. Even in patients with a poor prognosis, quality of life can be enhanced with a good palliative care approach that from the outset addresses important complications of gastrointestinal cancer, such as obstruction, ascites, and cachexia. Continued improvements in management of such complications have significantly improved quality of life for these patients and benefit from the coordinated efforts of the primary care physician, medical oncologist, and palliative care team.

ESOPHAGEAL CANCER (1, 2, 3, 4, 5, 6 and 7)

As is true of many malignancies, carcinoma of the esophagus is difficult to diagnose and treat because symptoms usually do not occur until late in the course of illness. As a result, by the time patients become symptomatic, palliation is often the only therapeutic option. Of the approximately 17,500 new cases of esophageal cancer diagnosed annually in the USA, there are approximately 15,000 deaths. Thus, improvements in prevention and early detection are necessary to make a significant impact on the overall mortality from this disease.

Histologic Types

There are two major histologic types: epidermoid (squamous cell carcinoma) and adenocarcinoma. Worldwide, squamous cell carcinoma remains the most common histologic type. However, in the United States, the incidence of squamous cell carcinoma continues to decline, and adenocarcinoma is increasing in frequency.

Risk Factors

Risk factors for squamous cell carcinoma include heavy smoking, excessive alcohol use, achalasia, and a diet low in fruits and vegetables. A diet rich in cruciferous vegetables and yellow and green vegetables as well as ingestion of nonsteroidal agents and aspirin decrease the risk. Risk factors for adenocarcinoma are less well established, but chronic severe gastroesophageal reflux with Barrett esophagus is a principal etiologic factor; both duration and severity contribute to risk. Obesity may also be a risk factor for adenocarcinoma. Similar to squamous cell cancer, use of aspirin and nonsteroidals is associated with a decreased risk. Given the advanced stage by the time symptoms develop and the poor prognosis in treating these patients, prevention is the best means for improving outcome (see later discussion).

Clinical Presentation and Course

Adenocarcinoma often appears in the setting of Barrett esophagus, a premalignant metaplastic change that is the consequence of prolonged severe acid reflux disease. Barrett esophagus has a significant potential for dysplastic transformation leading to malignancy (see Chapter 61). Aside from heartburn, such patients are usually asymptomatic at the time of malignant transformation.

Early symptoms of esophageal cancer frequently go unnoticed because they are usually nonspecific (e.g., a mild burning discomfort associated with swallowing, sometimes referred to as odynophagia). By the time of usual presentation, symptoms include dysphagia and progressive inanition, manifestations of late disease. Dysphagia usually indicates a markedly narrowed esophageal lumen and a substantial tumor burden.

These tumors commonly begin as superficial mucosal lesions. They tend to spread silently under the mucosa and extend readily into the mediastinum due to the absence of a serosal surface barrier. Tumor may extend regionally into the trachea and regional lymph nodes and vertically up and down the esophageal mucosa and submucosa. Distant metastases most commonly occur in the liver and intra-abdominal node-bearing areas. The next most frequent sites include the peritoneal cavity, lung, bone, and brain. At the time of diagnosis, less than one third of patients have cancer confined to the esophageal wall, the stage in which cure is most likely to occur with surgical resection.

Diagnosis and Staging

Next to prevention, early diagnosis is the next best means for improving outcome. Patients with a long-standing history of severe heartburn should be considered for endoscopy and biopsy because they have an increased risk of Barrett esophagus and adenocarcinoma (see Chapter 61). Those found to have metaplastic change indicative of Barrett esophagus are candidates for a program of regular surveillance endoscopy and biopsy (see Chapter 61). Those who show dysplastic change need referral for possible surgical resection. New onset of odynophagia in a heavy smoker or drinker should also trigger consideration of endoscopy. Although the presence of small nodules, minor erosions, thickened folds, or mucosal depressions is suggestive of early cancer, mucosal biopsy is required for definitive diagnosis.

In addition to biopsy to establish the diagnosis and determine depth of tumor penetration, there are a number of noninvasive measures useful to the staging evaluation. Physical examination should include a check for supraclavicular adenopathy and hepatomegaly. Computed tomography (CT) of the chest and abdomen should be performed to check for local extent of disease, evidence of mediastinal invasion, lymphadenopathy, and evidence of distant spread. Magnetic resonance imaging (MRI) provides a similar degree of sensitivity for detection of invasion, but is more expensive than is CT. Positron emission tomography (PET) scanning may also be useful in evaluation, especially to rule out metastatic disease not detectable on CT. Increasingly, PET-CT is utilized to stage patients for candidacy for surgical resection. Endoscopic ultrasound (EUS) is proving useful in determining depth of invasion and may be superior to CT for this purpose. The optimal use of these evolving diagnostic and staging modalities is the subject of ongoing study to best determine their optimal use. Although imaging of the brain (with either CT or MRI) is not universally recommended, it should be considered, especially if neurologic complaints ensue, given the relatively high frequency of brain metastases.

From a staging standpoint, the most important distinction is between patients with potentially resectable disease and those who are not surgical candidates. As noted, the most curable lesions are those confined to the mucosa. Unfortunately, nearly 75% of patients who present with dysphagia have at least locally advanced disease.

Principles of Management

Surgery remains the treatment of choice for cure. However, only a relatively small percentage of patients have potentially curable disease at the time of detection, and even after surgical resection, the rates of local recurrence and distant metastasis remain high. Consequently, a neoadjuvant program of chemotherapy and radiation followed by surgery continues to be explored to reduce the risk of recurrence. A number of randomized phase III trials have shown a statistically significant survival benefit leading to the recommendation of neoadjuvant therapy for patients with all but the earliest stages of potentially resectable disease. Surgery alone is reserved for those with stage I or less disease. Unfortunately, most patients have unresectable disease at the time of presentation, and for them therapy remains palliative.

Nutrition

Nutrition is a top priority given that much of morbidity of esophageal carcinoma is due to the severe dysphagia, odynophagia, and inanition that characterize advanced disease. Many patients are unable to swallow even their own saliva. Even partial obstruction leads to weight loss and cachexia. Weight loss greater than 10% at time of presentation is a poor prognostic sign. Good nutrition is essential for tolerance of surgery, chemotherapy, and radiation therapy. Pureed diets and liquid diet supplements are helpful, and hyperalimentation is used as temporary support during treatment for patients with the potential for meaningful survival.

Surgery

Surgery remains an essential component of curative therapy. In combination with neoadjuvant therapy, it provides potential for cure in the approximately 15% to 20% of cases found to have potentially resectable disease and for those with severe dysplasia or carcinoma in situ found during surveillance biopsy of Barrett esophagus. The type of esophagectomy performed is determined
by tumor location with attempt to have tumor-free margins of at least 2 cm. Except for very early disease picked up by surveillance (which might allow for a more localized resection), most cases usually require resection of at least a substantial portion of the esophagus due to the tendency of disease to spread submucosally. Perioperative morbidity and mortality historically have been high in such surgeries although these have significantly declined in the past decade. Death rates in most recent series are less than 5% to 10% with another 30% having major nonfatal complications. Median survival for patients undergoing surgery for cure is approximately 2 years, although considerably higher for those with very early disease confined to a small area of mucosa. Three-year survival is approximately 25% to 30%.

Surgery may also be performed for palliation to reestablish ability to swallow; resection is most successful in patients with disease confined to the distal esophagus. However, even partial esophagectomy is a major procedure, with high risk of major postoperative complications and surgical mortality.

Increasingly, stents are being utilized to try to maintain patency of the esophagus for patients who are not surgical candidates. As both the structure of stents and procedures for placing them endoscopically have improved, they have had an increasingly important role in the palliation of dysphagia. However, there is still significant room for improvement.

Radiation Therapy

Radiation therapy is a consideration in persons with locally advanced disease not amenable to surgical resection. However, the central intrathoracic location of esophageal cancer, adjacent to such key structures as the heart, lungs, and spinal cord, makes delivery of curative doses (without sensitizing chemotherapy) difficult without causing radiation injury. A program of concurrent chemotherapy (see below) enables use of lower radiation doses and provides superior survival compared with radiation alone in patients with localized disease, be it adenocarcinoma or squamous cell cancer. Local-regional persistence of disease is a principal cause of treatment failure, suggesting that in the small subset of patients where it becomes feasible, surgery after chemoradiation should be considered.

Chemotherapy

High risk of distant and local failures with surgery and radiation has prompted trials of chemotherapeutic regimens for use in combination with radiation alone or as combined chemoradiotherapy as neoadjuvant therapy for curative-intent surgery. The addition of cisplatin and fluorouracil improves outcomes in patients treated with radiation therapy or neoadjuvant chemoradiotherapy. Weekly carboplatin and paclitaxel with radiation therapy has also been shown to improve outcomes as neoadjuvant therapy prior to surgery. Better chemotherapeutic regimens continue to be sought. Various combinations, including agents such as paclitaxel, irinotecan, 5-fluorouracil, epirubicin, and platinum agents (cisplatin and oxaliplatin), have been shown to be active against esophageal cancers.

Monoclonal Antibodies

As the molecular changes important for survival and growth of esophageal cancer cells are discovered, agents that specifically target these will be explored alone and in combination with chemotherapy and/or radiation therapy. For the subset of esophageal and gastric cancers that have increased expression of the HER2 protein, addition of trastuzumab (a monoclonal antibody directed against HER2) improves survival in combination with chemotherapy for patients with metastatic disease. Other biologic agents (e.g., anti-epidermal growth factor receptor (EGFR) agents and anti-vascular endothelial growth factor agents such as bevacizumab) are being explored in combination with chemotherapeutic agents. Ongoing studies are evaluating which combinations of these agents either alone or in combination with radiation therapy provide the greatest benefit to patients with acceptable toxicity.

Multimodality Therapy

As outlined above, the combination of all three modalities (chemotherapy, radiation therapy, and surgery) as combined neoadjuvant chemotherapy and radiation therapy followed by surgical resection is the most common approach utilized for patients with potentially respectable disease that is stage II or higher. Patients with earlier stage disease usually undergo surgical resection alone although approaches to improve therapy continue to be explored.

Laser Therapy

Laser treatment is available for palliation in patients too ill to undergo surgery or radiation. Adverse effects are few, and therapy can be performed on an outpatient basis, although a brief hospital stay for observation may be needed immediately after treatment. However, this is usually only applicable for small lesions, and even when relief can be achieved, there is no change in survival rate.

Stenting and Dilatation

For dysphagic patients too ill for surgery, palliation can be provided by endoscopic stent placement. Esophageal dilatation is useful for temporary relief of obstructive symptoms. Gastrostomy may be of help for nutrition but provides no symptomatic relief from disabling dysphagia.

Prevention

Prevention remains the most effective means of dealing with this devastating cancer. Efforts to achieve cessation of smoking and alcohol abuse (see Chapters 54 and 228) are essential to reducing the risk of squamous cell cancers. Surveillance endoscopy plus biopsy of high-risk patients (e.g., those with Barrett esophagus— see Chapter 61) offers the potential to identify dysplastic transformation and early adenocarcinoma, hopefully leading to marked improvements in survival. The optimal approach to surveillance remains to be determined (see Chapter 61). Similarly, the identification of chronic symptomatic reflux as a risk factor for adenocarcinoma raises the possibility that acid suppression therapy (e.g., by proton pump inhibition) might reduce the chances of malignant transformation of esophageal mucosa (see Chapter 61). Prospective randomized study is needed to determine whether this will actually lead to a reduction in mortality.

GASTRIC CANCER (8, 9, 10, 11, 12, 13, 14 and 15)

Approximately 21,000 new cases of gastric cancer are diagnosed in the United States each year with 10,540 deaths. Over the past century, the incidence has decreased markedly in the United States, although this cancer remains one of the most common worldwide with an estimated 990,000 cases yearly. Overall mortality has remained relatively unchanged over the past 20 years except for a small improvement in survival for patients with resectable disease who receive neoadjuvant and/or adjuvant therapy. Overall 5-year survival is approximately 78% for early-stage disease but declines rapidly to 20% for those with stage IIIA disease and less than 10% for those with stage IIIB or IV disease. Onset is uncommon before the age of 40 years, but incidence increases markedly thereafter. Early diagnosis is
essential for improving outcome. Unfortunately, because of the absence of early symptoms and nonspecific nature of symptoms when they do occur, most patients are still not diagnosed until they have advanced disease.

Histologic Types

Approximately 90% of gastric cancers are adenocarcinomas, with those that are well differentiated and circumscribed having a much better prognosis than those that are poorly differentiated and infiltrative. Lymphomas are the second most common histology although GISTS, leiomyosarcomas, neuroendocrine tumors, and metastatic disease are also seen.

Risk Factors

Throughout the world, dietary factors appear to play a major role, linked at least in part by the contribution of Helicobacter pylori infection to pathogenesis.

Helicobacter pylori Infection

Large-scale epidemiologic studies find a strong independent association between Helicobacter infection and risk of gastric carcinoma. Helicobacter pylori infection is most prevalent among populations with inadequate means of food preservation and high risk of food spoilage, populations with the highest prevalences of gastric cancer. The decline in gastric cancer in the United States over the last century may be related to improvements in food handling. Infection of the gastric mucosa by H. pylori leads to chronic inflammation and development of atrophic gastritis, a recognized premalignant change. Infection during childhood is believed to be especially harmful. It is estimated that up to 70% of cases are causally related to Helicobacter infection, but only a small number of persons with the infection develop gastric carcinoma, suggesting additional causative factors.

Other Dietary Factors

In countries where risk is high, research suggests that, besides H. pylori infection, dietary factors make an important contribution to risk. Use of salting, smoking, or pickling rather than refrigeration to preserve foods appears to play a role as does low consumption of vegetables and fruits, fiber, and antioxidants (such as garlic, vitamins A and C).

Other Risk Factors

Other identified risk factors include smoking, previous gastric surgery (usually Billroth II anastomosis), and chronic atrophic gastritis. Increased prevalences also occur among Native Americans, Asians, Hispanics, and Scandinavians. Genetic factors include blood type A, hereditary nonpolyposis colorectal cancer (HNPCC), familial adenomatous polyposis (FAP), Li-Fraumeni syndrome, and family history of gastric cancer history where genetic abnormality has not been defined.

Clinical Presentation and Course

Early diagnosis is difficult because presenting symptoms are often subtle. Unexplained iron deficiency anemia or asymptomatic guaiac stool test positivity may be the only manifestation. Nonspecific abdominal pain, gastric ulceration with or without bleeding, weight loss, nausea, decreased appetite, early satiety, dysphagia, melena, and obstructive symptoms are the major patterns of clinical presentation, but most are manifestations of advanced disease.

The earliest symptom in the majority of patients is abdominal discomfort; however, it may be subtle and resemble dyspepsia. Most are free of the nausea, vomiting, anorexia, and weight loss that characterize more advanced disease. Gastric ulcer is an important presentation, characterized by a suspicious appearance on barium study or endoscopy or a more benign-appearing radiologic defect that fails to heal completely or quickly recurs after 6 weeks of ulcer therapy (see Chapter 68).

The disease often progresses silently until signs or symptoms of metastatic disease appear. Spread occurs by direct extension and by seeding of the lymphatics, blood vessels, and peritoneal surface. After the peritoneal surface, the most frequent distant metastatic sites are liver (40%), lung (15%), and bone (15%). Among patients who come to surgery, approximately 80% are found to have lymph node metastases. Clinical manifestations include weight loss, anorexia, early satiety, abdominal pain, or ascites, often causing the patient to seek medical attention.

Diagnosis

A high index of suspicion is warranted; early diagnosis provides the best chance for cure. Patients over the age of 40 years presenting with any of the manifestations noted above should undergo testing as early as possible. Endoscopy with brushings and biopsy is the preferred method for definitive diagnosis. In the absence of an ulcer, all atypical areas of mucosa should be biopsied. Endoscopy has largely replaced upper gastrointestinal series for diagnosis, in part because it permits the obtaining of biopsy specimens.

Principles of Management

Surgery is the treatment of choice, but the ability to achieve cure is limited by the subsequent development of metastatic disease in a high percentage of patients. Neoadjuvant and/or adjuvant chemotherapy either given alone pre- and postoperatively or postoperatively in combination with radiation therapy has been shown to improve survival although overall survival remains poor. Prevention and early detection are the best hopes at present in improving outcomes.

Surgery

Surgery is the primary mode of treatment, both for cure and palliation. Median survival for patients managed by complete surgical resection is in excess of 3 years. The 5-year survival rate varies according to location of the tumor being better for distal as compared to proximal cancers. When lymph node involvement is found, survival falls significantly. Postoperatively, surgical loss of the stomach’s food reservoir function necessitates small frequent feedings. Without careful patient education and use of high-calorie supplements, total gastrectomy can lead to malnutrition. Subtotal or total gastrectomy is optimal for management of bleeding or obstruction related to tumors at the gastroesophageal junction. Linitis plastica or total wall involvement of the stomach is incurable and not manageable by surgery except when necessary for palliation.

Chemotherapy and Monoclonal Antibodies

Several studies have now established a role for either preand postoperative chemotherapy or postoperative adjuvant chemotherapy (in combination with radiation therapy) for improving survival of patients with resected gastric cancer at high risk for recurrence or development of metastatic disease. Ongoing studies are attempting to build on these findings to
improve outcomes. Combination chemotherapy programs include the following:

5-Fluorouracil (5-FU), epirubicin, and cisplatin (capecitabine may be used instead of 5-FU and oxaliplatin substituted for cisplatin)
A taxane (e.g., docetaxel), 5-FU, and cisplatin (or oxaliplatin)
5-FU (or capecitabine) and oxaliplatin
Irinotecan and cisplatin

Response rates of 40% to 50% are observed in patients with metastatic disease. Complete responses are rare. Clinical research is continuing to attempt to identify the most active combinations and the potential role of newer agents, such as targeted therapy. Approximately 20% of patients have tumors with increased expression of HER2. In such patients, trastuzumab (a monoclonal antibody targeting HER2) improves survival when used in conjunction with chemotherapy. The average duration of responses is 6 to 9 months, and there are short-term improvements in survival, although there is no improvement in long-term survival.

Radiation

Radiation, in conjunction with chemotherapy, is an important component of postoperative adjuvant treatment of patients with resected stage IB to IV gastric adenocarcinoma. It may also be useful in the palliation of patients, with bleeding or obstruction, who are not candidates for resection. However, surgery remains the modality of choice for palliation of these symptoms when feasible.

Patient Monitoring

Except when being used to evaluate response to therapy, patient monitoring should be primarily guided by symptoms and not by routine testing for potential metastatic sites, because only palliative therapeutic options exist for patients with advanced disease.

Prevention

Given the poor prognosis of gastric cancer, prevention deserves attention. Avoidance of smoking and smoking cessation are the most important steps in decreasing the risk of gastric cancer. In addition, although the relationship between H. pylori infection and gastric carcinoma is well established, it remains to be proven that eradication or prevention of Helicobacter infection will reduce risk. Nonetheless, treatment is worth consideration (see Chapters 55 and 68). Improvement in food handling and preservation and assuring that young children are not regularly exposed to foods preserved by salting, smoking, or pickling or spoiled food are reasonable public health measures based on current epidemiologic evidence. Other dietary measures worth undertaking include increasing fruit and vegetable intake, increasing foods rich in antioxidants (e.g., olive oil and garlic), increasing fiber in the diet, and decreasing salt intake. Although aspirin or other NSAID use is associated with a lower risk of gastric cancer, their routine use in the general population for this purpose cannot be recommended. Early detection through endoscopic or radiologic screening has been carried out in populations where risk is very high (e.g., Japan), but such measures would not be cost-effective in the United States, where disease prevalence is relatively low (see Chapter 55).

Gastric Lymphomas (see also Chapter 84)

Unlike adenocarcinoma, gastric lymphomas have a much higher cure rate. Of special note are the patients with MALT lymphomas limited to the stomach that are associated with H. pylori infection. Although these make up only an estimated 10% of gastric lymphomas, they are important to recognize since 50% to 80% of these lymphomas can regress after treatment with anti-Helicobacter therapy. Therefore, it is important to recognize those lymphomas in which an initial trial of H. pylori therapy is warranted.

Gastrointestinal Stromal Tumor (GIST)

This is a relatively uncommon malignancy with approximately 4,500 to 5,000 new cases per year in the United States, although it is the most common sarcoma of the GI tract. Common sites are stomach (60% to 70%) and small intestine (20% to 25%), but this tumor can arise anywhere in the GI tract. It originates from a component of the autonomic nervous system, the intestinal cells of Cajal. A high frequency of these tumors has characteristic mutations (e.g., 80% to 90% in the KIT receptor, 3% to 5% in PDGFR-alpha). Significant improvements in the care of patients with unresectable disease have occurred using agents that target these mutations. Median age is in the late 50s; incidence is slightly higher in men than in women.

Risk Factors

The only known risk factor is rare genetic syndromes (e.g., a syndrome of paragangliomas and GISTS associated with mutations in succinate dehydrogenase genes, familial GISTS with mutations in the c kit gene; mutations in PDGFR-alpha). There are no known environmental risk factors.

Clinical Presentation and Course

As with other gastrointestinal malignancies, clinical presentation can be subtle, making early diagnosis difficult. Many are asymptomatic; only about half of patients are diagnosed with symptoms. Unexplained iron deficiency anemia or asymptomatic guaiac stool test positivity may be the only manifestation. Other patients present with melena. Nonspecific abdominal pain is the other most common presentation. Weight loss, nausea, vomiting, decreased appetite, early satiety, dysphagia, and obstructive symptoms can also occur, but most are manifestations of advanced disease.

Unfortunately, more than 50% of patients either present with unresectable disease or develop recurrent or metastatic disease at some point. Metastases develop locally and at distant sites, most frequently the liver (over 50% of first metastases). Local recurrences are also fairly common. Lung metastases are uncommon (except in those with primary rectal tumors), and lymph node metastases are relatively uncommon.

Diagnosis

A high index of suspicion is warranted; early diagnosis provides the best chance for survival. Patients over the age of 40 years presenting with any of the manifestations noted above should undergo testing as early as possible. Endoscopy with biopsy is the preferred method for definitive diagnosis, although given the vascular nature of these lesions this should be done by experienced individuals. PET-CT is especially helpful in evaluating patients prior to surgical resection or in monitoring patients for response to imatinib.

Principles of Management

Surgery is the treatment of choice, but adjuvant use of tyrosine kinase inhibition also improves survival for patients at higher risk of recurrence or metastases.

Surgery.

Surgery is the primary mode of treatment, both for cure and palliation, offering the best chance for survival. Median survival for patients managed by complete surgical resection is in excess of 5 years.

Chemotherapy.

Historically, traditional chemotherapy had limited efficacy against gastrointestinal stromal tumor (GIST). The advent of small molecule tyrosine kinase inhibitors that act at the KIT and PDGFR-alpha receptors (e.g., imatinib and sunitinib) has markedly changed prognosis for patients with unresectable disease. At least 3 years of adjuvant therapy with imatinib improves overall survival for patients at increased risk of recurrence or metastasis (i.e., those with tumors □3 cm in diameter)—effect of longer-term treatment is under study. Imatinib serves as the initial treatment; sunitinib is reserved for those that have progressed on imatinib. Despite improved short-term survival, patients eventually progress, giving impetus to exploring for new agents.

Radiation.

These tumors are relatively radioresistant, limiting the role for this modality to palliation (e.g., painful metastases or uncontrolled GI bleeding when surgery is not possible).

Patient Monitoring.

Consensus conference recommendations include CT scanning every 3 to 6 months for 5 years for patients at intermediate or high risk of recurrence and then yearly thereafter for patients with completely resected disease.

Prevention and Early Detection.

Patients with one of the rare genetic factors associated with high risk for development of GIST (see earlier discussion of Risk Factors) should be monitored closely for possible development of the tumor. Otherwise, the best hope for early diagnosis is vigilant workup at onset of symptoms suggesting a possible gastrointestinal lesion.

PANCREATIC ADENOCARCINOMA (16, 17, 18, 19, 20, 21, 22, 23 and 24)

Pancreatic adenocarcinoma is the fourth leading cause of cancer death in the United States. Mortality is high (˜95% at 5 years); fewer than 20% survive 1 year. High death rates are due partially to difficulties in early detection, which stem from the tumor’s retroperitoneal location and the fact that most early disease is asymptomatic. There are approximately 44,000 new cases annually and 33,790 deaths. The disease is rare before age 40, but incidence rises rapidly thereafter; men and women are equally affected. Endocrine or neuroendocrine pancreatic cancers can be an important cause of ectopic hormone production (e.g., insulin, glucagon, corticotropin).

Risk Factors

Hypotheses regarding pathogenesis include concentration and excretion of carcinogens by acinar cells inducing neoplastic transformation among ductal cells. Established risk factors include smoking (the strongest association of the general risk factors), diabetes mellitus (there is a small increased risk of pancreatic cancer in those with diabetes), chronic pancreatitis (especially when it is due to genetic mutations), and history of radiation therapy to the pancreatic area (such as delivered for some patients with Hodgkin disease or germ cell tumors). Exposure to potential environmental toxins, such as dry-cleaning chemicals and gasoline, is a possible contributing factor although this is still an area of investigation.

Clinical Presentation and Course

In most instances, the tumor remains asymptomatic until late in the course of disease, with presentation determined largely by the tumor’s location. In about two thirds of cases, the cancer begins in the pancreatic head; in the remainder, it occurs in the body or tail. Disease originating in the pancreatic head near the pancreaticobiliary junction may extend locally to obstruct bile flow and cause painless jaundice—one of the few potentially early symptomatic presentations of pancreatic cancer. Jaundice, with or without pain, is an eventual manifestation in about 50% of patients, although in many it is due to metastasis or late extension.

More often than not, symptoms are late in onset and nonspecific. Disease of the body or tail may present with vague upper abdominal or back pain or discomfort; unexplained weight loss, depression, diabetes, or pancreatitis; or even migratory thrombophlebitis. Persistent nausea and vomiting suggest invasion and obstruction of the upper gastrointestinal tract. Carcinomas of the tail may not cause symptoms until they metastasize. Endocrine or neuroendocrine pancreatic cancers that ectopically produce hormones such as insulin, glucagon, or gastrin can present with symptoms related to the specific hormone released.

The clinical course of pancreatic carcinoma is dominated by regional extension into the retroperitoneum and metastases, most commonly to lymph nodes, peritoneal cavity, and liver. The tumor tends to spread perineurally and lymphatically. Untreated, median survival for patients with extrapancreatic tumor is 12 weeks from time of presentation and 19 to 42 weeks for those with tumor confined to the pancreas.

Diagnosis

Ultimately, tissue is needed to establish the diagnosis because symptoms and signs may be nonspecific and there are no definitive blood tests. Evaluation begins with an abdominal CT, which can detect lesions as small as 1 cm (and sometimes smaller) and provides imaging of the biliary tree and pancreatic ducts as well as the lymph nodes, liver, and peritoneal cavity. CT has supplanted ultrasound as the imaging technique of choice, providing better definition of the tumor and adjacent structures and helping to determine anatomy. MRI techniques do not routinely offer a significant advantage over CT although, depending on the exact situation and local expertise, one imaging modality may be favored over the other. The potential role for CT-PET to detect metastatic disease not seen with CT alone is currently being investigated, especially in patients being considered for surgery. As imaging technology further evolves, its optimal use continues to be readdressed and reconsidered.

When a distinct pancreatic mass is identified in the absence of clearly identifiable metastatic disease, fine-needle aspiration biopsy can be performed. Where available, this is usually done with the aid of EUS evaluation, the best means of optimally defining a site to biopsy and obtain tissue. Alternatively, especially when there is metastatic or clearly unresectable disease, biopsy can be done percutaneously, guided by direct ultrasound or CT visualization. Limiting the yield from needle biopsy is the large zone of fibrosis and inflammation that typically surrounds the tumor. The procedure is usually the confirmatory test of choice in patients with disease believed to be metastatic or unresectable. Drawbacks include a substantial falsenegative rate and the potential risk of seeding along the needle tract.

Patients with a mass at the pancreaticobiliary junction are excellent candidates for endoscopic retrograde cholangiopancreatography (ERCP). Early ampullary lesions causing jaundice can be visualized and biopsied directly, leading to prompt diagnosis, definitive treatment, and improved 5-year survival (as high as 50%). A pancreatogram is taken during ERCP, checking for ductal narrowing, obstruction, and extravasation of dye, additional signs of malignancy (although they also can occur in chronic pancreatitis). An irregular stricture longer than 10 mm
is characteristic of cancer. Cytologic sampling, especially that obtained by brushings, has a reported sensitivity approaching 85%, although results vary.

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