Hospital Medicine

Gastric cancer

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I. What every physician needs to know.

Gastric cancer is a relatively uncommon malignancy in the Western world. However, when it does occur, it is typically more advanced and lethal. Gastric cancer is much more common in Asian countries and many of these countries have rigorous screening programs that allow for early detection and treatment.

In Western countries, the low incidence makes screening less useful. Throughout the world, the incidence of distal gastric cancer has been declining, likely because of improvements in food safety and refrigeration. However, the incidence of more proximal gastric cancer, which is generally more lethal, is on the rise.

II. Diagnostic Confirmation: Are you sure your patient has gastric cancer?

There are multiple findings on history, physical exam and imaging that can be suggestive of the diagnosis of gastric cancer. However, biopsy and tissue diagnosis is needed in order to confirm the diagnosis.

A. History Part I: Pattern Recognition:

Symptoms of gastric cancer will generally depend on the stage of the disease. At an early stage, there are often no symptoms. As the disease becomes more advanced, patients may experience mild GERD, bloating, early satiety or increased belching. If the tumor is more proximal or more infiltrative, patients may also complain of dysphagia. There may also be symptoms of anemia from occult gastrointestinal bleeding such as fatigue or shortness of breath.

With more advanced disease, patients may develop weight loss, anorexia or gastrointestinal bleeding. Patients can also develop symptoms of gastric outlet obstruction such as nausea and vomiting. Patients with metastatic disease can have a variety of symptoms depending on the location of metastases but can develop ascites, jaundice or lymphadenopathy.

B. History Part 2: Prevalence:

The greatest risk factor for the development of gastric cancer is a history of Helicobacter pylori infection. The exact mechanism for this relationship is not known but there has been speculation that infection may lead to atrophic gastritis which can increase the risk for malignancy.

Age is another important risk factor, the peak incidence of disease is in patients aged 50-70. The disease is also more common in men, with a male to female ratio of 1.5 to 1. There is also a higher incidence in smokers, lower socio-economic groups and in developing countries.

Additionally, there is a distinctive geographic pattern for gastric cancer, with the highest rates in China and Japan, and the lowest rates in North America, Western Europe, Australia and Africa. Migration from a high-risk area to a low-risk area can decrease risk and this decrease is proportional to the age of migration.

Atrophic gastritis, distal gastrectomy and Menetriers disease, which is a hyperplastic hypersecretory gastropathy, are also key risk factors. Around 10-15% of cases occur in patients with a family history of gastric cancer but it has been difficult to understand whether this is due to genetic or environmental factors. There is also an association between gastric cancer and hereditary nonpolyposis colorectal cancer and Peutz-Jeghers syndrome.

Protective factors are likely consumption of a diet high in raw fruits and vegetables, lower consumption of salts and preservatives, access to refrigeration and good food storage and maintenance of a normal weight.

C. History Part 3: Competing diagnoses that can mimic gastric cancer.

There can be many potential symptoms of gastric cancer depending on the stage and location of the malignancy. Conditions such as GERD, gastroparesis, esophageal strictures, esophageal or gastric motility disorders and esophageal malignancies can all share symptoms with gastric cancer. The best way to distinguish these disorders from gastric cancer is generally through endoscopy and biopsy.

D. Physical Examination Findings.

Physical findings will vary depending on the stage of disease and the patient will likely have a fairly normal physical examination unless advanced or metastatic disease is present. Patients may have findings associated with anemia from occult gastrointestinal bleeding such as paleness or a flow murmur. Patients may also have signs of weight loss or wasting.

If metastatic disease is present, left sided lymphadenopathy, a supraclavicular node (Virchow's node) or a node in or around the umbilicus (Sister Mary Joseph node) may be palpable. These patients may also have a palpable ovarian mass (Krukenberg tumor) or a shelf in the pelvic cul-de-sac may be felt on rectal exam (Blumer's rectal shelf).

Malignant ascites or obstructive jaundice can also be present. Patients can also develop paraneoplastic findings such as the sudden appearance of multiple seborrheic keratoses, acanthosis nigricans, venous or arterial thrombosis.

E. What diagnostic tests should be performed?

Patients suspected of having gastric cancer should have a complete history and physical, along with basic laboratory testing and imaging. Additionally, endoscopy is usually required for direct visualization and biopsy of the area.

1. What laboratory studies should be ordered to help establish the diagnosis? How should the results be interpreted?

Patients should have a comprehensive chemistry panel and complete blood count to evaluate the severity of disease. Labs will generally indicate chronic disease with hypoproteinemia and anemia. Patients may have anemia related to both chronic disease and iron deficiency associated with occult gastrointestinal bleeding.

If there are metastases to the liver, there may be abnormal liver function tests or evidence of coagulopathy. There are currently no serum markers that are useful for diagnosis. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) can be elevated in 30-40% of cases. If elevated, they can be useful for monitoring therapy but not for establishing diagnoses.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Many patients will either have an upper gastrointestinal (GI) series or an upper endoscopy performed in order to evaluate their initial complaints.

Upper GI with double contrast of air and barium is often a useful first study as it is low-cost, non-invasive and low-risk. The sensitivity of an upper GI for detecting gastric cancer ranges from 85-95%.

It allows the observer to see the gastric defect, see its affect on motility and to see any effect of outside obstruction. Also, if there is abnormal expansion during insufflation, this can be suggestive of an infiltrating cancer. However, it does not afford the opportunity to directly visualize or biopsy the lesion.

Upper endoscopy is more expensive and invasive but offers the opportunity to directly visualize the lesion and take biopsies. If a mass is visualized, biopsies are taken. If an ulcer is present, the strategy is often to rescope in six weeks and biopsy if the ulcer remains unhealed. Less than 5% of ulcers that are biopsied are malignant.

If biopsy is performed, 8-10 samples are generally taken because this improves the yield. If an ulcer is biopsied, samples are generally taken from the edge of the lesion as the tissue in this area tends to be less necrotic. Diagnostic accuracy is greater than 95% if multiple biopsies are taken. Infiltrating cancers or gastrointestinal lymphomas are generally harder to diagnose because there is not a discreet area to biopsy.

Once gastric cancer is diagnosed with biopsy, further evaluation must be performed in order to stage the disease. Determining the tumor (T) staging is the factor that influences the treatment plan the most. Endoscopic Ultrasonography (EUS) is generally the preferred method for evaluating the T stage because it can evaluate tumor depth and proximal lymph nodes and can often evaluate celiac and mediastinal nodes.

EUS accuracy for tumor staging is 65-92% and for node staging is 50-95%. The drawback of EUS is that it is more invasive, can be operator dependent and may be limited if there is stenosis. If EUS cannot be performed, CT or MRI can be performed. In fact, as CT and MRI technologies improve, they may become more comparable to EUS.

Additional staging is generally performed to look for evidence of metastatic disease. Generally, a CT of the thorax, abdomen and pelvis is performed. If CT scanning cannot be performed because of the inability to give contrast, MRI is an acceptable alternative. Staging can also include diagnostic laparoscopy for selected patients. It can be useful for detecting small liver metastases or peritoneal spread; 20-30% of patients will have peritoneal spread at the time of diagnosis.

3. What pathologic studies should be performed?

Gastric and lymph node biopsies and cytologic washings from EUS or from laparoscopy are needed to establish the diagnoses of gastric cancer. Greater than 95% of gastric cancers are adenocarcinomas. The stomach is also the most common site of GI lymphomas. Other tissue types include squamous cell, adenoacanthoma, carcinoid and leiomyosarcoma.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

As stated previously, there are no serum markers that are useful in the diagnosis of gastric cancer and these should not be ordered while establishing the diagnosis. CEA and CA 19-9 levels are only elevated in 30-40% of cases. When elevated, they can be useful in monitoring response to treatment.

III. Default Management.

After the initial basic work-up is complete, consultation is needed in order to aid diagnosis and treatment. The diagnosis can only be confirmed by tissue biopsy. Which site to biopsy will depend on which lesions are present on imaging.

Metastatic lesions may be more accessible and can be biopsied by radiology or surgery. More often, Gastroenterology will need to be consulted for endoscopy and gastric biopsy. While awaiting definitive diagnosis, supportive care should be offered for treatment of symptoms.

Once the diagnosis is established, consultation of a multi-disciplinary team should be initiated. Radiology, surgery, gastroenterology, oncology and often palliative care will likely need to be involved.

A. Immediate management.

While awaiting confirmation of the diagnosis and staging, supportive care should be offered for symptoms such as pain, nausea and dehydration. Additionally, a discussion should be initiated with the patient about goals of care and the degree of invasive intervention desired.

B. Physical Examination Tips to Guide Management.

Physical examination findings will vary depending on the stage of the disease and the location of metastases. In general, these patients are at risk and should be monitored for:

  • gastrointestinal bleeding

  • thromboembolic disease

  • gastric perforation

  • development of gastric outlet obstruction

  • anorexia and dehydration

  • pain

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Laboratory monitoring will depend on the patient's situation. Patients who present with gastrointestinal bleeding will need to have monitoring of complete blood counts and coagulation studies. Patients undergoing surgery or chemotherapy may also need occasional monitoring of blood counts. Patients with anorexia or nausea and vomiting will need monitoring of renal function and electrolytes.

D. Long-term management.

Long term management will depend on the stage of the disease and the patient's goals. The only opportunity for cure is surgical resection and there are multiple therapeutic interventions that can be offered.

Surgery

The goal of surgery for resectable cancers is achievement of an R0 resection which is a resection that offers surgical margins of 4cms that are negative for malignancy. This goal is only achieved in about 50% of patients because the disease tends to present in a more advanced stage, especially in Western countries.

The surgical strategy will depend on the stage of the disease. If the cancer is less than 2cms and is non-ulcerated, endoscopic resection can frequently be offered. If endoscopic treatment is not an option, then there are a few different surgical strategies. A D1 resection consists of a gastrectomy or partial gastrectomy along with the removal of the lesser and greater omentum and the associated lymph nodes. Typically, 1-6 lymph nodes are removed with this strategy.

If the cancer is distal, usually only a partial gastrectomy is performed. A D2 resection consists of the same strategy as a D1 resection along with greater lymph node resection and possible splenectomy and partial pancreatectomy. Typically, 7-15 lymph nodes are removed with this strategy.

The D2 resection is more commonly performed in Asia but there is controversy about which strategy is better in the West, where there are less cases and thus less surgical experience. Some data suggests that D2 resections are associated with higher morbidity but this is not the case at higher volume centers.

Another approach is a modified D2 resection which typically involves a more extended lymph node dissection without the splenectomy or pancreatectomy. In the future, there will likely be an emerging role for laparoscopic surgery but currently more data is needed to show that this approach is equivalent. Tumors are considered unresectable if there is evidence of metastases, peritoneal spread or if the tumor surrounds large vascular structures.

Neoadjuvant therapy

Therapy prior to surgery is often considered for a variety of reasons. Prior to surgery, there are intact tissue beds and normal vasculature which may allow better delivery of therapy. Additionally, patients may be more medically fit to withstand therapies prior to surgery.

Moreover, the MAGIC/UK Medical Research Council Trial compared patients who received three cycles of pre-operative therapy and three cycles of post-operative therapy compared to surgery alone and found that survival was improved in the chemotherapy group with a 25% relative risk reduction in death.

Frequently, patients with resectable cancer are given either pre-operative chemotherapy or chemoradiation. Therapeutic regimens will vary but the ECF regimen consisting of epirubicin, cisplatin and 5-FU is a frequently used chemotherapy regimen. Patients with unresectable disease or patients with resectable disease who are not fit for surgery are generally given chemoradiotherapy. After the therapy is completed, they can be restaged and reconsidered for surgery.

Adjuvant Therapy

Therapy after surgery depends on the stage of the disease and on the surgical margins achieved from surgery. Patients with carcinoma in situ or with T1 tumors that invade only the lamina propria or submucosa can generally be treated with resection and observation.

Patients with tumors with higher risk features or with nodal disease who have R0 resections (negative surgical margins) are often treated with chemotherapy and may be considered for chemoradiation. Typical chemotherapy regimens contain 5-FU with or without leucovorin or capecitabine.

Patients who have microscopically positive surgical margins are often treated with chemoradiation. Patients who have macroscopically positive margins or evidence of metastatic disease after surgery are often treated with palliative chemotherapy. Patients with metastatic or recurrent cancer should be evaluated for HER-2-neu expression as they can be candidates for targeted therapy with trastuzumab in addition to standard chemotherapy.

Other targeted therapies for cancers with overexpression of other markers are being evaluated. Targeted markers under evaluation include VEGFR (vascular enothelial growth factor receptor) and EGFR (epidermal growth factor receptor).

Long Term Supportive Care and Palliative Care

For patients with inoperable disease and an adequate functional status, palliative chemotherapy is often offered. Palliative chemotherapy can improve both survival and quality of life.

Additionally, if the patient has a good response, they may be able to be restaged and re-evaluated for surgery. Typical regimens contain 5-FU and cisplatin. Other agents such as anthracyclines and leucovorin can be added depending on the situation.

As advanced disease becomes more progressive, multiple symptoms may become problematic and there are a variety of treatment modalities that can address these issues:

  • Bleeding can develop as the tumor becomes more invasive. Acute episodes can be treated with endoscopy or angiography with embolization. Localized radiation can also be helpful in treating less acute bleeding and with reducing recurrence.

  • Obstruction can be another significant issue as it can cause severe nausea, pain and anorexia. If there is a focal obstruction, patients can be treated endoscopically with a self-expanding metal stent. This may not be an option for patients with more distal or multiple obstructions. Stents can also potentially fail by becoming obstructed by additional tumor growth. If stenting is not an option, or if the patient has a longer anticipated life expectancy, surgical intervention with gastric bypass can be considered. Typically, a gastrojejunostomy is performed. For patients with obstruction that cannot be treated by stenting and who are not candidates for surgery, placement of a percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) can be considered for comfort.

  • Pain is a frequent issue that can be treated with standard pain control but also may be helped by radiation therapy.

E. Common Pitfalls and Side-Effects of Management

Management of gastric cancer is complicated by the lack of robust data to guide standard management. This issue is further complicated in Western countries where the malignancy generally presents in a more advanced stage and there is often less experience with treatment protocols. Consultation and communication with specialists will be needed.

A. Renal Insufficiency.

Many chemotherapeutic agents will need to be adjusted or avoided in renal failure or insufficiency. For example, epirubicin often needs a dose adjustment in renal insufficiency, and cisplatin carries a risk of nephrotoxicity and is often avoided when there is renal impairment.

B. Liver Insufficiency.

Chemotherapeutic agents may need to be adjusted for hepatic insufficiency. For example, epirubicin often needs dose adjustment when there is evidence of hepatic impairment.

Patients with surgically resectable disease but with concurrent significant liver disease may not be candidates for surgery. They will likely require close medical scrutiny and discussion with the surgical team to determine if they will be able to tolerate surgery.

C. Systolic and Diastolic Heart Failure

5-FU is the second most common cause of chemotherapeutic cardiotoxicity after anthracyclines. It can cause chest pain, myocardial infarction, arrhythmia or pulmonary edema. Patients with prior coronary disease or ischemic heart failure are likely at higher risk for this complication.

D. Coronary Artery Disease and Vascular Disease

5-FU can cause cardiotoxicity, likely by inducing coronary vasospasm. This can cause chest pain, myocardial infarction, arrhythmia or pulmonary edema. If these complications occur, the agent will need to be stopped, often indefinitely.

Patients with pre-existing coronary artery disease are likely at higher risk for this complication.

Patients with coronary artery disease who are undergoing surgical resection may also need additional evaluation for surgical risk as well as medical optimization before undergoing surgery.

E. Diabetes or other Endocrine issues

No definite change in management.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients on chromic steroids for immunosuppression who are undergoing surgery for definitive treatment or palliation will need to be placed on stress dose steroids in the peri-operative period to avoid relative adrenal insufficiency.

H. Primary Lung Disease (COPD, Asthma, ILD)

No definite change in management. However, if patients have poor functional status secondary to chronic lung disease, they may be less ideal candidates for surgical resection or chemotherapy.

I. Gastrointestinal or Nutrition Issues

The most common symptoms associated with gastric cancer and its treatment will be gastrointestinal. Patients undergoing chemotherapy will commonly experience mucositis, nausea, vomiting, diarrhea and anorexia. They will likely need additional nutritional support and symptomatic treatment.

J. Hematologic or Coagulation Issues

Patients with gastric cancer are at high risk for the development of thromboembolic disease. If these patients develop an acute thrombus associated with their malignancy, treatment with low molecular weight heparin is preferred over coumadin therapy.

K. Dementia or Psychiatric Illness/Treatment

Patients with gastric cancer will have a variety of complex medical and possible end of life decisions to make. This process can be complicated by significant psychiatric disease or dementia. Identification of proxy decision makers should be a priority. If decision making capacity is in question, consultation with psychiatry may be needed.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

One of the most important elements of information that should be passed along during hospitalization is the level of invasive care desired by the patient. Depending on disease burden, patients are at risk for:

  • gastrointestinal bleeding

  • gastric perforation

  • thromboembolic disease

  • gastric outlet obstruction

  • dehydration

  • electrolyte abnormalities

  • pain

B. Anticipated Length of Stay.

There is no typical length of stay and the hospital course will likely depend on the symptoms and disease burden. Some patients may only require a brief stay for symptom management and can be discharged once an appropriate treatment and follow-up plan is in place. Some patients may have more significant symptoms such as perforation or obstruction that may require surgery or other interventions.

C. When is the Patient Ready for Discharge.

Readiness for discharge will depend on the patient's situation. Many patients will need management of symptoms such as pain, anorexia, dehydration or gastric obstruction. Once the patient's symptoms have been adequately managed and an appropriate discharge plan has been made, the patient will likely be ready for discharge.

D. Arranging for Clinic Follow-up

Follow-up care will depend on the patient's situation and disease stage. Patients undergoing active treatment will likely need follow-up with multiple specialists.

1. When should clinic follow up be arranged and with whom

Multidisciplinary care will be needed in follow-up. For patients with resectable disease, surgery, medical oncology and radiation oncology follow-up will be needed. For patients with metastatic disease who desire continued treatment, follow-up with medical and possibly radiation oncology will be needed. Coordination with consultants will be needed as follow-up is arranged.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

No specific tests are needed prior to discharge but coordination with consultants regarding this issue will likely help to expedite treatment planning.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

No specific tests.

E. Placement Considerations.

Depending on the functional status of the patient and the disease burden, nursing home or hospice placement may be indicated. If the functional status of the patient is poor enough to warrant nursing home placement, the likelihood that they will tolerate further therapy may be low and further treatment may be delayed until the patient has recovered enough to live independently. Discussion with the patient about prognosis and goals of care will help guide the need for a hospice.

F. Prognosis and Patient Counseling.

Overall, the rates of mortality for gastric cancer have been declining in the past few decades. This is likely related to improved screening and treatment in areas with a high number of cases. Additionally, there has been a decline in the overall rates of gastric cancer, mostly due to a reduction of tumors in the distal stomach.

However, the incidence of tumors in the cardia, which are more likely to recur and carry a worse prognosis, is increasing. Also, in areas with less cases, survival remains poor. The overall five-year survival for gastric cancer in the United States and Europe is dependent on the stage of the cancer. For stage I disease it is 58-78%, for stage II disease it is 35%, but overall survival is poor at 15-35%.

A. Core Indicator Standards and Documentation.

There are currently no core indicators for gastric cancer.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Patients with gastric cancer are at high risk for thromboembolic disease and should be maintained on DVT prophylaxis unless there is a significant contraindication. Establishment of an appropriate treatment plan with the help of a multidisciplinary team is the intervention that is most likely to prevent readmission.

What's the evidence?

Catalano, V, Labianca, R, Beretta, G, Gatta, G, Braud, F, Custem, E. "Gastric Cancer.". Critical Reviews in Oncology/Hematology. vol. 71. 2009. pp. 127-164.

Cunningham, S, Schulick, R. "Palliative Management of Gastric Cancer.". Surgical Oncology. vol. 16. 2007. pp. 267-275.

Lim, L, Michael, M, Mann, B, Leong, T. "Adjuvant Therapy in Gastric Cancer". Journal of Clinical Oncology. vol. 23. 2005. pp. 6220-6232.

Palli, D. "Epidemiology of Gastric Cancer: An Evaluation of Available Evidence.". Journal of Gastroenterology. vol. 35. 2000. pp. 84-89.

Okines, A, Verheij, M, Allum, W, Cunningham, D, Cervantes, A. "Gastric Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up.". Annals of Oncology. vol. 21. 2010. pp. v50-v54.

Fuchs, C, Mayer, R. "Gastric Carcinoma". New England Journal of Medicine. vol. 333. 1995. pp. 32-41.

Kwee, R, Kwee, T. "Imaging in Local Staging of Gastric Cancer: A Systematic Review.". Journal of Clinical Oncology. vol. 25. 2007. pp. 2107-2116.

Ajani, J, Barthel, J, Bentrem, J, D'Amico, T, Das, P, Denlinger, C, Fuchs, C, Gerdes, H, Glasgow, R, Hayman, J. "Gastric Cancer. NCCN Clinical Practice Guidelines in Oncology.". 2011.

Moehler, M, Lyros, O, Gockel, I, Galle, P, Lang, H. "Multidisciplinary Management of Gastric and Gastroesophageal Cancers.". World Journal of Gastroenterology. vol. 14. 2008. pp. 3773-3780.

Menges, M, Hoehler, T. "Current Strategies in Systemic Treatment of Gastric Cancer and Cancer of the Gastroesphageal Junction". Journal of Cancer Research in Clinical Oncology. vol. 135. 2009. pp. 29-38.

Rajdev, L. "Treatment Options for Surgically Resectable Gastric Cancer". Current Treatment Options in Oncology. vol. 11. 2010. pp. 14-23.

Dalzell, J, Samuel, L. "The Spectrum of 5-Fluorouracil Cardiotoxicity.". Anti-Cancer Drugs. vol. 20. 2009. pp. 79-80.

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