Gastric Cancer

Gastric CancerElwyn C Cabebe, MD, Adjunct Clinical Faculty, Department of Internal Medicine, Division of Medical Oncology, Stanford University School of MedicineVivek K Mehta, MD, Radiation Oncologist, Director, Center for Advanced Targeted Radiotherapies, Department of Radiation Oncology, Swedish Cancer Institute, Seattle, Washington; George Fisher, MD, PhD, Associate Professor, Department of Internal Medicine, Division of Medical Oncology, Stanford University School of Medicine

Updated: Dec 7, 2010

Introduction

Background

Gastric cancer was once the second most common cancer in the world. In most developed countries,

however, rates of stomach cancer have declined dramatically over the past half century. In the

United States, stomach malignancy is currently the 14th most common cancer.

Decreases in gastric cancer have been attributed in part to widespread use of refrigeration, which

has had several beneficial effects: increased consumption of fresh fruits and vegetables; decreased

intake of salt, which had been used as a food preservative; and decreased contamination of food by

carcinogenic compounds arising from the decay of unrefrigerated meat products. Salt and salted

foods may damage the gastric mucosa, leading to inflammation and an associated increase in DNA

synthesis and cell proliferation. Other factors likely contributing to the decline in stomach cancer

rates include lower rates of chronic Helicobacter pylori infection, thanks to improved sanitation and

use of antibiotics, and increased screening in some countries.[1 ]

Nevertheless, gastric cancer is still the second most common cause of cancer-related death in the

world, and it remains difficult to cure in Western countries, primarily because most patients present

with advanced disease. Even patients who present in the most favorable condition and who undergo

curative surgical resection often die of recurrent disease. However, 2 studies have demonstrated

improved survival with adjuvant therapy: a US study using postoperative chemoradiation[2 ]and a

European study using preoperative and postoperative chemotherapy.[3 ]

Anatomic aspects

The molecular biology responsible for carcinogenesis, tumor biology, and response to therapy in

stomach cancer are active areas of investigation but are not addressed in this review. Instead, this

article focuses on clinical management, which first requires a thorough understanding of gastric

anatomy.

An image depicting stomach anatomy can be seen below.

Stomach and duodenum, coronal section.

The stomach begins at the gastroesophageal junction and ends at the duodenum. The stomach has

3 parts: the uppermost part is the cardia; the middle and largest part is the body, or fundus; and the

distal portion, the pylorus, connects to the duodenum. These anatomic zones have distinct histologic

features. The cardia contains predominantly mucin-secreting cells. The fundus contains mucoid cells,

chief cells, and parietal cells. The pylorus is composed of mucus-producing cells and endocrine cells.

The stomach wall is made up of 5 layers. From the lumen out, the layers include the mucosa, the

submucosa, the muscularis layer, the subserosal layer, and the serosal layer. The peritoneum of the

greater sac covers the anterior surface of the stomach. A portion of the lesser sac drapes posteriorly

over the stomach. The gastroesophageal junction has limited or no serosal covering. The right

portion of the anterior gastric surface is adjacent to the left lobe of the liver and the anterior

abdominal wall. The left portion of the stomach is adjacent to the spleen, the left adrenal gland, the

superior portion of the left kidney, the ventral portion of the pancreas, and the transverse colon.

The site of stomach cancer is classified on the basis of its relationship to the long axis of the

stomach. Approximately 40% of cancers develop in the lower part, 40% in the middle part, and 15%

in the upper part; 10% involve more than one part of the organ. Most of the decrease in gastric

cancer incidence and mortality in the United States has involved cancer in the lower part of the

stomach; the incidence of adenocarcinoma in the cardia has actually shown a gradual increase.

Pathophysiology

Ooi et al identified 3 oncogenic pathways that are deregulated in the majority (>70%) of gastric

cancers: the proliferation/stem cell, NF-kappa β, and Wnt/beta-catenin pathways. Their study

suggests that interactions between these pathways may play an important role in influencing disease

behavior and patient survival.[4 ]

Understanding the vascular supply of the stomach allows understanding of the routes of

hematogenous spread. The vascular supply of the stomach is derived from the celiac artery. The left

gastric artery, a branch of the celiac artery, supplies the upper right portion of the stomach. The

common hepatic artery branches into the right gastric artery, which supplies the lower portion of the

stomach, and the right gastroepiploic branch, which supplies the lower portion of the greater

curvature.

Understanding the lymphatic drainage can clarify the areas at risk for nodal involvement by cancer.

The lymphatic drainage of the stomach is complex. Primary lymphatic drainage is along the celiac

axis. Minor drainage occurs along the splenic hilum, suprapancreatic nodal groups, porta hepatis,

and gastroduodenal areas.

Frequency

United States

The American Cancer Society estimates that 21,130 cases of gastric cancer will be diagnosed in

2009 (12,820 in men, 8,310 in women) and that 10,620 persons will die of the disease.[5 ]Gastric

cancer is the seventh leading cause of cancer deaths.

International

Once the second most common cancer worldwide, stomach cancer has dropped to fourth place, after

cancers of the lung, breast, and colon and rectum. However, stomach cancer remains the second

most common cause of death from cancer. The American Cancer Society estimates that in 2007

there were an estimated one million new cases, nearly 70% of them in developing countries, and

about 800,000 deaths.[1 ]

Tremendous geographic variation exists in the incidence of this disease around the world. Rates of

the disease are highest in Asia and parts of South America and lowest in North America.[1 ]The

highest death rates are recorded in Chile, Japan, South America, and the former Soviet Union.

Mortality/Morbidity

The 5-year survival rate for curative surgical resection ranges from 30-50% for patients with stage II

disease and from 10-25% for patients with stage III disease. Because these patients have a high

likelihood of local and systemic relapse, some physicians offer them adjuvant therapy. The operative

mortality rate for patients undergoing curative surgical resection at major academic centers is less

than 3%.

A review of 8 trials by Rothwell et al found allocation to aspirin reduced death caused by cancer.

Individual patient data were available from 7 of the 8 trials. Benefit was apparent after 5 years of

follow-up. The 20-year risk of cancer death was also lower in the aspirin group for all solid cancers. A

latent period of 5 years was observed before risk of death was decreased for esophageal,

pancreatic, brain, and lung cancers. A more delayed latent period was observed for stomach,

colorectal, and prostate cancer. Benefit was only seen for adenocarcinomas in lung and esophageal

cancers. The overall effect on 20-year risk of cancer death was greatest for adenocarcinomas.[6 ]

Race

The rates of gastric cancer are higher in Asian and South American countries than in the United

States. Japan, Chile, and Venezuela have developed a very rigorous early screening program that

detects patients with early stage disease (ie, low tumor burden). These patients appear to do quite

well. In fact, in many Asian studies, patients with resected stage II and III disease tend to have better

outcomes than similarly staged patients treated in Western countries. Some researchers suggest that

this reflects a fundamental biologic difference in the disease as it manifests in Western countries.

In the United States, Asian and Pacific Islander males and females have the highest incidence of

stomach cancer, followed by black, Hispanic, white, American Indian, and Inuit populations.

Sex

In the United States, gastric cancer affects slightly more men than women; the American Cancer

Society estimates that in 2009, 12,820 new cases will occur in men and 8,310 in women.[5 ]Worldwide, however, gastric cancer rates are about twice as high in men as in women.[1 ]

Age

Most patients are elderly at diagnosis. The median age for gastric cancer in the United States is 70

years for males and 74 years for females. The gastric cancers that occur in younger patients may

represent a more aggressive variant or may suggest a genetic predisposition to development of the

disease.

Clinical

History

In the United States, about 25% of stomach cancer patients present with localized disease, 31%

present with regional disease, and 32% present with distant metastatic disease; the remainder of

cases surveyed were listed as unstaged.

Early disease has no associated symptoms; however, some patients with incidental complaints are

diagnosed with early gastric cancer. Most symptoms of gastric cancer reflect advanced disease.

Patients may complain of indigestion, nausea or vomiting, dysphagia, postprandial fullness, loss of

appetite, melena, hematemesis, and weight loss.

Late complications include pathologic peritoneal and pleural effusions; obstruction of the gastric

outlet, gastroesophageal junction, or small bowel; bleeding in the stomach from esophageal varices

or at the anastomosis after surgery; intrahepatic jaundice caused by hepatomegaly; extrahepatic

jaundice; and inanition resulting from starvation or cachexia of tumor origin.

Physical

All physical signs are late events. By the time they develop, the disease is almost invariably too far

advanced for curative procedures.

Signs may include a palpable enlarged stomach with succussion splash; hepatomegaly; periumbilical

metastasis (Sister Mary Joseph nodule); and enlarged lymph nodes such as Virchow nodes (ie, left

supraclavicular) and Irish node (anterior axillary). Blumer shelf (ie, shelflike tumor of the anterior

rectal wall) may also be present. Some patients experience weight loss, and others may present with

melena or pallor from anemia.

Paraneoplastic syndromes such as dermatomyositis, acanthosis nigricans, and circinate erythemas

are poor prognostic features.

Other associated abnormalities also include peripheral thrombophlebitis and microangiopathic

hemolytic anemia.

Causes

Gastric cancer may often be multifactorial, involving both inherited predisposition and environmental

factors.[7 ]Environmental factors implicated in the development of gastric cancer include diet,

Helicobacter pylori infection, previous gastric surgery, pernicious anemia, adenomatous polyps,

chronic atrophic gastritis, and radiation exposure.

Diet

A diet rich in pickled vegetables, salted fish, salt, and smoked meats correlates with an increased

incidence of gastric cancer.[7 ]

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect. [8 ]

Smoking

Smoking is associated with an increased incidence of stomach cancer in a dose-dependent manner,

both for number of cigarettes and for duration of smoking.

Smoking increases the risk of cardiac and noncardiac forms of stomach cancer.[9 ]Cessation of

smoking reduces the risk.

A meta-analysis of 40 studies estimated that the risk was increased by approximately 1.5- to 1.6-fold

and was higher in men.[10 ]

Helicobacter pylori infection

Chronic bacterial infection with H pylori is the strongest risk factor for stomach cancer.

H pylori may infect 50% of the world's population, but many fewer than 5% of infected individuals

develop cancer. It may be that only a particular strain of H pylori is strongly associated with

malignancy, probably because it is capable of producing the greatest amount of inflammation. In

addition, full malignant transformation of affected parts of the stomach may require that the human

host have a particular genotype of interleukin (IL) to cause the increased inflammation and an

increased suppression of gastric acid secretion. For example, IL-17A and IL-17F are inflammatory

cytokines that play a critical role in inflammation. Wu et al found that carriage of IL-17F 7488GA and

GG genotypes were associated with an increased risk of gastric cancer.[11 ]

H pylori infection is associated with chronic atrophic gastritis, and patients with a history of prolonged

gastritis have a sixfold increased risk of developing gastric cancer. Interestingly, this association is

particularly strong for tumors located in the antrum, body, and fundus of the stomach but does not

seem to hold for tumors originating in the cardia.[12 ]

Previous gastric surgery

Previous surgery is implicated as a risk factor. The rationale is that surgery alters the normal pH of

the stomach, which may in turn lead to metaplastic and dysplastic changes in luminal cells.[13 ]

Retrospective studies demonstrate that a small percentage of patients who undergo gastric polyp

removal have evidence of invasive carcinoma within the polyp. This discovery has led some

researchers to conclude that polyps might represent premalignant conditions.

Genetic factors

Some 10% of stomach cancer cases are familial in origin.

Genetic factors involved in gastric cancer remain poorly understood, though specific mutations have

been identified in a subset of gastric cancer patients. For example, germline truncating mutations of

the E-cadherin gene (CDH1) are detected in 50% of diffuse-type gastric cancers, and families that

harbor these mutations have an autosomal dominant pattern of inheritance with a very high

penetrance.[14 ]

Other hereditary syndromes with a predisposition for stomach cancer include hereditary

nonpolyposis colorectal cancer, Li-Fraumeni syndrome, familial adenomatous polyposis, and Peutz-

Jeghers syndrome.

Epstein-Barr virus

The Epstein-Barr virus may be associated with an unusual (<1%) form of stomach cancer,

lymphoepithelioma-like carcinoma.

Pernicious anemia

Pernicious anemia associated with advanced atrophic gastritis and intrinsic factor deficiency is a risk

factor for gastric carcinoma.

Gastric ulcers

Gastric cancer may develop in the remaining portion of the stomach following a partial gastrectomy

for gastric ulcer.

Benign gastric ulcers may themselves develop into malignancy.

Obesity

Obesity increases the risk of gastric cardia cancer.

Radiation exposure

Survivors of atomic bomb blasts have had an increased rate of stomach cancer. Other populations

exposed to radiation may also have an increased rate of stomach cancer.

Bisphosphonates

A large cohort study examined whether use of oral bisphosphonates was associated with an

increased risk of esophageal or gastric cancers. No significant difference was observed for increased

risk of esophageal or gastric cancers between the bisphosphonate cohort and the control group.[15 ]

Differential Diagnoses

Esophageal Cancer Gastroenteritis, Bacterial

Esophageal Stricture Gastroenteritis, Viral

Esophagitis Lymphoma, Non-Hodgkin

Gastric Ulcers Malignant Neoplasms of the Small Intestine

Gastritis, Acute

Gastritis, Atrophic

Gastritis, Chronic

Workup

Laboratory Studies

The goal of obtaining laboratory studies is to assist in determining optimal therapy.

A CBC count can identify anemia, which may be caused by bleeding, liver dysfunction, or poor

nutrition. Approximately 30% of patients have anemia.

Electrolyte panels and liver function tests also are essential to better characterize the patient's

clinical state.

Carcinoembryonic antigen (CEA) is increased in 45-50% of cases.

Cancer antigen (CA) 19-9 is elevated in about 20% of cases.

Imaging Studies

Esophagogastroduodenoscopy has a diagnostic accuracy of 95%. This relatively safe and simple

procedure provides a permanent color photographic record of the lesion. This procedure is also the

primary method for obtaining a tissue diagnosis of suspected lesions. Biopsy of any ulcerated lesion

should include at least 6 specimens taken from around the lesion because of variable malignant

transformation. In selected cases, endoscopic ultrasound may be helpful in assessing depth of

penetration of the tumor or involvement of adjacent structures.

Double-contrast upper GI series and barium swallows may be helpful in delineating the extent of

disease when obstructive symptoms are present or when bulky proximal tumors prevent passage of

the endoscope to examine the stomach distal to an obstruction (more common with

gastroesophageal [GE]-junction tumors). These studies are only 75% accurate and should for the

most part be used only when upper GI endoscopy is not feasible.

Chest radiograph is done to evaluate for metastatic lesions.

CT scan or MRI of the chest, abdomen, and pelvis assess the local disease process as well as

evaluate potential areas of spread (ie, enlarged lymph nodes, possible liver metastases).

Endoscopic ultrasound allows for a more precise preoperative assessment of the tumor stage.

Endoscopic sonography is becoming increasingly useful as a staging tool when the CT scan fails to

find evidence of T3, T4, or metastatic disease. Institutions that favor neoadjuvant chemoradiotherapy

for patients with locally advanced disease rely on endoscopic ultrasound data to improve patient

stratification.

Histologic Findings

Adenocarcinoma of the stomach constitutes 90-95% of all gastric malignancies. The second most

common gastric malignancies are lymphomas. Gastrointestinal stromal tumors formerly classified as

either leiomyomas or leiomyosarcomas account for 2% of gastric neoplasms (see Gastric Stromal

Tumors). Carcinoids (1%), adenoacanthomas (1%), and squamous cell carcinomas (1%) are the

remaining tumor histologic types.

Adenocarcinoma of the stomach is subclassified according to histologic description as follows:

tubular, papillary, mucinous, or signet-ring cells, and undifferentiated lesions.

Pathology specimens are also classified by gross appearance. In general, researchers consider

gastric cancers ulcerative, polypoid, scirrhous (ie, diffuse linitis plastica), superficial spreading,

multicentric, or Barrett ectopic adenocarcinoma.

Researchers also employ a variety of other classification schemes. The Lauren system classifies

gastric cancer pathology as either Type I (intestinal) or Type II (diffuse). An appealing feature of

classifying patients according to the Lauren system is that the descriptive pathologic entities have

clinically relevant differences.

Intestinal, expansive, epidemic-type gastric cancer is associated with chronic atrophic gastritis,

retained glandular structure, little invasiveness, and a sharp margin. The pathologic presentation

classified as epidemic by the Lauren system is associated with most environmental risk factors,

carries a better prognosis, and shows no familial history.

The second type, diffuse, infiltrative, endemic cancer, consists of scattered cell clusters with poor

differentiation and dangerously deceptive margins. Margins that appear clear to the operating

surgeon and examining pathologist often are determined retrospectively to be involved. The

endemic-type tumor invades large areas of the stomach. This type of tumor is also not recognizably

influenced by environment or diet, is more virulent in women, and occurs more often in relatively

young patients. This pathologic entity is associated with genetic factors (such as E-cadherin), blood

groups, and a family history of gastric cancer.

Staging

The 2006 American Joint Committee on Cancer (AJCC) Cancer Staging Manual presents the

following TNM classification system for staging gastric carcinoma:[16 ]

Primary tumor

TX - Primary tumor (T) cannot be assessed

T0 - No evidence of primary tumor

Tis - Carcinoma in situ, intraepithelial tumor without invasion of lamina propria

T1 - Tumor invades lamina propria or submucosa

T2 - Tumor invades muscularis propria or subserosa

T3 - Tumor penetrates serosa (ie, visceral peritoneum) without invasion of adjacent

structures

T4 - Tumor invades adjacent structures

Regional lymph nodes

NX - Regional lymph nodes (N) cannot be assessed

N0 - No regional lymph node metastases

N1 - Metastasis in 1-6 regional lymph nodes

N2 - Metastasis in 7-15 regional lymph nodes

N3 - Metastasis in more than 15 regional lymph nodes

Distant metastasis

MX - Distant metastasis (M) cannot be assessed

M0 - No distant metastasis

M1 - Distant metastasis

Prognostic features

Two important factors influencing survival in resectable gastric cancer are depth of cancer invasion

through the gastric wall and presence or absence of regional lymph node involvement.

In about 5% of primary gastric cancers, a broad region of the gastric wall or even the entire stomach

is extensively infiltrated by malignancy, resulting in a rigid thickened stomach, termed linitis plastica.

Patients with linitis plastica have an extremely poor prognosis.[17 ]

Margins positive for presence of cancer are associated with a very poor prognosis.

The greater the number of involved lymph nodes, the more likely the patient is to develop local and

systemic failure after surgery.

In a study by Shen and colleagues,[18 ]the depth of tumor invasion and gross appearance, size, and

location of the tumor were 4 pathologic factors independently correlated with the number of

metastatic lymph nodes associated with gastric cancer.

Lee and colleagues found that surgical stage, as estimated during curative resection for gastric

cancer, complemented the pathologically determined stage for determining prognosis. Survival was

significantly poorer among patients with pathologic Stages II, IIIa, and IIIb disease in whom

intraoperative staging overestimated the extent of pathological stage.[19 ]

Staging

Stage 0 - Tis, N0, M0

Stage IA - T1, N0 or N1, M0

Stage IB - T1, N2, M0 or T2a/b, N0, M0

Stage II - T1, N2, M0 or T2a/b, N1, M0 or T2, N0, M0

Stage IIIA - T2a/b, N2, M0 or T3, N1, M0 or T4, N0, M0

Stage IIIB - T3, N2, M0

Stage IV - T1-3, N3, M0 or T4, N1-3, M0, or any T, any N, M1

Survival rates

Stage 0 - Greater than 90%

Stage Ia - 60-80%

Stage Ib - 50-60%

Stage II - 30-40%

Stage IIIa - 20%

Stage IIIb - 10%

Stage IV - Less than 5%.

Spread patterns

Cancer of the stomach can spread directly, via lymphatics, or hematogenously.

Direct extension into the omenta, pancreas, diaphragm, transverse colon or mesocolon, and

duodenum is common.

If the lesion extends beyond the gastric wall to a free peritoneal (ie, serosal) surface, then peritoneal

involvement is frequent.

The visible gross lesion frequently underestimates the true extent of the disease.

The abundant lymphatic channels within the submucosal and subserosal layers of the gastric wall

allow for easy microscopic spread.

The submucosal plexus is prominent in the esophagus and the subserosal plexus is prominent in the

duodenum, allowing proximal and distal spread.

Lymphatic drainage is through numerous pathways and can involve multiple nodal groups (eg,

gastric, gastroepiploic, celiac, porta hepatic, splenic, suprapancreatic, pancreaticoduodenal,

paraesophageal, and paraaortic lymph nodes).

Hematogenous spread commonly results in liver metastases.

Treatment

Surgical Care

Type of surgery

In general, most surgeons in the United States perform a total gastrectomy (if required for negative

margins), an esophagogastrectomy for tumors of the cardia and gastroesophageal junction, and a

subtotal gastrectomy for tumors of the distal stomach.

A randomized trial comparing subtotal with total gastrectomy for distal gastric cancer revealed similar

morbidity, mortality, and 5-year survival rates.[20 ]

Because of the extensive lymphatic network around the stomach and the propensity for this tumor to

extend microscopically, traditional teaching is to attempt to maintain a 5-cm surgical margin

proximally and distally to the primary lesion.

Lymph node dissection

The extent of the lymph node dissection is somewhat controversial.

Many studies demonstrate that nodal involvement indicates a poor prognosis, and more aggressive

surgical approaches to attempt to remove involved lymph nodes are gaining popularity.

Two randomized trials compared D1 (perigastric lymph nodes) with D2 (hepatic, left gastric, celiac,

and splenic arteries, as well as those in the splenic hilum) lymphadenectomy in patients who were

treated for curative intent. In the largest of these trials, postoperative morbidity (43% versus 25%)

and mortality (10% versus 4%) were higher in the D2 group.[21,22 ]

Most critics argue that these studies were underpowered and overestimated benefit. In addition, a

recent randomized trial found a much lower rate of complications than those earlier trials. Degiuli et

al reported complication rates of 17.9% and 12% with D2 and D1 dissections, respectively — a

statistically insignificant difference — and postoperative mortality rates of 2.2% and 3%, respectively.[23 ]

D2 dissections are recommended by the National Comprehensive Cancer Network over D1

dissections. A pancreas- and spleen - preserving D2 lymphadenectomy is suggested, as it provides

greater staging information, and may provide a survival benefit while avoiding its excess morbidity

when possible.

Outcome

The 5-year survival rate for a curative surgical resection ranges from 60-90% for patients with stage

I, 30-50% for patients with stage II disease, and 10-25% for patients with stage III disease.

Because these patients have a high likelihood of local and systemic relapse, some physicians offer

adjuvant therapy.

Consultations

Specialists recommend obtaining consultations freely in the management of most malignancies, and

gastric carcinoma is no exception. The gastroenterologist, surgical oncologist, radiation oncologist,

and medical oncologist work closely as a team.

Follow-up

Deterrence/Prevention

A diet that includes fruits and vegetables rich in vitamin C may have a protective effect.

Complications

Direct mortality rate within 30 days after a surgical procedure for gastric cancer has been reduced

substantially over the last 40 years. Most major centers report a direct mortality rate of 1-2%.

Early postoperative complications include anastomotic failure, bleeding, ileus, transit failure at the

anastomosis, cholecystitis (often occult sepsis without localizing signs), pancreatitis, pulmonary

infections, and thromboembolism. Further surgery may be required for anastomotic leaks.

Late mechanicophysiologic complications include dumping syndrome, vitamin B-12 deficiency, reflux

esophagitis, and bone disorders, especially osteoporosis.

Postgastrectomy patients often are immunologically deficient, as measured by blastogenic and

delayed cutaneous hypersensitivity responses.

Prognosis

Unfortunately, only a minority of patients with gastric cancer who undergo a surgical resection will be

cured of their disease. Most patients have a recurrence.

Patterns of failure

Several studies have investigated the patterns of failure after surgical resection alone. Studies that

depend solely on the physical examination, laboratory studies, and imaging studies may

overestimate the percentage of patients with distant failure and underestimate the incidence of local

failure, which is more difficult to detect.

A reoperation series from the University of Minnesota may offer a more accurate understanding of

the biology of the disease. In this series of patients, researchers surgically reexplored patients 6

months after the initial surgery and meticulously recorded the patterns of disease spread. The total

local-regional failure rate approached 67%. The gastric bed was the site of failure in 54% of these

cases, and the regional lymph nodes were the site of failure in 42%. Approximately 26% of patients

had evidence of distant failure. The patterns of failure included local tumor regrowth, tumor bed

recurrences, regional lymph node failures, and distant failures (ie, hematogenous failures and

peritoneal spread). Primary tumors involving the gastroesophageal junction tended to fail in the liver

and the lungs. Lesions involving the esophagus failed in the liver.[24 ]

Adjuvant therapy

The pattern of failure prompted a number of investigations into adjuvant therapy. The rationale

behind radiotherapy is to provide additional local-regional tumor control. Adjuvant chemotherapy is

used either as a radiosensitizer or as definitive treatment for presumed systemic metastases.

Adjuvant radiotherapy

Moertel and colleagues randomized postoperative patients with advanced gastric cancer to receive

40 Grays (Gy) of radiotherapy or 40 Gy of radiotherapy with 5-FU as a radiosensitizer and

demonstrated improved survival associated with the combined-modality therapy.[25 ]

The British Stomach Cancer Group reported lower rates of local recurrence in patients who received

postoperative radiotherapy than in those who underwent surgery alone.[26 ]

The update of the initial Gastrointestinal Tumor Study Group series revealed higher 4-year survival

rates in patients with unresectable gastric cancer who received combined-modality therapy than in

those who received chemotherapy alone (18% vs 6%).[27 ]

In a series from the Mayo Clinic, patients were randomized to receive postoperative radiotherapy

with 5-FU or surgery alone, and improved survival was demonstrated in patients receiving adjuvant

therapy (23% vs 4%).[28 ]

Intraoperative radiotherapy

Some authors suggest that intraoperative radiotherapy (IORT) shows promising results.

This alternative method of delivering radiotherapy allows for a high dose to be given in a single

fraction while in the operating room so that other critical structures can be avoided.

The National Cancer Institute randomized patients with grossly resected stage III/IV gastric cancer to

receive either 20 Gy of IORT or 50 Gy of postoperative external beam radiation. Local failure was

delayed in the patients treated with IORT (21 mo vs 8 mo). Although the median survival duration

also was higher (21 mo vs 10 mo), this figure did not reach statistical significance.[29 ]

Adjuvant chemotherapy

Numerous randomized clinical trials comparing combination chemotherapy in the postoperative

setting to surgery alone did not demonstrate a consistent survival benefit.

Recent meta-analyses have shown a hint of statistical benefit. In one meta-analysis of 13

randomized trials, adjuvant systemic chemotherapy was associated with a significant survival benefit

(odds ratio for death, 0.80; 95% CI, 0.66-0.97). In subgroup analysis, there was a trend toward a

larger magnitude of effect for trials in which at least two thirds of the patients had node-positive

disease.[30 ]

A postoperative chemoradiation study was prompted in part by the patterns of local failure often

preceding systemic spread.

Adjuvant chemoradiotherapy

A randomized phase III study performed in the United States, Intergroup 0116, demonstrated a

survival benefit associated with postoperative chemoradiotherapy compared with surgery alone.[2 ]

In this study, patients underwent an en bloc resection.

Patients with T3 and/or N+ adenocarcinoma of the stomach or gastroesophageal junction were

randomized to receive a bolus of 5-fluorouracil (5-FU) and leucovorin (LV) and radiotherapy or

observation.

Patients who received the adjuvant chemoradiotherapy demonstrated improved disease-free survival

(from 32% to 49%) and improved overall survival rates (from 41% to 52%) compared to those who

were merely observed.

This regimen is considered the standard of care in the United States.

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy may allow downstaging of disease to increase resectability, decrease

micrometastatic disease burden prior to surgery, allow patient tolerability prior to surgery, determine

chemotherapy sensitivity, reduce the rate of local and distant recurrences, and ultimately improve

survival.

A European randomized trial also demonstrated survival benefit when patients were treated with 3

cycles of preoperative chemotherapy (epirubicin, cisplatin, and 5-fluorouracil) followed by surgery

and then 3 cycles of postoperative chemotherapy compared with surgery alone. The benefit was

comparable to that obtained with postoperative chemoradiation in the US trial.[3 ]However, the Gastric

Chemotherapy Group for Japan did not demonstrate a significant survival benefit with neoadjuvant

chemotherapy.

Choice of preoperative and postoperative chemotherapy versus postoperative chemotherapy and

radiation remains controversial, and an ongoing United States Intergroup study, CALGB 80101, will

look more closely at that question.

Advanced unresectable disease

Many patients present with distant metastases, carcinomatosis, unresectable hepatic metastases,

pulmonary metastases, or direct infiltration into organs that cannot be resected completely.

In the palliative setting, radiotherapy provides relief from bleeding, obstruction, and pain in 50-75% of

patients. The median duration of palliation is 4-18 months.

Surgical procedures such as wide local excision, partial gastrectomy, total gastrectomy, simple

laparotomy, gastrointestinal anastomosis, and bypass also are performed with palliative intent, with a

goal of allowing oral intake of food and alleviating pain.

Platinum-based chemotherapy, in combinations such as epirubicin/cisplatin/5-FU or

docetaxel/cisplatin/5-FU, represents the current first-line regimen. Other active regimens include

irinotecan and cisplatin and other combinations with oxaliplatin and irinotecan.

Results of cisplatin-based chemotherapy have been largely discouraging, with median time to

progression of 3-4 months and overall survival of approximately 6-9 months despite reported

response rates of up to 45%. Early results reported in 2007 by Japanese clinicians suggest some

improvement in both response rates and survival with the oral fluoropyrimidine S-1 used alone or in

combination with cisplatin.[31 ](S-1 combines 3 investigational drugs: tegafur, a prodrug of 5-FU;

gimeracil, an inhibitor of fluorouracil degradation; and oteracil or potassium oxanate, a GI tract

adverse-effect modulator.) These results remain to be confirmed by ongoing studies in Europe and

North America.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF) is currently

being evaluated for use in advanced gastric cancer.[32 ]

Novel treatment strategies may be guided by the use of gene signatures.[33 ]Kim et al reported that

combined overexpression of MYC, EGFR, and FGFR2 predicts a poor response of metastatic gastric

cancer to treatment with cisplatin and fluorouracil.[34 ]

Ishido et al reported that in patients receiving S-1 chemotherapy after gastrectomy for advanced

gastric cancer, intratumoral mRNA expression of thymidylate synthase (TS) is an independent

prognostic factor for response to chemotherapy. In 39 patients who received postoperative S-1,

recurrence-free survival and overall survival were significantly longer in patients with low TS

expression than in those with high TS expression (P=0.021 and 0.016, respectively), whereas in 40

patients treated with surgery only, TS expression did not correlate with survival.[35 ]

Overexpression of human epidermal growth factor receptor 2 (HER2) is a significant negative

prognostic factor for gastric cancer. In the international ToGA trial (trastuzumab with chemotherapy in

HER2-positive advanced gastric cancer), about 22% of patients with advanced gastric cancer were

found to have tumors that overexpressed HER2. In this phase III trial, 594 patients with HER2-

positive advanced gastric cancer were randomized to receive standard chemotherapy alone or

chemotherapy plus trastuzumab (Herceptin). Overall survival with trastuzumab was 13.8 months,

compared with 11.1 months in the chemotherapy group (hazard ratio, 0.74, P = .0046).[36 ]

Although modest, this 2.7-month improvement in overall survival is clinically meaningful in this group

of patients, who have a poor prognosis. In addition to the impact on overall survival, trastuzumab

improved all of the secondary end points, including progression-free survival (increased from 5.2 mo

to 6.7 mo; P = .002) and overall response rate (increased from 34.5% to 47%; P =.0017).

Trastuzumab was approved in October of 2010 for the treatment of HER2-overexpressing metastatic

gastric or gastroesophageal junction adenocarcinoma. It is administered in combination with cisplatin

and capecitabine or 5-fluorouracil in patients who have not received prior treatment for metastatic

disease. The trastuzumab dose consists of an initial cycle of 8 mg/kg intravenously (IV) infused over

90 minutes, followed by subsequent cycles of 6 mg/kg IV infused over 30-90 minutes every 3 weeks.

Treatment is continued until the disease progresses.

Patient Education

Multimedia

For excellent patient education resources, visit eMedicine's Esophagus, Stomach, and Intestine

Center. Also, see eMedicine's patient education article, Stomach Cancer.

Multimedia

Gastroesophageal Reflux DiseasePiero Marco Fisichella, MD, Assistant Professor of Surgery, Stritch School of Medicine, Loyola University; Director, Esophageal Motility Center, Loyola University Medical CenterMarco G Patti, MD, Professor of Surgery, Director, Center for Esophageal Diseases, University of Chicago Pritzker School of Medicine

Updated: Apr 28, 2009

Introduction

Background

Gastroesophageal reflux is a normal physiologic phenomenon experienced intermittently by most

people, particularly after a meal. Gastroesophageal reflux disease (GERD) occurs when the amount

of gastric juice that refluxes into the esophagus exceeds the normal limit, causing symptoms with or

without associated esophageal mucosal injury (ie, esophagitis).

For excellent patient education resources, visit eMedicine's Heartburn/GERD/Reflux Center and

Esophagus, Stomach, and Intestine Center. Also, see eMedicine's patient education articles

Gastroesophageal Reflux Disease (GERD), Heartburn, and Heartburn/GERD Medications.

Pathophysiology

The physiologic and anatomic factors that prevent the reflux of gastric juice from the stomach into the

esophagus include the following:

The lower esophageal sphincter (LES) must have a normal length and pressure and a

normal number of episodes of transient relaxation (relaxation in the absence of swallowing).

The gastroesophageal junction must be located in the abdomen so that the diaphragmatic

crura can assist the action of the LES, thus functioning as an extrinsic sphincter. The

presence of a hiatal hernia disrupts this synergistic action and can promote reflux (see

image below).

Barium swallow indicating hiatal hernia.

Esophageal clearance must be able to neutralize the acid refluxed through the LES.

(Mechanical clearance is achieved with esophageal peristalsis. Chemical clearance is

achieved with saliva.)

The stomach must empty properly.

Abnormal gastroesophageal reflux is caused by the abnormalities of one or more of the following

protective mechanisms:

A functional (frequent transient LES relaxation) or mechanical (hypotensive LES) problem of

the LES is the most common cause of gastroesophageal reflux disease (GERD).

Certain foods (eg, coffee, alcohol), medications (eg, calcium channel blockers, nitrates,

beta-blockers), or hormones (eg, progesterone) can decrease the pressure of the LES.

Obesity is a contributing factor in gastroesophageal reflux disease (GERD), probably

because of the increased intra-abdominal pressure.

From a therapeutic point of view, informing patients that gastric refluxate is made up not only of acid

but also of duodenal contents (eg, bile, pancreatic secretions) is important.

Frequency

United States

Heartburn is a common problem in the United States and in the Western world. Approximately 7% of

the population experience symptoms of heartburn daily. An abnormal esophageal exposure to gastric

juice is probably present in 20-40% of this population, meaning 20-40% of the people who

experience heartburn do indeed have gastroesophageal reflux disease (GERD). In the remaining

population, heartburn is probably due to other causes. Because many individuals control symptoms

with over-the-counter (OTC) medications and without consulting a medical professional, the condition

is likely underreported.

Mortality/Morbidity

In addition to the typical symptoms of gastroesophageal reflux disease (GERD) (eg,

heartburn, regurgitation, dysphagia), abnormal reflux can cause atypical symptoms, such as

coughing, chest pain, and wheezing. Additional atypical symptoms from abnormal reflux

include damage to the lungs (eg, pneumonia, asthma, idiopathic pulmonary fibrosis), vocal

cords (eg, laryngitis, cancer), ear (eg, otitis media), and teeth (eg, enamel decay).

Approximately 50% of patients with gastric reflux develop esophagitis (see image below).

Peptic esophagitis. A rapid urease test (RUT) is performed on the

esophageal biopsy sample. The result is positive for esophagitis.

Esophagitis is classified into the following 4 grades based on its severity: o Grade I – Erythema

o Grade II – Linear nonconfluent erosions

o Grade III – Circular confluent erosions

o Grade IV – Stricture or Barrett esophagus. Barrett esophagus is thought to be

caused by the chronic reflux of gastric juice into the esophagus. Barrett esophagus

occurs when the squamous epithelium of the esophagus is replaced by the

intestinal columnar epithelium (see image below). o

Esophagogastroduodenoscopy indicating Barrett esophagus.

o Barrett esophagus is present in 8-15% of patients with gastroesophageal reflux

disease (GERD) and may progress to adenocarcinoma (see images below) o

Gastroesophageal reflux disease (GERD)/Barrett

esophagus/adenocarcinoma sequence.

o

Endoscopy demonstrating intraluminal esophageal cancer.

o See Esophageal Cancer.

Race

White males are at a greater risk for Barrett esophagus and adenocarcinoma than other

populations.

Sex

No sexual predilection exists. Gastroesophageal reflux disease (GERD) is as common in

men as in women.

The male-to-female incidence ratio for esophagitis is 2:1-3:1. The male-to-female incidence

ratio for Barrett esophagus is 10:1.

Age

Gastroesophageal reflux disease (GERD) occurs in all age groups.

The prevalence of gastroesophageal reflux disease (GERD) increases in people older than

40 years.

Clinical

History

Gastroesophageal reflux disease (GERD) can cause typical (esophageal) symptoms or atypical

(extraesophageal) symptoms. However, a diagnosis of gastroesophageal reflux disease (GERD)

based on the presence of typical symptoms is correct in only 70% of patients.

Typical (esophageal) symptoms include the following: o Heartburn is the most common typical symptom of gastroesophageal reflux disease

(GERD). Heartburn is felt as a retrosternal sensation of burning or discomfort that

usually occurs after eating or when lying down or bending over. o Regurgitation is an effortless return of gastric and/or esophageal contents into the

pharynx. Regurgitation can induce respiratory complications if gastric contents spill

into the tracheobronchial tree. o Dysphagia occurs in approximately one third of patients because of a mechanical

stricture or a functional problem (eg, nonobstructive dysphagia secondary to

abnormal esophageal peristalsis). Patients with dysphagia experience a sensation

that food is stuck, particularly in the retrosternal area.

Atypical (extraesophageal) symptoms include the following: o Coughing and/or wheezing are respiratory symptoms resulting from the aspiration

of gastric contents into the tracheobronchial tree or from the vagal reflex arc

producing bronchoconstriction. Approximately 50% of patients who have GERD-

induced asthma do not experience heartburn. o Hoarseness results from irritation of the vocal cords by gastric refluxate and is often

experienced by patients in the morning. o Reflux is the most common cause of noncardiac chest pain, accounting for

approximately 50% of cases. Patients can present to the emergency department

with pain resembling a myocardial infarction. Reflux should be ruled out (using

esophageal manometry and 24-h pH testing if necessary; see image below) once a

cardiac cause for the chest pain has been excluded. Alternatively, a therapeutic trial

of a high-dose proton pump inhibitor (PPI) can be tried. o

Ambulatory pH monitoring indicating episodes of reflux correlating

with the heartburn experienced by the patient.

Physical

The physical examination is noncontributory.

Causes

See Pathophysiology.


Achalasia Esophagitis

Cholelithiasis Gastritis, Chronic

Coronary Artery Atherosclerosis Irritable Bowel Syndrome

Esophageal Cancer Peptic Ulcer Disease

Esophageal Spasm

Other Problems to Be Considered

Some studies have shown that gastroesophageal reflux disease (GERD) is highly prevalent in

patients who are morbidly obese and that a high body mass index (BMI) is a risk factor for the

development of this condition.[1,2,3,4,5,6 ]

The mechanism by which a high BMI increases esophageal acid exposure is not completely

understood. Increased intragastric pressure and gastroesophageal pressure gradient, incompetence

of the LES, and increased frequency of transient LES relaxations may all play a role in the

pathophysiology of gastroesophageal reflux disease (GERD) in patients who are morbidly obese.

To further support the hypothesis that obesity increases esophageal acid exposure is the

documentation of a dose-response relationship between increased BMI and increased prevalence of

gastroesophageal reflux disease (GERD) and its complications. Therefore, the pathophysiology of

GERD in patients who are morbidly obese might differ from that of patients who are not obese. The

therapeutic implication of such a premise is that the correction of reflux in patients who are morbidly

obese might be better achieved with a procedure that first controls obesity.

Workup

Laboratory Studies

Laboratory tests are seldom useful in establishing a diagnosis of gastroesophageal reflux

disease (GERD).

Imaging Studies

Barium esophagogram o A barium esophagogram is particularly important for patients with gastroesophageal

reflux disease (GERD) who experience dysphagia. o A barium esophagogram can show the presence and location of a stricture and the

presence and shape of a hiatal hernia.

Esophagogastroduodenoscopy (EGD) o EGD identifies the presence and severity of esophagitis and the possible presence

of Barrett esophagus (see image below). o

Esophagogastroduodenoscopy indicating Barrett esophagus.

o EGD also excludes the presence of other diseases (eg, peptic ulcer) that can

present similarly to gastroesophageal reflux disease (GERD). o Although EGD is frequently performed to help diagnose gastroesophageal reflux

disease (GERD), it is not the most cost-effective diagnostic study because

esophagitis is present in only 50% of patients with GERD.

Other Tests

Esophageal manometry o Esophageal manometry defines the function of the LES and the esophageal body

(peristalsis). o Esophageal manometry is essential for correctly positioning the probe for the 24-

hour pH monitoring.

Ambulatory 24-hour pH monitoring o Ambulatory 24-hour pH monitoring is the criterion standard in establishing a

diagnosis of GERD with a sensitivity of 96% and a specificity of 95%. o Ambulatory 24-hour pH monitoring quantifies the gastroesophageal reflux and

allows a correlation between the symptoms of reflux and the episodes of reflux. o Patients with endoscopically confirmed esophagitis do not need pH monitoring to

establish a diagnosis of gastroesophageal reflux disease (GERD).

Indications for esophageal manometry and prolonged pH monitoring include the following:

o Persistence of symptoms while taking adequate antisecretory therapy, such as PPI

therapy o Recurrence of symptoms after discontinuation of acid-reducing medications

o Investigation of atypical symptoms, such as chest pain or asthma, in patients

without esophagitis o Confirmation of the diagnosis in preparation for antireflux surgery

Radionuclide measurement of gastric emptying o Although delayed gastric emptying is present in as many as 60% of patients with

gastroesophageal reflux disease (GERD), this emptying is usually a minor factor in

the pathogenesis of the disease in most patients (except in patients with advanced

diabetes mellitus or connective tissue disorders). o Patients with delayed gastric emptying typically experience postprandial bloating

and fullness in addition to other symptoms.

Treatment

Medical Care

Treatment of gastroesophageal reflux disease (GERD) is a stepwise approach. The goals are to

control symptoms, to heal esophagitis, and to prevent recurrent esophagitis or other complications.

The treatment is based on lifestyle modification and control of gastric acid secretion.

Lifestyle modifications include the following: o Losing weight (if overweight)

o Avoiding alcohol, chocolate, citrus juice, and tomato-based products

o Avoiding large meals

o Waiting 3 hours after a meal before lying down

o Elevating the head of the bed 8 inches

Pharmacologic therapy o Antacids were the standard treatment in the 1970s and are still effective in

controlling mild symptoms of gastroesophageal reflux disease (GERD). Antacids

should be taken after each meal and at bedtime. o Histamine H2-receptor antagonists are the first-line agents for patients with mild to

moderate symptoms and grades I-II esophagitis. Histamine H2 receptor antagonists

are effective for healing only mild esophagitis in 70-80% of patients with

gastroesophageal reflux disease (GERD) and for providing maintenance therapy to

prevent relapse. Tachyphylaxis has been observed, suggesting that pharmacologic

tolerance can reduce the long-term efficacy of these drugs. o Additional H2 blocker therapy has been reported to be useful in patients with severe

disease (particularly those with Barrett esophagus) who have nocturnal acid

breakthrough. o PPIs are the most powerful medications available for treating this condition. These

agents should be used only when gastroesophageal reflux disease (GERD) has

been objectively documented. PPIs work by blocking the final step in the H+ ion

secretion by the parietal cell. They have few adverse effects and are well tolerated

for long-term use. However, data have shown that PPIs can interfere with calcium

homeostasis and aggravate cardiac conduction defects. These agents have also

been responsible for hip fracture in postmenopausal women.[7 ] o A research review by the Agency for Healthcare Research and Quality (AHRQ)

concluded, on the basis of grade A evidence, that PPIs were superior to histamine

H2-receptor antagonists for the resolution of gastroesophageal reflux disease

(GERD) symptoms at 4 weeks and healing of esophagitis at 8 weeks.[8 ]In addition,

the AHRQ found no difference between individual PPIs (omeprazole, lansoprazole,

pantoprazole, and rabeprazole) for relief of symptoms at 8 weeks. For symptom

relief at 4 weeks, esomeprazole 20 mg was equivalent, but esomeprazole 40 mg

superior, to omeprazole 20mg.[8 ] o Prokinetic agents improve the motility of the esophagus and stomach. These agents

are somewhat effective but only in patients with mild symptoms; other patients

usually require additional acid-suppressing medications, such as PPIs. Long-term

use of prokinetic agents may have serious, even potentially fatal, complications and

should be discouraged.

Surgical Care

Approximately 80% of patients have a recurrent but nonprogressive form of gastroesophageal reflux

disease (GERD) that is controlled with medications. Identifying the 20% of patients who have a

progressive form of the disease is important, because they may develop severe complications, such

as strictures or Barrett esophagus. For patients who develop complications, surgical treatment

should be considered at an earlier stage to avoid the sequelae of the disease that can have serious

consequences.

Indications for fundoplication include the following: o Patients with symptoms that are not completely controlled by PPI therapy can be

considered for surgery. Surgery can also be considered in patients with well-

controlled gastroesophageal reflux disease (GERD) who desire definitive, one-time

treatment. o The presence of Barrett esophagus is an indication for surgery. Whether acid

suppression improves the outcome or prevents the progression of Barrett

esophagus remains unknown, but most authorities recommend complete acid

suppression in patients with histologically proven Barrett esophagus. o The presence of extraesophageal manifestations of gastroesophageal reflux

disease (GERD) may indicate the need for surgery. These include the following: (1)

respiratory manifestations (eg, cough, wheezing, aspiration); (2) ear, nose, and

throat manifestations (eg, hoarseness, sore throat, otitis media); and (3) dental

manifestations (eg, enamel erosion). o Young patients

o Poor patient compliance with regard to medications

o Postmenopausal women with osteoporosis

o Patients with cardiac conduction defects

o Cost of medical therapy

Laparoscopic fundoplication o Laparoscopic fundoplication is performed under general endotracheal anesthesia.

Five small (5- to 10-mm) incisions are used (see image below). The fundus of the

stomach is wrapped around the esophagus to create a new valve at the level of the

gastroesophageal junction. o

Laparoscopic Nissen fundoplication.

o The essential elements of the operation are as follows:

Complete mobilization of the fundus of the stomach with division of the

short gastric vessels

Reduction of the hiatal hernia

Narrowing of the esophageal hiatus

Creation of a 360° fundoplication over a large intraesophageal dilator

(Nissen fundoplication)o Laparoscopic fundoplication lasts 2-2.5 hours. The hospital stay is approximately 2

days. Patients resume regular activities within 2-3 weeks. o Approximately 92% of patients obtain resolution of symptoms after undergoing

laparoscopic fundoplication. o The AHRQ found, on the basis of limited evidence, that laparoscopic fundoplication

was as effective as open fundoplication for relieving heartburn and regurgitation,

improving quality of life, and decreasing use of antisecretory medications.[8 ]

Several randomized clinical trials have challenged the benefits of surgery in controlling

gastroesophageal reflux disease (GERD). o Lundell followed up his cohort of patients for 5 years and did not find surgery to be

superior to PPI therapy.[9 ] o Spechler found that, at 10 years after surgery, 62% of patients were back on

antireflux medications.[10 ] o A very rigorous, randomized study by Anvari et al reestablished surgery as the

criterion standard in treating gastroesophageal reflux disease (GERD).[11 ]The

investigators showed that, at 1 year, the outcome and the symptom control in the

surgical group was better than that in the medical group.[11 ]

o A British multicenter randomized study conducted by Grant et al also compared

surgical treatment versus medical therapy in patients with documented evidence of

gastroesophageal reflux disease (GERD).[12 ]The type of laparoscopic fundoplication

was decided by the respective surgeons. Individuals who had received medication

for their condition had taken them for a median of 32 months before participating in

the study. o The investigators reported that by 12 months, 38% of those who had undergone

surgery were taking reflux medication compared with 90% of the individuals

randomized to medical management.[12 ]In addition, other health measure favored

the randomized surgical group.

Long-term results of laparoscopic antireflux surgery have shown that, at 10 years, 90% of

patients are symptom free, and only a minority still takes PPIs.[13 ]

Medication

The goals of pharmacotherapy are to prevent complications and to reduce morbidity in patients with

gastroesophageal reflux disease (GERD).

H2-Receptor Antagonists

H2-receptor antagonists are reversible competitive blockers of histamine at the H2 receptors,

particularly those in the gastric parietal cells where they inhibit acid secretion. The H2 antagonists

are highly selective, do not affect the H1 receptors, and are not anticholinergic agents. Although

intravenous (IV) administration of H2 blockers may be used to treat acute complications

(eg, gastrointestinal bleeding), the benefits are not yet proven.

Ranitidine (Zantac)

Inhibits histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces

gastric acid secretion, gastric volume, and hydrogen concentrations.

Dosing

Adult

150 mg PO bid (300 mg PO bid or 150 mg qid)

Pediatric

<12 years: Not established

>12 years

PO: 1.25-2.5 mg/kg/dose q12h; not to exceed 300 mg/d

IV/IM: 0.75-1.5 mg/kg/dose q6-8h; not to exceed 400 mg/d

Interactions

May decrease the effects of ketoconazole and itraconazole; may alter the serum levels of ferrous

sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in patients with renal or liver impairment; if changes in renal function occur during therapy,

consider adjusting the dose or discontinuing treatment

Cimetidine (Tagamet)

Inhibits histamine at H2 receptors of gastric parietal cells, which results in reduced gastric acid

secretion, gastric volume, and hydrogen concentrations.

Dosing

Adult

400 mg PO bid (800 mg bid or 400 mg PO qid)

Pediatric

Not established

Suggested dose is 1-2 mg/kg/d PO/IV divided q6h; not to exceed 40 mg/d

Interactions

Can increase blood levels of theophylline, warfarin, tricyclic antidepressants, triamterene, phenytoin,

quinidine, propranolol, metronidazole, procainamide, and lidocaine

Contraindications


Precautions

Pregnancy


Precautions

Elderly people may experience confusional states; may cause impotence and gynecomastia in young

males; may increase the levels of many drugs; adjust the dose or discontinue treatment if changes in

renal function occur

Famotidine (Pepcid)

Competitively inhibits histamine at H2 receptor of gastric parietal cells, resulting in reduced gastric

acid secretion, gastric volume, and hydrogen concentrations.

Dosing

Adult

20 mg PO bid (40 mg bid)

Pediatric

Not established; 1-2 mg/kg/d PO/IV divided q6h suggested; not to exceed 40 mg/dose

Interactions

May decrease the effects of ketoconazole and itraconazole

Contraindications


Precautions

Pregnancy


Precautions

If changes in renal function occur during therapy, consider adjusting the dose or discontinuing

treatment.

Nizatidine (Axid)

Competitively inhibits histamine at the H2 receptor of the gastric parietal cells, resulting in reduced

gastric acid secretion, gastric volume, and hydrogen concentrations.

Dosing

Adult

150 mg PO bid (300 mg PO qhs)

Pediatric

Not established

Interactions

None reported

Contraindications


Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if

benefits outweigh risk to fetus

Precautions

Caution in patients with renal or liver impairment; if changes in renal function occur during therapy,

consider adjusting the dose or discontinuing treatment

Proton Pump Inhibitors

Proton pump inhibitors inhibit gastric acid secretion by inhibition of the H+/K+ ATPase enzyme system

in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients

whose conditions do not respond to H2 receptor antagonist therapy.

Omeprazole (Prilosec)

Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers. May use for up to 8 wk

to treat all grades of erosive esophagitis.

Dosing

Adult

20 mg PO qd or bid

Pediatric

Not established

Interactions

May decrease the effects of itraconazole and ketoconazole; may increase the toxicity of warfarin,

digoxin, and phenytoin

Contraindications


Precautions

Pregnancy



Precautions

Bioavailability may increase in the elderly.

Lansoprazole (Prevacid)

Inhibits gastric acid secretion. Used for up to 8 wk to treat all grades of erosive esophagitis.

Dosing

Adult

15-60 mg PO qd or 15 mg bid

Pediatric

Not established

Interactions

May decrease the effects of ketoconazole and itraconazole; may increase theophylline clearance

Contraindications


Precautions

Pregnancy



Precautions

Consider adjusting the dose in patients with liver impairment.

Rabeprazole (Aciphex)

For short-term (4- to 8-wk) treatment and relief of symptomatic erosive or ulcerative GERD. In

patients not healed after 8 wk, consider additional 8-wk course.

Dosing

Adult

20 mg PO qd for 4-8 wk

Pediatric

Not established

Interactions

None reported

Contraindications


Precautions

Pregnancy



Precautions

Symptomatic response does not exclude the possibility of malignancy.

Esomeprazole (Nexium)

S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+ ATPase enzyme system at

secretory surface of gastric parietal cells.

Dosing

Adult

20-40 mg PO qd for 4-8 wk

Pediatric

Not established

Interactions

None reported

Contraindications


Precautions

Pregnancy



Precautions

Symptomatic relief with proton pump inhibitors may mask the symptoms of gastric malignancy.

Prokinetics

Prokinetic agents increase LES pressure to help reduce reflux of gastric contents. They also

accelerate gastric emptying.

Metoclopramide (Reglan)

GI prokinetic agent that increases GI motility, increases resting esophageal sphincter tone, and

relaxes pyloric sphincter.

Dosing

Adult

10 mg PO qid

Pediatric

Not established

Interactions

May antagonize the effects of metoclopramide; opiate analgesics may increase metoclopramide

toxicity in the CNS

Contraindications

Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation;

history of seizure disorders

Precautions

Pregnancy


Precautions

Caution in patients with a history of mental illness and Parkinson disease

Follow-up

Complications

Esophagitis (esophageal mucosal damage) occurs in approximately 50% of patients with

gastroesophageal reflux disease (GERD).

Barrett esophagus is one of the most serious complications of gastroesophageal reflux

disease (GERD), because it may progress to cancer (see images below).

Peptic esophagitis. A rapid urease test (RUT) is performed on the


Endoscopy demonstrating intraluminal esophageal cancer.

Even though a prospective randomized trial has never been performed to compare PPIs to

laparoscopic fundoplication, the authors believe fundoplication is preferable for the following

reasons: o PPIs, although effective in controlling the acid component of the refluxate, do not

eliminate the reflux of bile, which some believe to be a major contributor to the

pathogenesis of Barrett epithelium. o Patients with Barrett esophagus tend to have lower LES pressure and worse

esophageal peristalsis than patients without Barrett esophagus. Patients with

Barrett esophagus are also exposed to a larger amount of reflux.

o A fundoplication offers the only possibility of stopping any kind of reflux by creating

a competent LES. However, until the definitive answer is known, the authors

recommend that patients with Barrett esophagus continue to undergo periodic

endoscopic surveillance even after laparoscopic fundoplication.

Respiratory complications include pneumonia, asthma, and interstitial lung fibrosis.

Prognosis

Most patients with gastroesophageal reflux disease (GERD) do well with medications,

although a relapse after cessation of medical therapy is common and indicates the need for

long-term maintenance therapy.

Identifying the subgroup of patients who may develop the most serious complications of

gastroesophageal reflux disease (GERD) and treating them aggressively is important.

Surgery at an early stage is most likely indicated in these patients.

After a laparoscopic Nissen fundoplication, symptoms resolve in approximately 92% of

patients.

Miscellaneous

Medicolegal Pitfalls

Esophageal manometry and pH monitoring are considered essential before performing an

antireflux operation. Endoscopy reveals that 50% of patients do not have esophagitis. The

only way to determine if abnormal reflux is present and if symptoms are actually caused by

gastroesophageal reflux is through pH monitoring.

Achalasia can present with heartburn. Only esophageal manometry and pH monitoring can

be used to distinguish achalasia from gastroesophageal reflux disease (GERD). Therapy is

completely different for the 2 conditions.

Multimedia

Media file 1: Esophagogastroduodenoscopy indicating Barrett esophagus.

Media file 2: Gastroesophageal reflux disease (GERD)/Barrett

esophagus/adenocarcinoma sequence.

Media file 3: Barium swallow indicating hiatal hernia.

Media file 4: Ambulatory pH monitoring indicating episodes of reflux correlating

with the heartburn experienced by the patient.

Media file 5: Laparoscopic Nissen fundoplication.

Media file 6: Peptic esophagitis. A rapid urease test (RUT) is performed on the


Media file 7: Endoscopy demonstrating intraluminal esophageal cancer.

References

Colon Cancer, AdenocarcinomaTomislav Dragovich, MD, PhD, Associate Professor of Medicine and Director of Clinical Gastrointestinal Cancer Program, Arizona Cancer Center, University of Arizona College of MedicineVassiliki L Tsikitis, MD, Assistant Professor of Surgery, Section of Surgical Oncology, University of Arizona Medical Center

Updated: Dec 23, 2010

Introduction

Background

Invasive colorectal cancer is a preventable disease. Early detection through widely applied screening

programs is the most important factor in the recent decline of colorectal cancer in developed

countries (see Deterrence/Prevention). Full implementation of the screening guidelines[1 ]can cut

mortality rate from colorectal cancer in the United States by an estimated additional 50%; even

greater reductions are estimated for countries where screening tests may not be widely available at

present. New and more comprehensive screening strategies are also needed.

Fundamental advances in understanding the biology and genetics of colorectal cancer are taking

place. This knowledge is slowly making its way into the clinic and being employed to better stratify

individual risks of developing colorectal cancer, discover better screening methodologies, allow for

better prognostication, and improve one’s ability to predict benefit from new anticancer therapies.

In the past 10 years, an unprecedented advance in systemic therapy for colorectal cancer has

dramatically improved outcome for patients with metastatic disease. Until the mid 1990s, the only

approved agent for colorectal cancer was 5-fluorouracil. New agents that became available in the

past 10 years include cytotoxic agents such as irinotecan and oxaliplatin,[2 ]oral fluoropyrimidines

(capecitabine and tegafur), and biologic agents such as bevacizumab, cetuximab, and panitumumab.[3 ]

Though surgery remains the definitive treatment modality, these new agents will likely translate into

improved cure rates for patients with early stage disease (stage II and III) and prolonged survival for

those with stage IV disease. Further advances are likely to come from the development of new

targeted agents and integration of those agents with other modalities such as surgery, radiation

therapy, and liver-directed therapies.

An image depicting standard colectomies for adenocarcinoma of the colon can be seen below.

Standard colectomies for adenocarcinoma of the colon.

Pathophysiology

Genetically, colorectal cancer represents a complex disease, and genetic alterations are often

associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma.

Sequence of molecular and genetic events leading to transformation from adenomatous polyps to

overt malignancy has been characterized by Vogelstein and Fearon.[4 ]The early event is a mutation

of APC (adenomatous polyposis gene), which was first discovered in individuals with familial

adenomatous polyposis (FAP). The protein encoded by APC is important in activation of oncogene c-

myc and cyclin D1, which drives the progression to malignant phenotype. Although FAP is a rare

hereditary syndrome accounting for only about 1% of cases of colon cancer, APC mutations are very

frequent in sporadic colorectal cancers.

In addition to mutations, epigenetic events such as abnormal DNA methylation can also cause

silencing of tumor suppressor genes or activation of oncogenes, compromising the genetic balance

and ultimately leading to malignant transformation.

Other important genes in colon carcinogenesis include KRAS oncogene , chromosome 18 loss of

heterozygosity (LOH) leading to inactivation of SMAD4 (DPC4), and DCC (deleted in colon cancer)

tumor suppression genes. Chromosome arm 17p deletion and mutations affecting p53 tumor

suppressor gene confer resistance to programmed cell death (apoptosis) and are thought to be late

events in colon carcinogenesis.

A subset of colorectal cancers is characterized with deficient DNA mismatch repair. This phenotype

has been linked to mutations of genes such as MSH2, MLH1, and PMS2. These mutations result in

so-called high frequency microsatellite instability (H-MSI), which can be detected with an

immunocytochemistry assay. H-MSI is a hallmark of hereditary nonpolyposis colon cancer syndrome

(HNPCC, Lynch syndrome), which accounts for about 6% of all colon cancers. H-MSI is also found in

about 20% of sporadic colon cancers.

Frequency

United States

The American Cancer Society estimated that 148,810 individuals would be diagnosed with colorectal

cancer and 49,960 would die from this disease in the United States in 2008.[5 ]

International

In 2003, the World Health Organization estimated that approximately 940,000 individuals were be

diagnosed with colorectal cancer worldwide and 492,000 died from it that year.

Mortality/Morbidity

Colorectal cancer is a major health burden worldwide. The incidence and mortality from colon cancer

has been on a slow decline over the past 20 years in the United States; however, colon cancer

remained the third most common cause of cancer-related mortality in 2008. A multitude of risk factors

have been linked to colorectal cancer, including heredity, environmental exposures, and

inflammatory syndromes affecting gastrointestinal tract.

A review of 8 trials by Rothwell et al found allocation to aspirin reduced death caused by cancer.

Individual patient data were available from 7 of the 8 trials. Benefit was apparent after 5 years of

follow-up. The 20-year risk of cancer death was also lower in the aspirin group for all solid cancers. A

latent period of 5 years was observed before risk of death was decreased for esophageal,

pancreatic, brain, and lung cancers. A more delayed latent period was observed for stomach,

colorectal, and prostate cancer. Benefit was only seen for adenocarcinomas in lung and esophageal

cancers. The overall effect on 20-year risk of cancer death was greatest for adenocarcinomas.[6 ]

Race

Recent trends in the United States suggest a disproportionally higher incidence and death from colon

cancer in African Americans than in whites. Hispanic persons have the lowest incidence and

mortality from colorectal cancer.

Sex

The incidence of colorectal cancer is about equal for males and females.

Age

Age is a well-known risk factor for colorectal cancer, as it is for many other solid tumors. The timeline

for progression from early premalignant lesion to malignant cancer ranges from 10-20 years. The

incidence of colorectal cancer peaks at about age 65 years.

Clinical

History

Due to increased emphasis on screening practices, colon cancer is now often detected during

screening procedures. Other common clinical presentations include iron-deficiency anemia, rectal

bleeding, abdominal pain, change in bowel habits, and intestinal obstruction or perforation. Right-

sided lesions are more likely to bleed and cause diarrhea, while left-sided tumors are usually

detected later and could present with bowel obstruction.

Physical

Physical findings could be very nonspecific (fatigue, weight loss) or absent early in the disease

course. In more advanced cases, abdominal tenderness, macroscopic rectal bleeding, palpable

abdominal mass, hepatomegaly, and ascites could be present on physical examination.

Causes

Colorectal cancer is a multifactorial disease process, with etiology transcending genetic factors,

environmental exposures (including diet), and inflammatory conditions of digestive tract.

Though much about colorectal cancer genetics remains unknown, current research indicates that

genetic factors have the greatest correlation to colorectal cancer. Hereditary mutation of the APC

gene is the cause of familial adenomatous polyposis (FAP), where affected individuals carry an

almost 100% risk of developing colon cancer by age 40 years.

Hereditary nonpolyposis colon cancer syndrome (HNPCC, Lynch syndrome) carries about 40%

lifetime risk of developing colorectal cancer; individuals with this syndrome are also at increased risk

for urothelial cancer, endometrial cancer, and other less common cancers. Lynch syndrome is

characterized by deficient mismatch repair (dMMR) due to inherited mutation in one of the mismatch

repair genes, such as hMLH1, hMSH2, hMSH6, hPMS1, hPMS2, and possibly other undiscovered

genes. HNPCC is a cause of about 6% of all colon cancers. Although the use of aspirin may reduce

the risk of colorectal neoplasia in some populations, a study by Burn et al found no effect on the

incidence of colorectal cancer among carriers of Lynch syndrome with use of aspirin, resistant starch,

or both.[7 ]

Dietary factors are the subject of intense and ongoing investigations.[8 ]Epidemiological studies have

linked increased risk of colorectal cancer with a diet high in red meat and animal fat, low-fiber diet,

and low overall intake of fruits and vegetables. Factors associated with lower risk include folate

intake, calcium intake, and estrogen replacement therapy. However, most of these studies were

retrospective epidemiological studies and have yet to be validated in prospective, placebo-controlled,

interventional trials.

Lifestyle choices such as alcohol and tobacco consumption, obesity, and sedentary habits have also

been associated with increased risk for colorectal cancer.

Association between body mass index (BMI) and risk of colorectal adenomas and cancer has been

reported, but few studies have had adequate sample size for conducting stratified analyses. Jacobs

et al pooled data from 8,213 participants in 7 prospective studies of metachronous colorectal

adenomas to assess whether the association between BMI and metachronous neoplasia varied by

sex, family history, colorectal subsite, or features of metachronous lesions. Exploratory analyses

indicated that BMI was significantly related to most histologic characteristics of metachronous

adenomas among men but not among women. The researchers concluded that body size may affect

colorectal carcinogenesis at comparatively early stages, particularly among men.[9 ]

Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease also carry an increased

risk of developing colorectal adenocarcinoma. The risk for developing colorectal malignancy

increases with the duration of inflammatory bowel disease and the greater extent of colon

involvement.


Arteriovenous malformation (AVM) Ileus

Carcinoid/Neuroendocrine Tumors and Rare Tumors of GI Tract Ischemic bowel

Crohn Disease Small Intestinal Carcinomas

Diverticulosis, Small Intestinal Ulcerative Colitis

Gastrointestinal Lymphoma

Workup

Laboratory Studies

Laboratory studies are done with a goal of assessing patients organ function (liver, kidneys) in

anticipation of diagnostic and therapeutic procedures (imaging, biopsy, surgery, chemotherapy) and

also to estimate tumor burden (CEA level).

Complete blood cell count

Chemistries and liver function tests

Serum carcinoembryonic antigen (CEA) should be obtained preoperatively as it carries

prognostic value and when highly elevated may indicate more advanced, disseminated

disease.

Imaging Studies

Adequate imaging of the chest and abdomen should be obtained for staging purposes,

ideally preoperatively. o Chest radiograph or chest CT scan

o Abdominal barium study to better delineate primary lesion preoperatively

o Abdominal/pelvic computerized tomography (CT scan), contrast ultrasound of the

abdomen/liver, and abdominal/pelvic MRI are appropriate for imaging abdomen and

liver, for the purpose of staging.

Positron emission tomography (PET) scans are emerging as a very useful modality for

staging and assessment of colorectal cancers. The newest addition, a fusion PET-CT scan,

allows for detection of metastatic deposits and has added tissue-based resolution of CT

scan. Of note, some histologies, especially a mucinous signet-ring cell variant of colorectal

cancer, may not be well visualized on a PET scan.

Procedures

A suspicion of colorectal cancer diagnosis warrants rectal examination and colonoscopy with

a biopsy of suspicious lesion. o Colonoscopy

o Sigmoidoscopy

o Double contrast barium enema

After tissue diagnosis is confirmed, further workup is driven by the clinical setting (eg,

profuse bleeding and obstruction may require an emergent surgery), patient status and

comorbidities, and presenting symptoms.

Histologic Findings

The microscopic appearance of colon adenocarcinomas may be that of well-differentiated or poorly

differentiated glandular structures. Normal topological architecture of colonic epithelium in terms of a

crypt-villous axis is lost.

Staging

The TNM staging system has become the international standard for staging of colorectal cancer. It

uses 3 descriptors: T for primary tumor, N for lymph nodal involvement, and M for metastasis.

In turn, these are divided into the following categories:

Tumor categories

Tx:No description of the tumor's extent is possible because of incomplete information.

Tis: In situ carcinoma; the tumor involves only the muscularis mucosa

T1: The cancer has grown through the muscularis mucosa and extends into the submucosa

T2:The cancer has grown through the submucosa and extends into the muscularis propria

T3: The cancer has grown through the muscularis propria and into the outermost layers of

the colon but not through them; it has not reached any nearby organs or tissues

T4a: The cancer has grown through the serosa (visceral peritoneum)

T4b: The cancer has grown through the wall of the colon and is attached to or invades

nearby tissues or organs

Node categories

Nx:No description of lymph node involvement is possible because of incomplete information

N0:No cancer in nearby lymph nodes

N1a:Cancer cells found in 1 nearby lymph node

N1b:Cancer cells found in 2 to 3 nearby lymph nodes

N1c:Small deposits of cancer cells found in areas of fat near lymph nodes, but not in the

lymph nodes themselves.

N2a:Cancer cells found in 4 to 6 nearby lymph nodes

N2b: Cancer cells found in 7 or more nearby lymph nodes

Metastasis categories

M0:No distant spread seen

M1a: The cancer has spread to 1 distant organ or set of distant lymph nodes

M1b:The cancer has spread to more than 1 distant organ or set of distant lymph nodes, or

has spread to distant parts of the peritoneum

Table 1. TNM Staging System for Colon Cancer

Stage Primary Tumor (T) Regional Lymph Node (N)

Remote Metastasis (M)

Stage 0 Carcinoma in situ (Tis) N0 M0

Stage I

Tumor may invade submucosa (T1) or muscularis propria (T2)

N0

M0

Stage II

Tumor invades muscularis (T3) or adjacent organs or structures (T4)

N0

M0

Stage IIA T3 N0 M0

Stage IIB T4a N0 M0

Stage IIC T4b N0 M0

Stage IIIA T1-4 N1-2 M0

Stage IIIB T1-4 N1-2 M0

Stage IIIC T3-4 N1-2 M0

Stage IVA T1-4 N1-3 M1a

Stage IVB T1-4 N1-3 M1b

Prognostic factors associated with staging

Patient prognosis is a function of clinical and histopathologic stage of colon cancer at diagnosis. In

addition to the well-established significance of standard pathological features such as depth of bowel

wall penetration (T), number of locoregional lymph nodes involved (N), and presence of extra-colonic

metastases (M), several other factors have been proven to be of importance (see list below). These

include number of harvested and processed lymph nodes, histologic grade, and evidence of

lymphovascular and perineural invasion.

Bowel obstruction at diagnosis, ulcerative growth pattern, perforation, and elevated preoperative

CEA level have all been shown to be associated with worse prognosis. Molecular prognostic factors

such as p53, loss of heterozygosity for 18q,[10 ]mutations of deleted in colon cancer gene (DCC),

EGFR amplification, and KRAS mutations have all been investigated but are not currently used as

prognostic factors in standard clinical practice.

Deficient mismatch repair (dMMR), which is associated with high frequency microsatellite instability

(H-MSI), has been recently shown to be associated with better clinical outcome for patients with

resectable colon cancer; this was based on a retrospective analysis of several large randomized

trials of adjuvant therapy for colon cancer.[11,12 ]In addition, it appears that patients with dMMR (H-MSI)

did not benefit from fluorouracil-based adjuvant therapy.[13 ]This may become a useful test for

prognosis and treatment planning in patients with resectable colon cancer.

Selected prognostic factors and 5-year relapse-free survival in patients with colorectal cancer, based

on the Mayo Clinic calculator (http://www.mayoclinic.com/calcs) for population of patients aged 60-69

years (data regarding numbers of lymph nodes analyzed is from Le Voyer el al, 2003[14 ]) are as

follows (prognostic factor, 5-year relapse-free survival):

T3N0 (11-20) nodes analyzed – 79%

T3N0 low grade – 73%

T3N0 (≤ 10 lymph nodes examined) – 72%

T3N0 high grade – 65%

T4N0 low grade – 60%

T4N0 high grade – 51%

T3N1 – 49%

T3N2 – 15%

A review of Surveillance, Epidemiology, and End Results (SEER) population-based data on colon

cancer by the AJCC Hindgut Taskforce found that that T1-2N2 cancers have a better prognosis than

T3-4N2,T4bN1 have a similar prognosis to T4N2, T1-2N1 have a similar prognosis to T2N0/T3N0,

and T1-2N2a have similar prognosis to T2N0/T3N0 (T1N2a) or T4aN0 (T2N2a); in addition,

prognosis for T4a lesions is better than T4b by N category. The number of positive nodes affects

prognosis. The Taskforce proposed the following revisions of the TN categorization for colon cancer[15

]:

Shift T1-2N2 lesions from IIIC to IIIA/IIIB

Shift T4bN1 from IIIB to IIIC

Subdivide T4/N1/N2

Revise substaging of stages II/III.

Treatment

Medical Care

Systemic chemotherapy

5-Fluorouracil remains the backbone of chemotherapy regimens for colon cancer, both in the

adjuvant and metastatic setting. In the past 10 years, it was established that combination regimens

provide improved efficacy and prolonged progression-free survival in patients with metastatic colon

cancer. In addition to 5-fluorouracil, oral fluoropyrimidines such as capecitabine (Xeloda) and tegafur

are increasingly used as monotherapy or in combination with oxaliplatin (Eloxatin) and irinotecan

(Camptosar). Some of the standard combination regimens employ prolonged continuous infusion of

fluorouracil (FOLFIRI, FOLFOX)[16 ]or capecitabine (CAPOX, XELOX, XELIRI). Availability of new

classes of active drugs and biologics for colorectal cancer pushed the expected survival for patients

with metastatic disease from 12 months 2 decades ago to about 22 months currently.

A meta-analysis of 6 randomized phase II and II trials examined the efficacy of capecitabine with

oxaliplatin (CAP/OX) compared with fluorouracil with oxaliplatin (FU/OX) in metastatic colorectal

cancer. CAP/OX resulted in a lower response rate but overall progression-free survival and overall

survival were not affected and were similar in both treatment regimens. Characteristic toxicity

occurred in the FU schedules and thrombocytopenia and hand-foot syndrome were more prominent

in the CAP regimens.[17 ]

In a phase III multicenter trial, Kim et al compared overall survival of second-line therapy for patients

with advanced colorectal carcinoma refractory to fluorouracil. Fluorouracil, leucovorin, and oxaliplatin

(FOLFOX4) (n=246) versus irinotecan (n=245) was compared (crossover to the other treatment was

mandated if disease progression occurred). Overall survival did not significantly differ between

FOLFOX4 and irinotecan; however, FOLFOX 4 improved response rate (RR) and time to progression

(TTP) compared with irinotecan (P=0.0009 for each RR and TTP). FOLFOX4 was associated with

more neutropenia and paresthesias.[18 ]

Key clinical questions relate to the most advantageous selection of drug combination and the

sequence of different treatment options in individual patients with colorectal cancer. This information

is to be derived from information on tumor biology, patient performance status, organ function, and

pharmacogenomics testing.

Adjuvant (postoperative) chemotherapy

The standard therapy for patients with stage III and some patients with stage II colon cancer for the

last 2 decades consisted of fluorouracil in combination with adjuncts such as levamisole and

leucovorin.[19,20,21 ]This approach has been tested in several large randomized trials and has been

shown to reduce individual 5-year risk of cancer recurrence and death by about 30%.

Two recent large randomized trials (MOSAIC and NASBP-C06) investigated the addition of

oxaliplatin to fluorouracil (FOLFOX4 and FLOX, respectively) and demonstrated a significant

improvement in 3-year disease-free survival for patients with stage III colon cancer. The addition of

irinotecan to fluorouracil in the same patient population provided no benefit based on the results from

two large randomized trials (CALGB 89803 and PETACC 3). Another randomized study, XACT,

demonstrated noninferiority of capecitabine (Xeloda) compared to 5-FU/leucovorin as adjuvant

therapy for patients with stage III colon cancer. A large trial comparing capecitabine plus oxaliplatin

(XELOX) versus FOLFOX has completed accrual, but survival data have not yet been reported.

The role of adjuvant chemotherapy for stage II colon cancer is controversial. A large European trial

(QUASAR) demonstrated small but significant benefit (3.6%) in terms of absolute 5-year survival rate

for those patients who received 5-fluorouracil/leucovorin versus those in the control group. Ongoing

adjuvant trials are investigating additional risk stratification of stage II colon cancer based on

clinicopathological and molecular markers (ECOG 5202 trial).

Though information on results of adjuvant therapy in stage II and III colon cancer is limited, a data set

assembled by the Adjuvant Colon Cancer Endpoints group with fluorouracil-based adjuvant therapy

was recently analyzed. The authors concluded that adjuvant chemotherapy provides significant

disease-free survival benefit because it reduces the recurrence rate particularly within the first 2

years of adjuvant therapy but with some benefit in years 3-4.[22 ]

Biologic agents

Bevacizumab (Avastin) was the first anti-angiogenesis drug to be approved in clinical practice and

the first indication was for metastatic colorectal cancer. This is a humanized monoclonal antibody to

vascular endothelial growth factor (VEGF) and a pivotal trial demonstrated improved progression-free

and overall survival when bevacizumab was added to chemotherapy (IFL, fluorouracil plus

irinotecan).

A pooled analysis of cohorts of older patients (aged 65 years or older) from 2 randomized clinical

trials examined the benefit of bevacizumab plus fluorouracil-based chemotherapy in first-line

treatment of metastatic colorectal cancer. The study concluded that adding bevacizumab to

fluorouracil-based chemotherapy improved overall survival and progression-free survival in older

patients as it does in younger patients, without increased risks of treatment in the older age group.[23 ]

Two other biologic agents approved for colorectal cancer are epidermal growth factor receptor

(EGFR)-targeted monoclonal antibodies. Cetuximab (Erbitux) is a chimeric monoclonal antibody

approved as monotherapy or in combination with irinotecan (Camptosar) in patients with metastatic

colorectal cancer refractory to fluoropyrimidine and oxaliplatin therapy.[24 ]

Panitumumab (Vectibix) is fully human monoclonal antibody and the current indication as a

monotherapy for patients with colorectal cancer in whom combination chemotherapy failed or was

not tolerated. A recent trial by Hecht et al evaluated panitumumab added to bevacizumab and

chemotherapy (oxaliplatin- and irinotecan-based) as first-line treatment of metastatic colorectal

cancer and concluded that the addition of panitumumab resulted in increased toxicity and decreased

progression-free survival.[25 ]

Two clinical trials investigated the role of panitumumab (fully human monoclonal antibody against the

EGFR) in the first-line[26 ]and in second-line[27 ]in combination with chemotherapy (FOLFOX and

FOLFIRI). The results of both studies suggest clinical benefit of adding panitumumab to

chemotherapy for patients with wild-type KRAS colorectal cancer, in terms of improving progression-

free survival (PFS) and response rate. Panitumumab becomes an option, or an alternative to

cetuximab, for those patients who have tumors without KRAS mutation. No head-to-head

comparisons between panitumumab containing combinations versus cetuximab or even

bevacizumab (anti-VEGFR monoclonal antibody) chemotherapy combinations in patients with wild-

type KRAS tumors have been reported, leaving it up to the oncologist to prioritize the choice or

sequence of monoclonals in this patient population.

Intratumoral KRAS gene mutation can predict sensitivity to anti-EGFR antibodies.[28 ]Investigators

from a large international trial exploring the benefit of adding cetuximab to first-line chemotherapy

with FOLFIRI (CRYSTAL Trial) reported that only patients with wild-type KRAS derived clinical

benefit from cetuximab. Patients with mutant KRAS had no clinical benefit from adding cetuximab to

chemotherapy and experienced only unnecessary toxicity. KRAS mutations are present in about 40%

of colon adenocarcinomas. Based on these results, testing for KRAS mutation has been already

added to cetuximab indication by European regulatory agency (EMEA) and is expected to be added

to United States indication by the FDA as well.

Bokemeyer et al examined the overall response rate when combining cetuximab with oxaliplatin,

leucovorin, and fluorouracil (FOLFOX-4), as opposed to the regimen without cetuximab, for first-line

treatment of metastatic colorectal cancer in a randomized study. They also examined the influence of

the KRAS mutation status. They concluded that the overall response rate for cetuximab plus

FOLFOX-4 was higher than with FOLFOX-4 alone though a statistically significant increase in odds

for a response with the addition of cetuximab could not be established, except in patients with KRAS

wild-type tumors, for whom the addition of cetuximab increased chance of response and lowered risk

of disease progression.[29 ]

Other mutations that involve some of the kinases downstream from KRAS (such as BRAF and PI3K)

are being investigated and may result in even more selective methods to identify patients that may

benefit from EGFR inhibition.

Radiation therapy

While radiation therapy remains a standard modality for patients with rectal cancer, the role of

radiation therapy is limited in colon cancer. It does not have a role in the adjuvant setting, and in

metastatic settings, it is limited to palliative therapy for selected metastatic sites such as bone or

brain metastases. Newer, more selective ways of administering radiation therapy such as

stereotactic radiotherapy (CyberKnife) and tomotherapy are currently being investigated and may

extend indications for radiotherapy in the management of colon cancer in the future.

A prospective, multicenter, randomized phase III study by Hendlisz et al compared the addition of

yttrium-90 resin to a treatment regimen of fluorouracil 300 mg/m2 IV infusion (days 1-14 q8wk) with

fluorouracil IV alone. Yytrium-90 was injected intra-arterially into the hepatic artery. Findings showed

that the addition of radioembolization with yytrium-90 significantly improved time to liver progression

and median time to tumor progression.[30 ]

Surgical Care

Surgery is the only curative modality for localized colon cancer (stage I-III) and potentially provides

the only curative option for patients with limited metastatic disease in liver and/or lung (stage IV

disease). The general principles for all operations include removal of the primary tumor with

adequate margins including areas of lymphatic drainage.

For lesions in the cecum and right colon, a right hemicolectomy is indicated. During a right

hemicolectomy, the ileocolic, right colic, and right branch of the middle colic vessels are

divided and removed. Care must be taken to identify the right ureter, the ovarian or testicular

vessels, and the duodenum. If the omentum is attached to the tumor, it should be removed

en bloc with the specimen.

For lesions in the proximal or middle transverse colon, an extended right hemicolectomy can

be performed where the ileocolic, right colic, and middle colic vessels are divided and the

specimen is removed with its mesentery.

For lesions in the splenic flexure and left colon, a left hemicolectomy is indicated. The left

branch of the middle colic vessels, the inferior mesenteric vein, and the left colic vessels

along with their mesenteries are included with the specimen.

For sigmoid colon lesions, a sigmoid colectomy is appropriate. The inferior mesenteric artery

is divided at its origin, and dissection proceeds toward the pelvis until adequate margins are

obtained. Care must be taken during dissection to identify the left ureter and the left ovarian

or testicular vessels.

Total abdominal colectomy with ileorectal anastomosis may be required for patients who

have been diagnosed with HNPCC, attenuated familial adenomatous polyposis, and

metachronous cancers in separate colon segments or at times in acute malignant colon

obstructions with unknown status of the proximal bowel.

The advent of laparoscopy has revolutionized the surgical approach of colonic resections for

cancers. The same oncologic principles are respected. Large prospective randomized trials have

demonstrated that there are no significant differences with regard to intraoperative or postoperative

complications, perioperative mortality rates, readmission or reoperation rates, or rate of surgical

wound recurrence. At a median follow-up of 7 years, no significant differences existed in the 5-year

disease-free survival rate (69% versus 68% in the laparoscopy-assisted colectomy [LAC] and open

colectomy groups, respectively) or overall survival (76% versus 75%). Overall laparoscopic

colectomy provides comparable oncologic outcomes (cause-specific survival, disease recurrence,

number of lymph nodes harvested) to those achieved with an open approach.[31,32,33,34,35,36 ]

Standard management of patients with metastatic disease is systemic chemotherapy. The proper

use of elective colon/rectal resections in nonobstructed patients with stage IV disease is a source of

continuing debate. Medical oncologists properly note the major drawbacks to palliative resection,

such as loss of performance status and risks of surgical complications that potentially lead to delay in

chemotherapy. However, surgeons understand that elective operations have lower morbidity than

emergent operations on patients who are receiving chemotherapy. Only randomized prospective

data could eventually demonstrate the survival benefit of palliative resection for patients with stage IV

colon cancer. Data presented at the American Society of Clinical Oncology 45th Annual Meeting in

2009 indicated that patients with asymptomatic surgically incurable colorectal cancer do not require

immediate surgery for primary tumor removal.[37 ]

During the past decade, colonic stents have introduced an effective method of palliation for

obstruction in patients with unresectable liver metastasis.

Curative intent resections of liver metastases have significantly improved long-term survival with

acceptable postoperative morbidity. A multivariate analysis of 1001 patients who underwent

potentially curative resection of liver metastases identified 5 factors as independent predictors of

worse outcome: size greater than 5 cm, disease-free interval of less than a year, more than one

tumor, primary lymph-node positivity, and CEA greater than 200 ng/mL.[38 ]

Although resection is the only potentially curative treatment for patients with colon metastases, other

therapeutic options, for those who are not surgical candidates, include thermal ablation techniques.

Cryotherapy uses probes to freeze tumors and surrounding hepatic parenchyma. It requires

laparotomy and can potentially have significant morbidity including liver cracking, thrombocytopenia,

and disseminated intravascular coagulation (DIC). Radiofrequency ablation (RFA) uses probes that

heat liver tumors and the surrounding margin of tissue to create coagulation necrosis. RFA can be

performed percutaneously, laparoscopically, or through an open approach. Although RFA has

minimal morbidity, local recurrence is a significant problem and is correlated with tumor size. Hepatic

arterial infusion (HAI) of chemotherapeutic agents such as FUDR is a consideration following partial

hepatectomy.

Standard colectomies for adenocarcinoma of the colon are depicted in the image below.

Standard colectomies for adenocarcinoma of the colon.

Consultations

Surgical consultation o Colorectal cancer, especially early stage disease, can be cured surgically.

Following diagnosis and staging, obtaining surgical consultation for the possibility of

resection may be appropriate. After surgery, the stage of the tumor may be

advanced depending on the operative findings (eg, lymph node involvement,

palpable liver masses, peritoneal spread). o In the care of patients with colorectal cancer and isolated liver metastases, consider

surgical consultation for possible resection. In some cases, resection of previously

unresectable liver metastases may become feasible after cytoreduction with

neoadjuvant chemotherapy. Therefore, ongoing involvement of the surgical

oncologist is very important in patient care, even if the tumor is not considered

resectable at the time of diagnosis. o In advanced disease, surgical intervention may be helpful in palliative care of

bleeding or obstruction.

Gastroenterology consultation o Gastroenterology consultation is critical for screening of high-risk individuals (ie,

people with family history of colorectal cancer or polyposis syndromes) and those

individuals who are found to be inappropriately iron deficient or to have occult blood

on screening fecal examination. A colonoscopy or sigmoidoscopy is necessary to

visualize the colon endoscopically, to obtain biopsies, or to resect polyps. GI

consultation may be necessary in the management of advanced disease. Recent

advent of colorectal stents allows a nonsurgical management of impending

obstruction in patients who present with unresectable, metastatic disease. o GI consultation is necessary in the follow-up of patients after surgical resection and

adjuvant chemotherapy. Patients must be screened for recurrent disease in the

colon by colonoscopic examination at 1 year after surgery and then every 3 years.

Diet

Abundant epidemiological literature suggests association of risk for developing colorectal cancer with

dietary habits, environmental exposures, and level of physical activity. Less is known about effect of

diet and physical activity on the recurrence of colon cancer. A prospective observational study

involving patients from the CALGB 89803 adjuvant trial demonstrated adverse effect with regards to

risk for recurrence and increased mortality for patients following a "Western" diet (high intake of red

meat, refined grains, fat, and sweets) compared to patients with a "prudent" diet (high intake of fruits

and vegetables, poultry, and fish).

In another observational study from the same cohort of patients, patients were prospectively

monitored and physical activity was recorded. The study concluded that physical activity reduces the

risk of recurrence and mortality in patients with resected stage III colon cancer.

Kirkegaarde et al reported that adherence to a "healthy life style" recommendations based on

physical activity, waist circumference, smoking, alcohol intake, and diet may significantly reduce

colorectal cancer risk, by about 23%.[39 ]

These interesting and important observations pave the way for future interventional studies involving

diet and physical activity in patients with stage II and III colon cancer.

Activity

See Diet.

Medication

Commonly used combination regimens

Adjuvant therapy

5-Fluorouracil + leucovorin (weekly schedule, low dose leucovorin) o 5-Fluorouracil: 500 mg/m2 IV weekly for 6 weeks

o Leucovorin: 20 mg/m2 IV weekly for 6 weeks, administered before 5-fluorouracil

o Repeat cycle every 8 weeks for a total of 24 weeks.

LV5FU2 (de Gramont regimen) o 5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600 mg/m2 IV continuous infusion

for 22 hours on days 1 and 2 o Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil

o Repeat cycle every 2 weeks for a total of 12 cycles.

Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX4) o Oxaliplatin: 85 mg/m2 IV on day 1

o 5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600 mg/m2 IV continuous infusion

for 22 hours on days 1 and 2 o Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil

o Repeat cycle every 2 weeks for a total of 12 cycles.

Metastatic disease

Irinotecan + 5-fluorouracil + leucovorin (FOLFIRI regimen) o Irinotecan: 180 mg/m2 IV on day 1

o 5-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV continuous

infusion for 46 hours o Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion, prior to 5-fluorouracil

o Repeat cycle every 2 weeks.

Oxaliplatin + 5-fluorouracil + leucovorin (FOLFOX6) o Oxaliplatin: 100 mg/m2 IV on day 1

o 5-Fluorouracil: 400 mg/m2 IV bolus on day 1, followed by 2400 mg/m2 IV continuous

infusion for 46 hours o Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion, before 5-fluorouracil


Oxaliplatin + 5-fluorouracil + leucovorin (mFOLFOX7) o Oxaliplatin: 100 mg/m2 IV on day 1

o 5-Fluorouracil: 3000 mg/m2 IV continuous infusion on day 1 for 46 hours

o Leucovorin: 400 mg/m2 IV on day 1 as a 2-hour infusion, before 5-fluorouracil


Capecitabine + oxaliplatin (XELOX) o Capecitabine: 850-1000 mg/m2 PO bid on days 1-14

o Oxaliplatin: 100-130 mg/m2 IV on day 1

o Repeat cycle every 21 days.

FOLFOX4 + bevacizumab o Oxaliplatin: 85 mg/m2 IV on day 1

o 5-Fluorouracil: 400 mg/m2 IV bolus, followed by 600 mg/m2 IV continuous infusion

on days 1 and 2 o Leucovorin: 200 mg/m2 IV on days 1 and 2 as a 2-hour infusion before 5-fluorouracil

o Bevacizumab: 10 mg/kg IV every 2 weeks


Antineoplastic Agent, Antimetabolite (pyrimidine)

5-Fluorouracil (5-FU, Adrucil, Efudex)

Fluoropyrimidine analog. Cell cycle-specific with activity in the S-phase as single agent and has for

many years been combined with biochemical modulator leucovorin. Mainstay of medical

chemotherapy for colorectal cancer for patients for more than 40 y. Has activity as single agent that

inhibits DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific. Shown to be effective

in adjuvant setting. Classic antimetabolite anticancer drug with chemical structure similar to

endogenous intermediates or building blocks of DNA or RNA synthesis. 5-FU inhibits tumor cell

growth through at least 3 different mechanisms that ultimately disrupt DNA synthesis or cellular

viability. These effects depend on intracellular conversion of 5-FU into 5-FdUMP, 5-FUTP, and 5-

FdUTP. 5-FdUMP inhibits thymidylate synthase (key enzyme in DNA synthesis), which leads to

accumulation of dUMP, which then gets misincorporated into the DNA in the form of 5-FdUTP

resulting in inhibition of DNA synthesis and function with cytotoxic DNA strandbreaks. 5-FUTP is

incorporated into RNA and interferes with RNA processing. Current standard adjuvant therapy for

colon cancer involves combination 5-FU/LV chemotherapy. Saltz regimen (5-FU/LV/CPT11) now

standard first-line therapy for metastatic colon cancer. Because of toxicity, maximum of 400 mg/m2 of

5-FU and 100 mg/m2 of CPT11 can be used as starting dose. Levamisole is no longer an appropriate

component of adjuvant therapy.

Dosing

Adult

Bolus schedule: 425–600 mg/m2 weekly, with or without leucovorin

Protracted (pump) infusion: 200-300 mg/m2/24 h continuously

46 hour infusion (pump): 2400–3000 mg/m2/46 h, repeat every 14 days

Standard therapy: 500 mg/m2 IV weekly for 4 wk q6wk

Adjuvant therapy

Mayo Clinic regimen: 425 mg/m2/d IV bolus on days 1-5 after LV for 5 d every 4 wk; 6 mo of therapy

is current practice

Roswell Park regimen: Continuous infusion weekly for 6 wk; 2 wk off

Pediatric

Not established

Interactions

Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents;

enhanced bone marrow toxicity with other immunosuppressive agents

Contraindications

Documented hypersensitivity, bone marrow suppression, serious infection, topical administration

contraindicated in pregnancy

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (bone marrow

suppression) may occur; adjust dosage in renal impairment

Toxic effects include diarrhea, mucositis, myelosuppression, hand-foot syndrome (palmar-plantar

erythrodysesthesia), dry skin, hyperpigmentation, neurological toxicity (cerebellar ataxia), cardiac

toxicity

Capecitabine (Xeloda)

Fluoropyrimidine carbamate prodrug from of 5-fluorouracil (5-FU). Capecitabine itself is inactive.

Undergoes hydrolysis in liver and tissues to form the active moiety (fluorouracil), inhibiting

thymidylate synthetase, which in turn blocks methylation of deoxyuridylic acid to thymidylic acid. This

step interferes with DNA and to a lesser degree with RNA synthesis.

Dosing

Adult

1250 mg/m2 PO q12h pc for 2 wk followed by 1 wk of rest period; administer as 3-wk cycle

Pediatric

Not established

Interactions

Aluminum/magnesium hydroxide antacids or meals increase drug absorption; increased risk of

bleeding with anticoagulants (monitor INR and PT frequently), NSAIDs, platelet inhibitors,

thrombolytic agents; enhanced bone marrow toxicity with other immunosuppressive agents;

coadministration with leucovorin may cause diarrhea, dehydration, and death from severe

enterocolitis; may increase phenytoin levels

Contraindications

Documented hypersensitivity to drug or related products; severe renal impairment (CrCl <30

mL/min); dihydropyrimidine dihydrogenase (DPD) deficiency

Precautions

Pregnancy


Precautions

Adjust dose in moderate renal impairment (CrCl 30-50 mL/min); discontinue drug if intractable

diarrhea, bone marrow suppression, myocardial ischemia, or stomatitis develop; caution in patients

that have received extensive pelvic radiation or alkylating therapy; hand and foot syndrome

characterized by numbness, dysesthesia/paresthesia, tingling, erythema, blistering, severe pain,

desquamation, and painless or painful swelling may occur

Toxic effects include diarrhea, hand-foot syndrome, nausea and vomiting, elevations in bilirubin and

transaminases, myelosuppression, neurologic syndrome (cerebellar ataxia), cardiac toxicity

Antidote, Folic Acid Antagonist

Leucovorin (Folinic acid, Citrovorum Factor)

Reduced form of folic acid that does not require enzymatic reduction reaction for activation. Allows

for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. Current

standard therapy for colon cancer involves combination chemotherapy. Binds to and stabilizes

ternary complex of FdUTP (intracellular active metabolite of fluoropyrimidines) and thymidylate

synthetase (TS), augmenting cytotoxic effects of 5-fluorouracil. Used as an adjunct to fluorouracil.

Dosing

Adult

20-400 mg/m2 IV in combination with 5-fluorouracil

Standard therapy: 20 mg/m2 IV every wk for 4 wk q6wk

Adjuvant therapy: 20 mg/m2 IV before 5-FU on days 1-5 for 5 d q4wk (Mayo Clinic regimen); 6 mo of

therapy is current practice

Pediatric

Not established

Interactions

Decreases effect of methotrexate, phenytoin, phenobarbital, sulfamethoxazole and trimethoprim

combinations; increases toxicity of fluorouracil

Contraindications

Documented hypersensitivity; pernicious anemia or vitamin deficient megaloblastic anemias

Precautions

Pregnancy



Precautions

Do not administer intrathecally or intraventricularly

Toxic effects include skin rash, pruritus, facial flushing, and nausea and vomiting

Antineoplastic Agent, Miscellaneous

Irinotecan is a topoisomerase I inhibitor.

Irinotecan (Camptosar, CPT-11)

Semisynthetic derivative of camptothecin, an alkaloid extract from the Camptotheca acuminate tree.

Inactive in its parent form. Converted by the carboxylesterase enzyme to its active metabolite from,

SN-38.

SN-38 binds to and stabilizes the topoisomerase I-DNA complex and prevents the relegation of DNA

after it has been cleaved by topoisomerase I, inhibiting DNA replication. Effective in treatment of

colorectal cancer. Current standard therapy for metastatic colon cancer involves combination of 5-

FU/LV/CPT11 chemotherapy (see Standard Therapy).

Because of toxicity problems associated with Saltz regimen (5-FU/LV/CPT11), now standard first-line

therapy for metastatic colon cancer, maximum of 400 mg/m2 of 5-FU and 100 mg/m2 of CPT11 can

be used as starting dose.

Dosing

Adult

Monotherapy:

125 mg/m2 IV over 90 min weekly for 4 wk, followed by a 2-wk rest; schedule can be modified to 2 wk

followed by a 1-wk rest

300-350 mg/m2 IV on an every-3-wk schedule

180 mg/m2 IV as monotherapy or in combination with infusional 5-FU/LV on an every-2-wk schedule

Pediatric

Not established

Interactions

Concomitant administration with other antineoplastics may result in prolonged neutropenia and

thrombocytopenia in addition to increased morbidity/mortality

Contraindications

Documented hypersensitivity, severe diarrhea, febrile neutropenia, unresponsive or progressive

adenocarcinoma, and pregnancy

Precautions

Pregnancy



Precautions

Adverse effects include myelosuppression, alopecia, nausea, vomiting, and diarrhea (early and late),

and elevations in transaminases and bilirubin; monitor bone marrow function

Antineoplastic Agent, Alkylating Agent

Oxaliplatin is a platinum analog.

Oxaliplatin (Eloxatin, Diaminocyclohexane platinum, DACH-platinum)

Third-generation platinum-based antineoplastic agent used in combination with an infusion of 5-

fluorouracil (5-FU) and leucovorin for treatment of metastatic colorectal cancer in patients with

recurrence or progression following initial treatment with irinotecan, 5-FU, and leucovorin. Also

indicated for previously untreated advanced colorectal cancer in combination with 5-FU and

leucovorin. Covalently binds to DNA with preferential binding to the N-7 position of guanine and

adenine. DNA mismatch repair enzymes are unable to recognize oxaliplatin-DNA adducts in contrast

with other platinum-DNA adducts as a result of their bulkier size. Forms interstrand and intrastrand

Pt-DNA crosslinks that inhibit DNA replication and transcription. Cytotoxicity is cell-cycle nonspecific

with activity in all phases of the cell cycle.

Dosing

Adult

Day 1: 85 mg/m2 IV over 2 h; administer simultaneously with leucovorin 200 mg/m2; followed by 5-FU

400 mg/m2 IV bolus over 2-4 min, then 5-FU 600 mg/m2 IV continuous infusion in 500 mL D5W over

22 h

Day 2: Leucovorin 200 mg/m2 IV over 2 h, followed by 5-FU 400 mg/m2 IV bolus over 2-4 min, then 5-

FU 600 mg/m2 IV as a continuous infusion in 500 mL D5W over 22 h

Oxaliplatin can also be administered at 130 mg/m2 IV on a q3wk schedule

Pediatric

Not established

Interactions

May increase 5-FU serum concentration by approximately 20%

Contraindications

Documented hypersensitivity to oxaliplatin or other platinum compounds (allergic reactions may

present with facial flushing and rash, pneumonitis)

Precautions

Pregnancy


Precautions

Anaphylaxis may occur within minutes of administration; may cause neurotoxicity with acute and

chronic forms (acute toxicity seen in 80-85% of all patients and is characterized by a peripheral

sensory neuropathy with distal paresthesias, visual and voice changes, often triggered or

exacerbated by exposure to cold), pulmonary fibrosis, bone marrow suppression, GI tract symptoms

(eg, nausea, vomiting, diarrhea, stomatitis), renal or hepatic toxicity (decrease dose), or

thromboembolism, myelosuppression; dilute IV only in dextrose-containing solution

Antineoplastic Agent, Monoclonal Antibody

Cetuximab (Erbitux)

Recombinant, human/mouse chimeric monoclonal antibody that specifically binds to the extracellular

domain of human epidermal growth factor receptors (EGFR, HER1, c-ErbB-1). Cetuximab-bound

EGF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell growth,

induction of apoptosis, and decreased production of matrix metalloproteinase and vascular

endothelial growth factor.

Indicated for treating irinotecan-refractory, EGFR-expressed, metastatic colorectal carcinoma.

Treatment is preferably combined with irinotecan. May be administered as monotherapy if irinotecan

is not tolerated.

Dosing

Adult

First dose: 400 mg/m2 IV infused over 2 h

Weekly maintenance doses: 250 mg/m2 IV infused over 1 h

Not to exceed infusion rate of 10 mg/min (ie, 5 mL/min);

must administer with low-protein–binding 0.22 μ m in-line filter; premedication with an H1 antagonist

(eg, diphenhydramine 50 mg IV) recommended

Pediatric

Not established

Interactions

Limited data exist; none reported

Contraindications

None for metastatic colorectal carcinoma

Precautions

Pregnancy



Precautions

Caution with documented hypersensitivity, including allergy to murine proteins; may cause infusion-

related hypotension and airway distress (eg, bronchospasm, stridor, hoarseness), particularly with

the first infusion (90%); premedicate with diphenhydramine 50 mg IV; decrease dose with mild or

moderate (grade 1 or 2) infusion reaction and immediately and permanently discontinue with severe

(grade 3 or 4) infusion reactions; common adverse effects include acnelike rash, dry skin, pruritus,

tiredness or weakness, fever, diarrhea, constipation, abdominal pain, hypomagnesemia, infusion

reaction, paronychia, hypertrichia; may rarely cause interstitial lung disease; do not shake or dilute

solution; sunlight can exacerbate any skin reactions

Bevacizumab (Avastin)

Indicated in combination with a fluoropyrimidine-based chemotherapy as a first-line or second-line

treatment for metastatic colorectal cancer. Murine derived monoclonal antibody that inhibits

angiogenesis by targeting and inhibiting vascular endothelial growth factor (VEGF). Inhibiting new

blood vessel formation denies blood, oxygen, and other nutrients needed for tumor growth. Used in

combination with standard chemotherapy.

Dosing

Adult

5-10 mg/kg IV over 60 min q2wk until disease progression detected

Pediatric

Not established

Interactions

Coadministration with 5-fluorouracil increases incidence (2-fold) of serious and fatal arterial

thromboembolic events (ie, CVA, MI, TIAs, angina)

Contraindications


Precautions

Pregnancy



Precautions

Common adverse effects include hypertension, epistaxis, fatigue, thrombosis, increased risk of

bleeding, diarrhea, leukopenia, proteinuria, nephritic syndrome, headache, anorexia, and stomatitis;

may cause serious or fatal, but rare events including gastrointestinal perforation, intra-abdominal

infections, impaired wound healing, hemoptysis (particularly with lung cancers), reversible posterior

leukoencephalopathy syndrome (RPLS), nasal septum perforation, and internal bleeding; increases

risk of serious and fatal arterial thrombotic events with 5-fluorouracil

Do not initiate treatment for at least 28 days following major surgery, the surgical incision should be

fully healed; breastfeeding should be discontinued during and for at least 20 d following treatment

with bevacizumab

Panitumumab (Vectibix)

Recombinant human IgG2 kappa monoclonal antibody that binds to human epidermal growth factor

receptor (EGFR). Indicated to treat colorectal cancer that has metastasized following standard

chemotherapy.

Dosing

Adult

6 mg/kg IV infused over 60 min q2wk

Pediatric

Not established

Interactions

Data limited; none reported

Contraindications

None known

Precautions

Pregnancy



Precautions

Common adverse effects include rash (acneiform), paronychia, hypomagnesemia, fatigue, abdominal

pain, nausea, and diarrhea, pneumonitis; serious adverse effects include pulmonary fibrosis, severe

rash complicated by infections, infusion reactions (for grade I or II reaction, reduce infusion rate by

50%; for grade III or IV reaction, immediately discontinue permanently), ocular toxicity, abdominal

pain, vomiting, and constipation; administer using low-protein–binding filter

Follow-up

Further Outpatient Care

Pooled analysis form several large adjuvant trials reported that 85% of colon cancer recurrences

occur within 3 years from after resection of primary tumor. Therefore, patients with resected colon

cancer (stage II and III) should undergo regular surveillance for at least 5 years following resection.

An update of American Society of Clinical Oncology (2005) recommends physical examinations

every 3-6 months for the first 3 years, every 6 months during years 4 and 5, and subsequently at the

discretion of physician and based on individual risk assessment.

Serum CEA level should be checked every 3 months in patients with stage II or III disease for at least

3 years and every 6 months in years 4 and 5. Computerized tomography (CT) of the chest and

abdomen should be performed annually for at least 3 years after resection of primary tumor. All

patients with colon cancer should have preoperative or postoperative colonoscopy to document

absence of additional primary colon tumors or polyps. In the absence of high-risk pathology on the

first colonoscopy or increased susceptibility for colon cancer, follow-up colonoscopy should be

performed at 3 years after surgery and then, if normal, once every 5 years thereafter.

Deterrence/Prevention

Colorectal cancer prevention strategies are based on our understanding of colorectal carcinogenesis

and availability of pharmacologic agents that are effective yet minimally toxic. The efficacy of these

agents is usually first tested in high-risk populations.

Celecoxib (Celebrex), a selective cyclooxygenase-2 inhibitor was first tested in patients with familial

adenomatous polyposis (FAP). Celecoxib was effective in decreasing the number and size of polyps

on serial colonoscopies, which was the primary surrogate endpoint for this trial. The drug was

approved for FAP patients, although it remains to be seen if this intervention translates to reduced

cancer incidence and prolonged survival.

Other NSAIDs, such as sulindac and nonselective cyclooxygenase inhibitors were tested in lower risk

populations. Enthusiasm for cyclooxygenase-2 inhibitors as chemopreventive agents has dampened

because of a high incidence of cardiovascular toxicity (rofecoxib) in trial patients. An aspirin

prevention trial suggested a benefit in terms of polyp prevention with low-dose (81 mg) aspirin. Some

recent trials focused on combined inhibition of polyamine production and cyclooxygenase

inhibition. A recent report from a large randomized trial of a combination of sulindac and

dimethylformamine (DMFO), an inhibitor of ornithine decarboxylase (ODC), described a dramatic

effect of this combination in reducing polyp recurrence in patients with prior history of colon

polyps. Confirmatory trials are ongoing.[40 ]

Screening

The goal of colorectal cancer screening is to decrease mortality through diagnosis and treatment of

precancerous lesions (adenomatous colon polyps) and early curable cancerous lesions. The

evidence for the importance of early detection and removal of colorectal polyps in

preventing development of invasive cancer is mostly indirect but has been corroborated by data from

many trials.

In the United States, a Joint Guideline was developed by the American Cancer Society, US Multi-

Society Task Force on Colorectal Cancer, and the American College of Radiology. The Guideline

lists appropriate screening procedures and their indications and frequency based on projected

individual risks of developing colorectal cancer.

Their testing options for the early detection of colorectal cancer and adenomatous

polyps for asymptomatic adults aged 50 years and older can be summarized as follows:

Tests that detect adenomatous polyps and cancer o Flexible sigmoidoscopy every 5 years, or

o Colonoscopy every 10 years, or

o Double-contrast barium enema every 5 years, or

o computed tomographic colonography every 5 years

Tests that primarily detect cancer o Annual guaiac-based fecal occult blood test with high test sensitivity for cancer, or

o Annual fecal immunochemical test with high test sensitivity for cancer, or

o Stool DNA test with high sensitivity for cancer, interval uncertain

For individuals who carry an increased or high risk of developing colorectal cancer such as persons

with prior history of polyps, prior history of colorectal cancer, family history of colon cancer, or history

of inflammatory bowel diseases screening should start at an earlier age and be more frequent and

more stringent. Those genetically diagnosed or suspected of having hereditary familial syndromes

such as HNPCC or FAP should be treated as having high risk of developing colon and rectal cancer

and should adhere to a more intense surveillance protocol.[41 ]

Prognosis

The approximate 5-year survival rate for colorectal cancer patients in the United States (all stages

included) is 65%. Survival is inversely related to stage; patients with stage I have a 95% 5-year

survival rate, and those with stage III have only a 60% survival rate. For patients with metastatic,

stage IV disease, the 5-year survival rate is estimated at approximately 10% (see Staging).

Multimedia

Media file 1: Standard colectomies for adenocarcinoma of the colon.

References

Colon, AdenocarcinomaIsaac Hassan, MB, ChB, FRCR, DMRD, Former Senior Consultant Radiologist, Department of Radiology, St Bernard's Hospital, Gibraltar

Updated: Mar 2, 2009

Introduction

Background

Almost all colon cancers are primary adenocarcinomas, which are the third most common cancer in

both men and women in North America and Western Europe.

Cecal carcinoma. A large polypoid cecal mass involves the ileocecal valve and

causes small bowel obstruction.

Colon cancers are the most common gastrointestinal (GI) carcinomas and have the best prognosis.

The 5-year survival rates of approximately 50% may be improved by screening and removal of

adenomatous polyps.[1 ]

Pathophysiology

Tumors of the colon arise as intramucosal epithelial lesions, usually in adenomatous polyps or

glands. As cancers grow, they invade the muscularis mucosa and lymphatic and vascular structures

to involve regional lymph nodes, adjacent structures, and distant sites, especially the liver.[2 ]

Frequency

United States

Colorectal cancer is the third most common cancer diagnosis and the third leading cause of death

from cancer. It is the most common GI cancer. The American Cancer Society has estimated that in

2008, over 148,000 people will be diagnosed with colorectal cancer and about 50,000 will die of

colorectal cancer; 72% will occur in the colon and 28% in the rectum. About 96% colorectal cancers

are adenocarcinomas.[3 ]

The highest rates of the disease are found in the northeastern and north central states, and the

lowest rates are in the southern and western states (except the San Francisco Bay area and Hawaii).

The incidence of colon cancer has risen since 1950, while the incidence of rectal cancer has

remained stable. The increased incidence of colon cancer is believed to be a result of an increased

intake of fat and beef and a decreased intake of fiber.

International

The incidence of colon cancer is highest in the westernized countries of North America, Northern

Europe, Australia, and New Zealand. Intermediate rates are found in Southern Europe, and low rates

are found in Africa, Asia, and South America. A 60-fold difference exists between those areas with

the highest incidence of colon cancer and those areas with the lowest incidence. More than 940,000

new cases of colorectal cancer and nearly 500,000 deaths associated with colorectal cancer are

reported worldwide each year (World Health Organization, 2003).

Mortality/Morbidity

The prognosis of patients with colon cancer relates to the stage of the disease at the time of

diagnosis and to initial treatment. Although a tumor, node, metastasis(TNM)–based international

classification and a computed tomography (CT) staging system have been developed recently, the

Dukes classification (or one of its modifications) is widely used (Table 1, below). Prognosis is also

affected by the histologic grade of the tumor.

The complications of colon cancer include obstruction (common), perforation (uncommon),

intussusception and ischemic colitis proximal to an obstructing tumor (rare), and fistula formation in

the small bowel, bladder, or vagina (rare).

Table 1. Dukes Classification and 5-Year Survival*[4 ]

Stage Description 5-Year Survival

A Limited to the bowel wall 83%

B Extension to pericolic fat; no nodes 70%

C Regional lymph node metastases 30%

D Distant metastases (liver, lung, bone) 10%

*Modified from Zinkin.[ 4 ]

Several factors increase the risk for colonic cancer.

High-fat, low-fiber diet

Patient age greater than 50 years

Personal history of colorectal adenoma or carcinoma (3-fold risk)

First-degree relative with colorectal cancer (3-fold risk)

Familial polyposis coli, Gardner syndrome, and Turcot syndrome (all patients develop

colorectal carcinoma unless they undergo a colectomy)

Juvenile polyposis syndrome, Peutz-Jeghers syndrome, and Muir-Torre syndrome (risk

increased slightly)

Hereditary nonpolyposis colorectal cancer (as many as 50% of patients are affected)

Inflammatory bowel disease o Ulcerative colitis (risk is 30% after 25 years)

o Crohn disease (4- to 10-fold risk)

Race

International incidences reflect dietary differences in fat and fiber intake rather than racial differences.

When a developing country adopts a Western diet, colon cancer rates rise. Similarly, immigrants

from a low-incidence country soon experience the approximate incidence rate of their adopted

country.

Sex

Males and females are equally affected.

Age

Of patients with colon cancer, 90% are older than 50 years. The highest incidence rates are in

individuals aged 70-85 years. Only 10% of patients are younger than 50 years.

Anatomy

The colon is 150 cm long and is subdivided into the cecum and the ascending, transverse,

descending, and sigmoid colons. The ileocecal valve forms the junction between the small and large

bowel and demarcates the cecum from the ascending colon. The transverse and sigmoid colons

have a mesentery and are entirely intraperitoneal. The ascending and descending colons are

partially extraperitoneal.

The superior mesenteric artery supplies the colon between the ileocecal valve and the splenic

flexure. The inferior mesenteric artery supplies the colon distal to the splenic flexure. The colon wall

comprises 4 layers, including the mucosa, submucosa, muscularis propria (inner circular layer and

outer longitudinal layer, comprising 3 narrow bands), and serosa.

Presentation

Colon cancers progress slowly and may be asymptomatic for as many as 5 years; however, patients

usually have occult blood loss from their tumors.

Symptoms depend on the location of the primary tumor. Cancers of the cecum and ascending colon

usually grow larger than left-sided tumors before symptoms occur. Fatigue, shortness of breath, and

angina resulting from microcytic hypochromic anemia are common presenting features. Vague

abdominal discomfort or a palpable mass may occur later, but obstruction is uncommon (unless the

ileocecal junction is involved) because of the larger diameters of the cecum and ascending colon.

Cancers of the descending and sigmoid colons may present with large bowel obstruction. Perforation

is rare but may occur as a result of distention proximal to the tumor (usually in the cecum) or locally

(at the site of the tumor). The primary tumor may be palpable in the abdomen. Overt rectal bleeding

is more common in tumors of the sigmoid colon, whereas occult bleeding is typical with proximal

tumors. A change in bowel habits may be the only presenting feature. Weight loss, jaundice, and

ascites are associated with advanced metastatic disease.[5 ]

Signs and Symptoms:

May be asymptomatic

Microcytic hypochromic anemia (fatigue, shortness of breath, angina)

Vague abdominal discomfort

Change in bowel habit

Palpable mass

Rectal bleeding (overt or occult)

Large bowel obstruction

Perforation (rare)

Jaundice

Ascites

Preferred Examination

Begin the evaluation with a history and physical examination, including a digital rectal

examination.

Inspect the stool, and test for occult blood.

Perform blood tests, including a full blood count, liver function tests, and carcinoembryonic

antigen (CEA) level.

Perform either a sigmoidoscopy (rigid or flexible), along with a double-contrast barium

enema study, or a colonoscopy.

CT scan colonography or virtual colonoscopy, to evaluate the entire colon, is described in

CT scan section of this article.

Limitations of Techniques

Sigmoidoscopy

The 60-cm flexible sigmoidoscope has greater range than the rigid sigmoidoscope, which, at best,

only reaches the distal sigmoid (20 cm).

Double-contrast barium enema

A double-contrast barium enema study detects most colon tumors (80-95%); however, flexible

sigmoidoscopy should precede the barium enema as it is more accurate in detecting small rectal

lesions. The double contrast barium enema has a low perforation rate (1 in 25,000).

Colonoscopy

Colonoscopy detects more adenomatous polyps than a barium enema, and polyps can be excised

during the procedure. Colonoscopy is approximately 3 times more expensive, has a much higher

perforation rate (1 in 1700) than barium enema, and fails to reach the cecum in 5-30% of patients.


Colitis, Ischemic

Colon, Diverticulitis

Colon, Polyps

Crohn Disease

Tuberculosis, Gastrointestinal

Ulcerative Colitis

Other Problems to Be Considered

Colon lymphoma

Metastases to the colon

Radiography

Polypoid carcinoma. A large, irregular lobulated mass is present in the

rectosigmoid junction.

Annular carcinoma of the sigmoid colon. The lumen of the sigmoid is narrowed

severely by the circumferential mass with mucosal destruction and the

overhanging edges or shouldering at the tumor margins.

Flat carcinoma in the transverse colon. A broad-based contour defect with central

ulceration.

Double-contrast barium enema. 18-mm sessile polyp in the sigmoid colon showing

crescent sign.

Double-contrast barium enema. Stalked 15-mm polyp in sigmoid colon.

Cecal carcinoma. A large polypoid cecal mass involves the ileocecal valve and

causes small bowel obstruction.

Colonic urticaria in ascending colon proximal to obstructing carcinoma in the

hepatic flexure.

Local perforation and paracolic collection in an annular carcinoma of the

descending colon.

Synchronous annular carcinomas in the ascending colon and splenic flexure.

Annular carcinoma of the transverse colon is associated with a 2-cm polyp in the

sigmoid colon.

Findings

Advanced carcinoma

Most colon cancers are relatively advanced, measuring 3-4 cm in diameter at diagnosis. The

appearance of the tumors on double-contrast barium enema reflects the 3 morphologic types:

polypoid, annular, or flat.

Polypoid lesions vary from small, smooth tumors to larger lobulated masses with an irregular

surface and an associated contour deformity along 1 margin of the bowel wall (Image 1).

The incidence of carcinoma in an adenomatous polyp is related to its size and surface

features: larger, more irregular ulcerated lesions are more likely to contain carcinoma.

Annular lesions result from irregular, circumferential masses that severely constrict the

bowel lumen. The margins of the carcinoma show overhanging edges, the tumor shelf or

shoulder (termed "apple-core" lesion). The mucosal folds in the narrowed segment are

destroyed; ulceration may be present (Image 2).

Flat lesions, which are rare, are visualized as a unilateral, broad-based, contour defect.

Ulceration may be present (Image 3). Flat lesions may infiltrate the bowel wall and, if

extensive, cause areas of nondistensibility.

Early carcinoma

Small carcinomas usually present as a polypoid mass with a smooth outline; they may be

indistinguishable from a benign polyp. Rarely, they may present as a small flat lesion (Image 3).

Radiologic appearances

Radiologically, a polypoid mass is visualized either as a filling defect in the barium column (single-

contrast study) or, more commonly, as a barium-coated soft tissue mass protruding into the air-filled

lumen (double-contrast study).

A sessile polyp may be visualized as a crescent (or ring) shadow on the bowel wall (Image 4).

Lobulation is common in polypoid lesions larger than 2 cm in diameter.

Pedunculated polyps have stalks that may be identified easily on profile (Image 5). When the stalk is

seen through the polyp itself, this results in a target (or Mexican hat) appearance. Malignant change

may occur in the head of a stalked polyp. A long (2 cm or more) thin (5 mm or less) stalk may hinder

the spread of carcinoma from the head of the polyp into the wall.

Risk of malignancy

The risk of malignancy in a polyp increases with its size. Risk is less than 1% in polyps with less than

a 1 cm diameter. This risk of malignancy increases to 5% in adenomas of 1-2 cm in diameter.

Patients with polyps larger than 2 cm have a risk of 11-50%. Thus, all polypoid lesions from 0.5-3 cm

require endoscopic removal and histologic examination.

Local complications

Findings that result from complications of the primary tumor include the following:

Obstruction: Large bowel obstruction usually results in an annular carcinoma in the sigmoid

or descending colon. Primary colonic adenocarcinoma accounts for 75% of large bowel

obstruction in adults. Small bowel obstruction may be caused by a cecal lesion involving the

ileocecal valve (Image 6).

Colitis and colonic urticaria: Colitis is a rare complication and occurs proximal to an

obstructing tumor. Colonic urticaria (a term describing confluent, polygonal raised areas)

may be present from submucosal edema caused by the raised intraluminal pressure

proximal to the obstruction (Image 7).

Intussusception: This is rare in adults and usually occurs in polypoidal cecal tumors.

Perforation: A localized perforation caused by tumor necrosis may result in a paracolic

abscess simulating an inflammatory process (Image 8). Perforation also may occur proximal

to an obstructing tumor, usually in the cecum.

Fistulation: A tumor may extend through the bowel wall and invade adjacent organs. Fistulas

also may form between the tumor and adjacent organs.

Synchronous lesions

Approximately 5% of patients with colon cancer have more than 1 cancer at diagnosis (Image 9).

Approximately 35% of patients with colon cancer have an adenomatous polyp (Image 10).

Second tumors are more likely to be overlooked.

Plain abdominal radiography

Plain abdominal radiographs are useful in patients presenting with large bowel obstruction or

perforation.

Free gas below the diaphragm is detected best by plain erect chest radiograph.

Rarely, mucin-producing colon cancers show calcification in the primary tumor and in hepatic and

peritoneal secondary deposits.

Degree of Confidence

Double-contrast barium enema detects approximately 90% of colonic tumors.

The overall detection rate for single-contrast barium enema is approximately 80% but is much lower

for small polypoid tumors. Colonoscopy and biopsy are recommended in patients whose findings are

equivocal.

False Positives/Negatives

False-positive findings

Residual stool may adhere to the bowel wall and mimic a tumor.

The ileocecal valve may mimic a cecal tumor.

A submucosal mass, such as a lipoma, benign mucosal adenoma, or hyperplastic polyp,

may be indistinguishable from a small polypoid cancer.

False-negative findings

Inadequate bowel preparation: Residual stool may obscure a carcinoma. A repeat

examination or colonoscopy is required.

Diverticulosis: When severe sigmoid diverticulosis is present, the incidence of missed

cancers increases.

Diverticulitis: Strictures and paracolic collections may mimic a neoplasm.

Small lesions: Small lesions may be missed in a dense pool of barium.

Errors of perception: These are responsible for more than 50% of cancers that are missed

on barium enema; a second reading performed by a different observer may reduce such

errors.

Multiple cancers: Second lesions are more likely to be overlooked (satisfaction of search

error).

Strictures: Inflammatory bowel disease, ischemic colitis, radiation colitis, and tuberculous

colitis may mimic malignant strictures.

Extrinsic compression: Extrinsic compression of the colon by an adjacent tumor may mimic a

primary colonic tumor.

Prominent peritoneal implants on the surface of the colon: Carcinomatosis from ovarian

cancer or advanced endometriosis, for example, can mimic a primary colonic tumor.

Computed Tomography

Preoperative CT. Cecal wall thickening and infiltration of the pericolic fat.

Preoperative CT. Cecal carcinoma with circumferential involvement of the cecal

wall.

Preoperative CT. Irregular soft tissue mass involving the sigmoid colon. There is

associated diverticular disease.

Enhancing 6 x 4 cm mass from recurrent carcinoma. Note enlarged left iliacus

muscle from malignant involvement.

Barium enema. Typical annular carcinoma in the proximal sigmoid colon with

adjacent diverticular disease (same patient as in Image 13 in Multimedia).

Retroperitoneal lymphadenopathy from cecal carcinoma.

Enlarged portal nodes (observed between inferior vena cava and portal vein);

hepatic metastases.

Contrast-enhanced CT showing liver metastases. Several low-density metastases

from the colonic primary tumor involve both lobes of the liver.

CT scan following a partial hepatectomy for a metastasis in the right lobe.

Chest radiograph. Pulmonary metastases from colon cancer.

CT scan of cerebral metastasis from colon cancer. This is a rare site for metastases

from colonic cancer.

Enhancing mass in rectus sheath from metastasis from colon cancer (same patient

as in Image 14 in Multimedia).

Postradiotherapy inflammatory mass in the left iliac fossa. Note stranding into the

pericolic fat and presacral soft tissue swelling.

Dilated left ureter from inflammatory mass shown in Image 23 in Multimedia.

Findings

Indications for CT scan

CT scan is used for staging colon cancer before surgery, for assessing and staging recurrent

disease, and for detecting the presence of distant metastases.[6,7,8,9,10 ]

Preoperative CT scan is indicated if there is clinical suggestion of distant metastases or local

invasion of the adjacent organs or abdominal wall.

In older patients who may be unable to undergo colonoscopy or barium enema, modified CT scan

may be performed for primary detection of colorectal tumors.

Colonic tumors may be diagnosed on CT scan as an incidental finding.

Tumor staging: CT scan findings of primary colon cancer

CT scan staging (Table 2, below)or TNM staging (Table 3, below) systems may be used to assess

colonic neoplasms.

Table 2. CT Scan Staging System for Colonic Cancer*[11 ]

Stage Description

T1 Intraluminal polypoid mass; no thickening of bowel wall

T2 Thickened colonic wall > 6 mm; no periodic extension

T3a Thickened colonic wall plus invasion of adjacent muscle or organs

T3b Thickened colonic wall plus invasion of pelvic side wall or abdominal wall

T4 Distant metastases, usually liver, lung, or adrenal glands

* Modified from Thoeni.[ 11 ]

Table 3. TNM/Modified Dukes Classification System*[12 ]

TNM Stage Modified Dukes Stage Description

T1 N0 M0 A Limited to submucosa

T2 N0 M0 B1 Limited to muscularis propria

T3 N0 M0 B2 Transmural extension

T2 N1 M0 C1 T2, enlarged mesenteric nodes

T3 N1 M0 C2 T3, enlarged mesenteric nodes

T4 C2 Invasion of adjacent organs

Any T M1 D Distant metastases

*American Joint Committee on Cancer.[ 12 ]

Findings

A localized tumor may be seen on CT scan as an intraluminal or intramural mass of soft tissue

density adjacent to the gas-filled or contrast-filled bowel lumen; this is the appearance of a stage A

tumor (Tables 2 and 3). There is no mural thickening or pericolic fat invasion in stage A tumors. To

opacify the entire bowel, oral water-soluble contrast (1% Gastrografin) is administered at 12 hours

and at 2 hours before examination.

More advanced tumors are associated with thickening of the bowel wall (>6 mm) and infiltration of

the pericolic fat. Thin strands of tissue may extend from the tumor into the pericolic fat (Image 11).

Annular carcinomas are detected by a thickening of the bowel wall and narrowing of the lumen. This

thickening is concentric if the scanning plane is at right angles to the long axis of the bowel (Image

12).

Extracolonic tumor spread is indicated by a loss of tissue fat planes between the colon and

surrounding structures (Image 13). Invaded muscle may be enlarged (Image 14). The comparative

barium enema findings are shown in Image 15. Colonic tumors may invade the anterior abdominal

wall, liver, pancreas, spleen, or stomach.

Complications of the primary tumor

Obstruction, perforation, and fistula formation can be demonstrated by CT scan.

An intussuscepting colonic tumor may have a typical targetlike appearance with alternating rings of

soft tissue and fat on CT scan, if mesenteric fat is present between the intussusceptum and the

intussuscipiens.

A local perforation of a carcinoma may be associated with an extraluminal fluid collection.

N staging

Nodes greater than 10 mm in diameter are considered abnormal. CT scan is unable to distinguish

between enlarged benign nodes and enlarged malignant nodes. Furthermore, malignant foci may be

present in nodes less than 1 cm in diameter. Overall, 60% of affected nodes are detected by CT

scan.

Enlarged nodes may be detected in the mesentery and retroperitoneum (Image 16). Occasionally,

enlarged nodes are observed around the porta hepatis (Image 17).

Rectosigmoid tumors may metastasize to external iliac nodes.

M Staging

Hepatic metastases are the most common site of distant spread. Following injection of intravenous

contrast medium (Image 18), CT scan detects hepatic metastases as well-defined areas of low

density (compared with normal liver parenchyma) in the portal venous phase. In the earlier arterial

phase, hepatic metastases may show rim enhancement or become hyperdense or isodense (in

relation to normal liver).

Hepatic metastases may be suitable for surgical resection if they are small (usually <3 cm), number

fewer than 3, and are suitably located (Image 19), but others are suitable only for intra-arterial

chemotherapy or radiofrequency (RF) ablation (see Intervention).

Other common sites include the lungs, adrenal glands, peritoneum, and omentum.

Although pulmonary metastases may be detected by chest radiograph (Image 20), CT scan has a

higher sensitivity for small pulmonary metastases (<10 mm).

Adrenal metastases may occur in as many as 14% of patients with colon cancer. They manifest with

enlargement (>2 cm), asymmetry, and heterogeneity.

Bony and cerebral metastases are uncommon (Image 21).

Early cancers and polyps

Tumors less than 2 cm in diameter cannot be detected reliably by the standard CT scan technique.

In 1996, Vining introduced CT scan colonography (virtual colonoscopy) as a screening tool for the

detection of colorectal polyps and small cancers.[13 ]This technique involves a 3-dimensional computer

reconstruction from a volumetric data set that uses a workstation as well as distention of a clean

colon with air. Images are read as soft copy from the workstation using a combination of paging

through the 2-D axial images, aided by multiplanar and 3-D endoluminal images.

Multisectional helical scanners have reduced the time required to obtain the images (usually 30

seconds for each series; scans involve the patient in the prone and supine positions, using a reduced

tube current to minimize the radiation dose).

The length of time required for image analysis (currently ranging from 5-30 min) also has decreased

with the introduction of sophisticated software programs that enable a mathematically straightened

colon to be viewed. Advances in computer-aided diagnosis and novel methods of display are

expected to improve the performance of this test and reduce the reading time.

The sensitivity of virtual colonoscopy using multisectional helical scanners is greater than that of the

double-contrast barium enema. For polyps larger than 10 mm, it has a sensitivity of 91% but a

specificity of 76%. Sensitivity falls to 81% for 5- to 10-mm polyps. The examination has the

advantage of displaying incidental extracolonic findings as well. Data from several ongoing

retrospective and prospective multicenter trials are expected in the near future.

Colorectal cancer screening

CT colonography (virtual colonoscopy) has become an acceptable noninvasive option for colorectal

cancer screening that can reliably depict clinically important colorectal lesions. However, substantial

controversy remains regarding its exact role. Recent studies have shown that the sensitivity of CT

colonography may not be as high when performed and interpreted by radiologists who do not have

the required expertise and training. Significant lesions may be missed, and mucosal folds and

residual fecal matter may be misinterpreted as polyps, leading to unnecessary colonoscopy.

CT scan findings in recurrent colorectal cancer

A baseline CT scan study is obtained 3 months following resection of a colonic tumor and

reanastomosis. Recurrent tumor is staged by similar criteria as described above for primary cancers.

There is a local recurrence rate of 20-40% and a distant metastasis rate of approximately 35% after

curative resection. Most of these distant metastases occur within 2 years after surgery.

Although colonoscopy and barium enema reveal better mucosal detail of a local anastomotic

recurrence, CT scan is able to detect recurrence away from the anastomosis as well as

lymphadenopathy and distant metastases. A recurrent tumor mass is typically large and often

extrinsic to the bowel wall (see Images 14 and 22). CT scan criteria of a recurrent tumor include

invasion of adjacent structures, enlargement, and associated lymphadenopathy.

An inflammatory mass following surgery or radiation therapy may mimic a recurrent tumor and may

require biopsy for differentiation. Postoperative soft tissue masses are usually from granulation tissue

but may be the result of a hematoma or abscess. Of these, 60% decrease but 40% may remain

unchanged for up to 2 years. Both recurrent tumor and inflammatory masses can cause

hydronephrosis by ureteric obstruction (see Images 23 and 24).


Degree of Confidence: Colonic lesions smaller than 2 cm usually are not detected. The accuracy and

quality of CT scan studies can be increased using air contrast (rectal air insufflation), smooth muscle

relaxants, and laxatives.

CT scan:

More accurately assesses stage T4 cancers. The spatial resolution of CT scan is too low to

distinguish T2 from T3 lesions.

Has a 50% sensitivity for local invasion; it does not distinguish between direct tumor

infiltration and an inflammatory reaction induced by radiation therapy or surgery (Image 23).

Detects as many as 60% of pericolic nodes. Small nodes (<1 cm in diameter) may contain

tumor and are not detected. Nodes may be enlarged because of other reasons, such as

infection.

Detects 90% of liver metastases as well-defined rounded areas of low density following

intravenous contrast medium (Image 18).

For polyps larger than 10 mm, CT scan colonography (virtual colonoscopy) has a sensitivity of 91%

but a specificity of 76%. Sensitivity falls to 81% for 5- to 10-mm polyps.


Colon cancer may be indistinguishable from a large benign tumor as well as from metastasis to the

colon (usually from an ovarian primary).

CT scan signs for colon cancer are not specific and may be caused by any disease associated with

focal thickening of the colonic wall. These diseases include diverticulitis, Crohn disease, ischemic

colitis, and tuberculous colitis.

In cachectic patients, the absence of fat planes is a result of nutritional status and not tumor invasion.

A paracolic collection may be seen in diverticulitis, as well as in local perforation of a carcinoma.

Chronic radiation changes in the pelvis may mimic recurrent colonic tumors and require biopsy for

differentiation.

Tumors in the transverse colon and colonic flexures may be visualized incompletely. A primary

gastric carcinoma with extension into the colon may be indistinguishable from a colonic tumor

involving the stomach.

Enlarged lymph nodes may result from inflammation rather than tumor. Lymph nodes of normal size

may contain tumor.

Hypodense hepatic lesions may be caused by simple cysts rather than metastases (Image 18).

Hemangiomas also may cause confusion.

Magnetic Resonance Imaging

Findings

MRI provides greater contrast between soft tissues than CT scan.

Colonic tumors have low signal intensity (similar to adjacent skeletal muscle) on T1-weighted

sequences, which facilitates their differentiation from high-signal perirectal fat. T2-weighted images

are used to detect pelvic sidewall invasion.[14 ]

Tumor enhancement can be achieved by paramagnetic agents such as gadolinium. Gadolinium-

based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine

[MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have

been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing

dermopathy (NFD). For more information, see the eMedicine topic Nephrogenic Fibrosing

Dermopathy. The disease has occurred in patients with moderate to end-stage renal disease after

being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches

on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the

whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet;

pain deep in the hip bones or ribs; and muscle weakness. For more information, see the FDA Public

Health Advisory or Medscape.

The new technique of MRI colonography can detect colonic polyps greater than 1 cm in diameter and

will compete with CT scan colonography in screening programs.


MRI has lower sensitivity and higher specificity than CT scanning in T staging. The techniques have

a similar overall accuracy in T staging, as well as a similar overall accuracy (approximately 60%) in

the detection of enlarged lymph nodes (N staging) and liver metastasis (M staging).

In detecting local recurrence, MRI has a higher sensitivity (91%) than CT scan (82%) and a higher

specificity (100%) than CT scan (69%).

Nevertheless, most centers tend to use CT scanning rather than MRI for staging and follow-up

imaging of colonic neoplasms because of their greater experience with and the wider availability of

CT scans. In addition, spiral CT scan (and the newer multislice CT scan) can assess the whole

abdomen and pelvis in a much shorter time than MRI.


Limitations of MRI are similar to those of CT scanning.

Colon cancer may be indistinguishable from a large benign tumor and from metastasis to the colon

(usually from an ovarian primary).

MRI signs for colon cancer are not specific and may be caused by any disease associated with focal

thickening of the colonic wall. These diseases include diverticulitis, Crohn disease, ischemic colitis,

and tuberculous colitis.

A paracolic collection may be seen in diverticulitis, as well as in local perforation of a carcinoma.

Chronic radiation changes in the pelvis may mimic recurrent colonic tumors and require biopsy for

differentiation.

Enlarged lymph nodes may result from inflammation rather than tumor. Lymph nodes of normal size

may contain tumor.

Ultrasonography

Ultrasound scan through the right lobe of the liver showing large hyperechoic

metastasis from colon cancer.

Ultrasound scan of a large cecal carcinoma showing concentric thickening of the

hypoechoic bowel wall by the tumor.

Ultrasound scan demonstrating intussuscepting cecal carcinoma.

Findings

The primary role of ultrasound (US) in patients with colon cancer is the detection of hepatic

metastases.

US has a detection rate of 70-90% for hepatic metastases, which reflects the operator dependence

of this modality, the range of equipment available, and the size of the individual metastasis.

Hepatic metastases from a colonic primary tumor are usually hyperechoic (increased echogenicity in

relation to normal liver; Image 25) but also may be hypoechoic (decreased echogenicity).

On US, a colonic tumor typically appears as an echo-poor mass with a hyperechoic center, which is

known as the target sign (Image 26).

Other findings include localized irregular colonic wall thickening, an irregular contour, lack of normal

peristalsis, and an absence of the normal layered appearance of the colonic wall.

US may detect a colonic tumor as a chance finding or may be used specifically in instances when a

palpable abdominal mass is observed that is consistent with a colonic tumor (Image 26).

Intussuscepting colonic tumors have a characteristic targetlike appearance from concentric rings of

soft tissue and mesenteric-fat density (Image 27).


US usually cannot detect colonic tumors smaller than 2 cm.

US is difficult to use in rectosigmoid lesions.


US has a high false-negative rate for the detection of colonic tumors, with a sensitivity of 31-80%,

depending on tumor size, and cannot be used as a screening tool.

Conversely, US has a low false-positive rate, with a specificity greater than 90%. US may reduce the

need for more intrusive procedures in older patients and in those with advanced disease. Its primary

role in colon cancer management is to detect hepatic metastases, where it has a detection rate of 70-

90%.

Nuclear Imaging

Findings

Nuclear medicine has a small peripheral role in colon cancer.

Consider using radioimmunoscintigraphy with monoclonal antibody that recognizes CEA or tumor-

associated glycoprotein-72 to detect disease recurrence in the pelvis or extrahepatic abdomen.

Consider using positron emission tomography (PET) with fluorodeoxyglucose (FDG) to detect

recurrent disease.


A recent study by Meta et al evaluated the impact of FDG-PET on the management of patients with

colorectal carcinoma.[15 ]They noted a change in the clinical stage and major management decisions

in approximately 40% of patients.

Of the changes in clinical stages in 25 patients, the disease was upstaged in 20 patients (80%) and

downstaged in 5 patients (20%). As a result of PET findings, physicians avoided major surgery in

41% of patients for whom surgery was the intended treatment.


False-positive results may occur with FDG from nonspecific inflammatory reactions following

radiotherapy or in patients with abscesses.

Intervention

Stent placement is a relatively simple procedure that rapidly improves the general condition of

patients with colonic obstruction.[ 16 ]

Consider placing metallic stents across obstructing carcinomas of the left colon as a temporary

measure to reduce the need for emergency surgery.

In patients unfit for surgery or with unresectable tumors, stents are used as a palliative procedure.

Intra-arterial chemotherapy may be performed in patients with unresectable tumors.

Similarly, intra-arterial chemotherapy via the hepatic artery may be used in the management of liver

metastases from colorectal tumors.

Lesional heating techniques such as radiofrequency (RF) ablation and interstitial laser

photocoagulation cause preferential tumor necrosis. RF electrodes or laser fibers are inserted into

the hepatic metastasis under CT scan or US control. Promising results (40% 5-year survival) have

been achieved from RF thermal ablation in selected patients with hepatic metastases from colorectal

cancer

Medicolegal Pitfalls

Failure to recognize the signs and symptoms of colon cancer

Failure to appropriately screen patients at various levels of risk

Failure to detect a carcinoma or polyp (>10 mm) by double-contrast barium enema or

colonoscopy

Failure to stage the carcinoma correctly using CT scan or MRI

Multimedia

Media file 1: Polypoid carcinoma. A large, irregular lobulated mass is present in

the rectosigmoid junction.

Media file 2: Annular carcinoma of the sigmoid colon. The lumen of the sigmoid is

narrowed severely by the circumferential mass with mucosal destruction and the

overhanging edges or shouldering at the tumor margins.

Media file 3: Flat carcinoma in the transverse colon. A broad-based contour defect

with central ulceration.

Media file 4: Double-contrast barium enema. 18-mm sessile polyp in the sigmoid

colon showing crescent sign.

Media file 5: Double-contrast barium enema. Stalked 15-mm polyp in sigmoid

colon.

Media file 6: Cecal carcinoma. A large polypoid cecal mass involves the ileocecal

valve and causes small bowel obstruction.

Media file 7: Colonic urticaria in ascending colon proximal to obstructing

carcinoma in the hepatic flexure.

Media file 8: Local perforation and paracolic collection in an annular carcinoma of

the descending colon.

Media file 9: Synchronous annular carcinomas in the ascending colon and splenic

flexure.

Media file 10: Annular carcinoma of the transverse colon is associated with a 2-cm

polyp in the sigmoid colon.

Media file 11: Preoperative CT. Cecal wall thickening and infiltration of the

pericolic fat.

Media file 12: Preoperative CT. Cecal carcinoma with circumferential involvement

of the cecal wall.

Media file 13: Preoperative CT. Irregular soft tissue mass involving the sigmoid

colon. There is associated diverticular disease.

Media file 14: Enhancing 6 x 4 cm mass from recurrent carcinoma. Note enlarged

left iliacus muscle from malignant involvement.

Media file 15: Barium enema. Typical annular carcinoma in the proximal sigmoid

colon with adjacent diverticular disease (same patient as in Image 13 in

Multimedia).

Media file 16: Retroperitoneal lymphadenopathy from cecal carcinoma.

Media file 17: Enlarged portal nodes (observed between inferior vena cava and

portal vein); hepatic metastases.

Media file 18: Contrast-enhanced CT showing liver metastases. Several low-density

metastases from the colonic primary tumor involve both lobes of the liver.

Media file 19: CT scan following a partial hepatectomy for a metastasis in the right

lobe.

Media file 20: Chest radiograph. Pulmonary metastases from colon cancer.

Media file 21: CT scan of cerebral metastasis from colon cancer. This is a rare site

for metastases from colonic cancer.

Media file 22: Enhancing mass in rectus sheath from metastasis from colon cancer

(same patient as in Image 14 in Multimedia).

Media file 23: Postradiotherapy inflammatory mass in the left iliac fossa. Note

stranding into the pericolic fat and presacral soft tissue swelling.

Media file 24: Dilated left ureter from inflammatory mass shown in Image 23 in

Multimedia.

Media file 25: Ultrasound scan through the right lobe of the liver showing large

hyperechoic metastasis from colon cancer.

Media file 26: Ultrasound scan of a large cecal carcinoma showing concentric

thickening of the hypoechoic bowel wall by the tumor.

Media file 27: Ultrasound scan demonstrating intussuscepting cecal carcinoma.

References

1. Bromer MQ, Weinberg DS. Screening for colorectal cancer--now and the near future. Semin

Oncol. Feb 2005;32(1):3-10.

Gastric Cancer

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