Gastric cancer

Gastric cancer

What every physician needs to know:

Gastric adenocarcinoma is a major problem worldwide, with an estimated 900,000 individuals dying of this disease yearly. In the US, gastric cancer occurs in approximately 22,000 patients and is estimated to result in approximately 10,570 deaths annually.

This disease is most common in older persons with a median age of diagnosis in the US of 60 years. Symptoms include iron deficiency anemia, early satiety, and (with proximal lesions) dysphagia. Patients with gastric cancer may have systemic symptoms, including anorexia and weight loss, and diffuse abdominal discomfort. Many patients with the intestinal form of gastric cancer will have H. pylori present in the stomach and chronic gastritis (Figure 1 depicts the H.plyori bacterium).

Figure 1.

Are you sure your patient has gastric cancer? What should you expect to find?

The major common symptoms of gastric cancer are described above (Figure 2 shows symptoms in reference to where the tumor is located in the stomach). On physical exam, patients may have left supraclavicular adenopathy (Virchows nodes) or periumbilical nodules (Sister Joseph nodules) which indicate the presence of intra-peritoneal carcinomatosis.

Figure 2.

Also on rectal examination a firm anterior mass may be palpated. This is known as Blumer’s shelf and is the result of drop metastases from the primary tumor. Finally there may be ovarian enlargement from metastases (Krukenburg Tumor).

Beware of other conditions that can mimic gastric cancer:

There are other masses in the stomach which must be differentiated from adenocarcinoma (Figure 3 is an endoscopic view of an ulcerated gastric adenocarcinoma). Gastrointestinal Stromal Tumors (GIST) occur in the stomach and are treated very differently from adenocarcinomas. GISTs are diagnosed by their pathologic appearance and by immunohistochemical (IHC) staining.

Figure 3.

Lymphomas may also occur in the stomach and have characteristic histology. these tumors are also subclassified by special stains. Some low grade lymphomas, Mucosal Associated Lymphoid Tumors (MALTOMA) may be associated with H. pylori infection and in early stages, when they are polyclonal lymphoid masses, respond to antibiotic therapy. Neuroendocrine tumors such as carcinoids can occur in the stomach and are diagnosed by characteristic histopathology and special IHC staining.

Which individuals are most at risk for developing gastric cancer:

As noted previously, gastric adenocarcinoma is frequently associated with H. pylori infection of the stomach. Because widespread H. pylori gastritis is more common in poorly developed (and in some Asian) countries, gastric cancer is more common in these populations.

There are some dietary risk factors for gastric cancer. These tumors are more common in populations eating smoked and preserved foods, and less common in societies where fresh meats and vegetables are available in abundance.

Genetic risk for gastric adenocarcinoma is rare although E-Cadherin gene mutations have been identified in some families with hereditary diffuse gastric cancers. Gastric cancer also occurs as a component of Lynch Syndrome (hereditary non-polyposis colon cancer), which arises from mutations in DNA mismatch repair genes.

What laboratory and imaging studies should you order to characterize this patient's tumor (i.e., stage, grade, CT/MRI vs PET/CT, cellular and molecular markers, immunophenotyping, etc.) How should you interpret the results and use them to establish prognosis and plan initial therapy?

Endoscopy

In a patient suspected of having a gastric neoplasm the primary means of diagnosis is upper endoscopy with biopsy of areas of the stomach suspicious for abnormality. Patients with dysphagia as a significant symptom should be evaluated by endoscopy for distal esophageal, gastroesophageal junction, and proximal gastric masses. In some patients with infiltrating gastric cancers there are no mucosal abnormalities because the tumor infiltrates submucosally. It is important for the endoscopist to look for areas of stiffening in the stomach in these cases and biopsy should be performed in these cases.

A clue to areas of infiltrating gastric cancer is the failure of an area of the stomach to normally insufflate. Endoscopic ultrasound is useful if a lesion is present. This technique is particularly helpful in defining the depth of tumor penetration of the stomach wall. Endoscopic ultrasound (EUS) is almost always useful because it can define depth of tumor invasion (T Stage). EUS is less specific for defining lymph node metastases but can demonstrate enlargement of perigastric lymph nodes suggesting tumor involvement.

Pathology

The pathologic diagnosis is usually straight forward from the histopathology. In cases when there are questions about the diagnosis or site of origin of tumor, IHC staining can be helpful, but is far from being definitive for the diagnosis of gastric adenocarcinoma. The immunohistochemical profile may include staining for CK7, CK20, CEA, MUC-2, and Villin, but none of these markers is highly sensitive or specific.

Metastatic carcinoma to the stomach is rare, though occasionally melanoma will metastasize to the stomach mucosa, but this is readily apparent from the histopathology. Recent data have shown that approximately 20-30% of gastric cancers over-express the growth factor receptor human epidermal growth factor receptor human epidermal growth factor receptor 2 (HER2). Although HER2 expression is not prognostic, the minority of tumors which over-express HER2 may respond to therapeutic regimens containing the anti-HER2 monoclonal antibody trastuzamab. Thus it is reasonable to test newly diagnosed gastric cancer for HER2 expression.

Radiology

CT scanning is useful in staging, it can detect liver and lung metastases and enlarged lymph nodes, indicating whether gastrectomy is technically possible. PET/CT is useful in detecting metastases in some cases. However only about 75% of cases have PET uptake in the primary tumor. Proximal or GE Junction tumors are PET + whereas one-third of distal cancers are PET negative. PET is also not very sensitive for detecting intraperitoneal metastases. PET may also be of value when used before and after neoadjuvant (preoperative) therapy. Cases with excellent PET response to neoadjuvant therapy have a higher likelihood of improved survival than those with poor PET response (Figure 4 shows PET response to neoadjuvant therapy).

Figure 4.

Laparotomy

Abdominal carcinomatosis is a common form of metastasis for stomach cancer. Neither CT nor PET/CT is a sensitive means of detecting small amounts of abdominal carcinomatosis. For this reason, pre-operative diagnostic laparoscopy is valuable in detecting intraabdominal dissemination and therefore prevent laparotomy in cases that should not undergo gastrectomy.

Tumor markers

Tumor markers are of little value in gastric cancer. CEA or CA19-9 are elevated in 40-50% of cases but add little to patient management.

Staging

See Table I. The TNM staging of gastric cancer.

Note: In the last 20 years there have been 3 major revisions to the TNM staging system and one must be aware that some of the important older studies, for example the US Intragroup chemoradiation adjuvant trial, used different iterations of TNM than are currently in use.

What therapies should you initiate immediately i.e., emergently?

There are rarely any therapies that need to be emergently started in patients with a new diagnosis of gastric cancer.

Vigorous UGI bleeding is uncommon with adenocarcinoma. A minority of cases with GE junction or pyloric primary tumors may present with symptoms of obstruction and require emergent interventions to relieve symptoms. Occasionally in cases presenting with far advanced stomach cancer, therapeutic paracentesis or thoracentesis can improve patient comfort. In patients presenting with high grade upper GI obstruction, the initiation of paraenteral nutrition can be helpful in supporting the patient nutritionally while palliative antineoplastic therapy is initiated.

What should the initial definitive therapy for the cancer be?

Surgery

The primary therapy of gastric cancer should be gastrectomy if indicated. Reasons for patients not to undergo gastrectomy include the following:

• Presence of metastatic disease where resection of the primary tumor could not be done with curative intent.

• Locally advanced stomach tumor that makes gastrectomy technically impossible.

• Medically unfit and not judged able to tolerate major abdominal surgery.

The most appropriate gastrectomy is the D2 resection. This is defined as a complete resection of the primary stomach tumor with resection margins free of cancer and an en bloc resection of N1 and N2 lymph nodes. Figure 5 demonstrates the nodal anatomy of the stomach and can be used to define the type of gastrectomy to be performed for resectable gastric cancer. Adequate gastrectomy must include at least 15 lymph nodes, which means that the N1 and N2 nodes are removed en bloc, thus qualifying as a D2 dissection. Gastrectomies without adequate numbers of lymph nodes result in patients being understaged.

Figure 5.

If gastric cancer is identified pre-operatively, perioperative chemotherapy may be administered. In cases where a diagnosis is made at the time of surgery, postoperative chemoradiation is indicated.

Peri-operative chemotherapy

Peri-operative chemotherapy has been studied in resectable stomach cancer. Cunningham et al randomly allocated over 500 patients with resectable gastric cancer to surgery alone or pre-operative ECF (epirubicin, cisplatin, 5FU) chemotherapy followed by resection followed by additional post-operative chemotherapy.

ECF and similar regimens are detailed below. Typically 3 cycles are administered pre-operatively, and 3 cycles are administered post-operatively.

ECF

• Epirubicin 50mg/m²; IV every 3 weeks.

• Cisplatin 60mg/m²; IV every 3 weeks.

• 5FU 200mg/m²;/day IV continuous infusion.

EOF

• Epirubicin 50mg/m²; IV every 3 weeks.

• Oxaliplatin 130mg/m²; IV every 3 weeks.

• 5FU 200mg/m²; IV continuous infusion.

ECX

• Epirubicin 50mg/m²; IV every 3 weeks.

• Cisplatin 60mg/m²; IV every 3 weeks.

• Capecitabine 625mg/m²; orally twice daily continuously.

EOX

• Epirubicin 50mg/m²; IV every 3 weeks.

• Oxaliplatin 130mg/m²; IV every 3 weeks.

• Capecitabine 625mg/m²; orally twice daily continuously.

As with other anthracyclines, cumulative epirubicin dose may be associated with cardiotoxicity. In patients with normal cardiac function, cumulative dose should not exceed 1000mg/m²; (650mg/m²; if given with thoracic radiation therapy).

In the MAGIC trial, 5 year overall survival was 36% in the peri-operative chemotherapy patients versus 23% in the surgery only cases (P = 0.008), establishing peri-operative chemotherapy as the standard of care for patients with resectable gastric cancer who are identified before surgery. MAGIC has established the principle of perioperative chemotherapy. The use of chemotherapy regimens other than ECF, for example FOLFOX are appropriately being explored in the perioperative setting. It is likely that any well tolerated chemotherapy regimen that is active in advanced gastric cancer will be appropriate in the perioperative setting.

Post-operative chemoradiation

If the gastrectomy specimen is stage IB through stage IV M0, and the patient has a good performance status and has tolerated the gastrectomy well, the use of post-operative chemoradiation should be considered. This therapy has been shown to improve both disease free and overall survival in a phase III study of 580 cases.

The treatment regimen consists of the following:

• 5FU 425mg/m²; plus leucovorin 20mg/m²; daily x 5 days x 1 cycle.

• Followed by radiation therapy 4500 cGy (in 180 cGy fractions) to the gastric bed and draining lymph nodes concurrent with 5FU 400mg/m2 plus leucovorin 20mg/m²; daily on days 1-4 and the last 3 days of radiation.

• Followed one month later by 5FU 425mg/m²; plus leucovorin 20mg/m²; daily x 5 days x 2 cycles at monthly intervals.

Although a 5FU/leucovorin regimen was tested in the pivotal phase III trial, it is clear that whenever tested, the oral fluorinated pyrimidine capecitabine (Xeloda) is comparable to intravenous 5FU leucovorin. Therefore, it is reasonable to conclude that capecitabine can be substituted for 5FU in post-operative chemoradiation:

• Capecitabine 825mg/m²; orally twice daily during radiation.

Adjuvant (post-operative) chemotherapy (without radiation) has been studied for many years without identifying a widely accepted treatment regimen in North America or Europe. However, in Asia adjuvant chemotherapy with the fluorinated pyrimidine S-1 and with Oxaliplatin/fluorinated pyrimidine regimens have been shown to improve outcomes in patients with resected gastric cancers. In the Asian studies all patients had undergone well-characterized D2 gastrectomies performed by experienced gastric cancer surgeons. Although Asian postoperative chemotherapy regimens are not considered standards of care in the US, the NCCN (2013) has recommended that postoperative adjuvant chemotherapy with a regimen active in advanced gastric cancer such as an ECF variant or FOLFOX may be appropriate in the US only in those patients who have under gone D2 gastrectomy.

Metastatic gastric cancer

The treatment of metastatic gastric cancer is chemotherapy. Over the last 40 years, more than 100 chemotherapy regimens have been evaluated to some extent in gastric cancer. Almost all acceptable chemotherapy regimens in stomach cancer are based upon combinations of fluorinated pyrimidines and platinum compounds. The combination of 5FU and cisplatin is still considered an acceptable reference or control treatment in phase III trials of new chemotherapy regimens.

ECF is reasonably well tolerated and produces median survivals of over 8-9 months. The REAL-2 trial demonstrated that similar results are obtained when oxaliplatin replaces cisplatin and capecitabine replaces 5FU. Accordingly, EOF, ECX, EOX are also acceptable options. Many oncologists consider EOX a standard of care, not only because of its activity (median OS 11 months in REAL-2), but also because it avoids the toxicities of Cisplatin and uses oral medication rather than the logistically complicated infusional 5FU.

Another class of agents active in gastric cancer is the taxanes. A clinical trial compared a combination of docetaxel, cisplatin,and 5FU (DCF) to a control arm of cisplatin and 5FU in patients with metastatic gastric cancer. DCF was clearly superior than 5FU platinum (RR 25% versus 37%) and the median survival for DCF was slightly greater than 9 months. The 2-year survival for DCF was 18%, which is one of the longest 2-year survivals reported in this disease.

DCF must be given with caution because of toxicity. Diarrhea, mucositis and particularly neutropenia are significant problems with DCF. Grade III-IV neutrapenia was seen in an as many as 82% of cases. Febrile neutrapenia occurred in 29% of the cases. DCF uses relatively high doses of the myelosuppressive drugs Docetaxel (75mg/m²😉 and Cisplatin (75mg/m²;). There is some evidence that reduced dose DCF (D 40mg/m²;; C 40mg/m²; and F 1000mg/m²;/day x 2days) is active and substantially less toxic than the standard dose DCF.

It is not entirely clear whether the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab is active in gastric cancer. Phase II trials have suggested activity with chemotherapy; however, a large phase III trial, the AVAGAST study, showed no statistically significant benefits for survival when bevacizumab was added to active combination chemotherapy.

In AVAGAST 50% of cases were from Asia and only 20% were from north America. In all patients bevacizumab had no survival benefits. However the hazard ratio for the American cases was 0.63 (0.43-0.94) suggesting benefit. This apparent benefit in American cases requires confirmation before bevacizumab is considered a standard of care.

The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody has a role in the treatment of a subset of gastric cancer cases. Approximately 25% of gastric cancers express HER2 on the cell surface. In the ToGA trial, patients with HER2 expressing stomach cancers were randomly allocated to ECF chemotherapy with or without trastuzumab therapy. The best results were seen in cases whose tumors strongly (FISH + or IHC3+) expressed HER2.

The trastuzumab arm had a median survival of 13.8 months versus 11.1 months (HR=0.74; CI 0.60-0.91) for chemotherapy alone. The therapy was well tolerated and the use of trastuzumab plus chemotherapy is a standard of care in stomach cancer patients whose tumors express HER2. Nothing is yet known on whether in the small subset of HER2+ cases trastuzumab may have a role in the therapy of earlier stages of gastric cancer.

Although trastuzumab clearly has a role in the management of some gastric cancer cases, clinicians combining chemotherapy with trastuzumab should be aware of significant cardiotoxicity in breast cancer patients treated with this strategy. Gastric cases should be monitored closely for possible cardiac adverse events when receiving chemotherapy, as well as monoclonal antibody.

Recently, the anti-VEGFR2 monoclonal antibody ramucirumab has been shown to be active in gastric cancer. Fuchs et al in the REGARD trial showed outcome improvement versus placebo in gastric cancer patients who had progressed on first line therapy. Wilke et al in the RAINBOW trial showed that ramucirumab added to paclitaxel improved overall and disease free survival in patients failing 5-FU/platinum. Ramucirumab has been approved for the therapy of advanced stomach cancer by the FDA.

Selected chemotherapy regimens are as follows:

ECF

• Epirubicin 50 mg/m²; IV day 1 every 3 weeks.

• Cisplatin 60 mg/m²; IV day 1 every 3 weeks.

• 5FU 200 mg/m²;/day IV continuous infusion days 1-21.

EOF

• Epirubicin 50 mg/m²; IV day 1 every 3 weeks.

• Oxaliplatin 130 mg/m²; IV day 1 every 3 weeks.

• 5FU 200 mg/m²; IV continuous infusion days 1-21.

ECX

• Epirubicin 50 mg/m²; IV day 1 every 3 weeks.

• Cisplatin 60 mg/m²; IV day 1 every 3 weeks.

• Capecitabine 625 mg/m²; orally twice daily continuously Days 1-21.

EOX

• Epirubicin 50 mg/m²; IV every 3 weeks.

• Oxaliplatin 130 mg/m²; IV every 3 weeks.

• Capecitabine 625 mg/m²; orally twice daily continuously days 1-21.

DCF

• Docetaxel 75 mg/m²; IV day 1.

• Cisplatin 75 mg/m²; IV day 1.

• 5FU 1000 mg/m²;/day IV continuous infusion days 1-5.

• Repeat every 28 days.

Dose-modified DCF

• Docetaxel 40 mg/m²; IV day 1.

• 5FU 400 mg/m²; IV day 1.

• Leucovorin 400 mg/m²; IV day 1.

• 5FU 1000 mg/m²;/day IV continuous infusion days 1-2.

• Cisplatin 40 mg/m²; IV day 1.

• Repeat every 14 days.

Trastuzumab (with chemotherapy)

• 8 mg/kg IV loading dose

• then 6 mg/kg IV every 3 weeks.

Ramucirumab

• 8 mg/kg IV every 3 weeks.

Palliative approaches

The usual palliative therapies for unresectable and/or metastatic gastric cancer are radiation and chemotherapy. Acceptable chemotherapy regimens have been described above. Radiation may be used as palliation for pain, obstruction (if not amenable to local procedures like stenting and surgical/endoscopic by-pass). Palliative resection of an obstructing or bleeding primary tumor may be useful but a palliative total gastrectomy is rarely indicated and is usually poorly tolerated by patients with metastatic stomach cancer.

What other therapies are helpful for reducing complications?

The usual supportive care measures of antiemetics and parenteral hydration can be helpful in supporting patients through chemotherapy and/or chemoradiation. Appropriate use of opiates for pain must be available to patients. If the chemotherapy used is myelosuppressive, growth factors may have to be used.

As noted earlier, palliative paracentesis and thoracentesis are occasionally needed. Palliative radiation may be useful for relieving bowel obstruction in some cases and can also palliate pain from bone metastases when necessary.

What should you tell the patient and the family about prognosis?

It is important to make sure patients understand that adjunctive therapy with either peri-operative chemotherapy or post-operative chemoradiation has been convincingly demonstrated to improve survival. It is also important to let patients and families understand that metastatic gastric cancer is rarely curable, but there is progress being made through well designed clinical trials (ToGA for example) and that participation in such a trial should be seriously considered by patients.

It is difficult, impractical and likely to provide inaccurate information if one tries to give patients stage for stage survival figures. There are marked differences in survival by stage around the world. For example, in Asia, 60-65% of node positive cases are 5-year survivors after surgery alone. In the US and Western Europe, 20-25% of such cases survive.

Instead, it is best to look at prognosis as a function of therapy. For example, those patients capable of undergoing gastrectomy do better than those with unresectable cancer. Those cases receiving adjunctive therapies (chemoradiation or peri-operative chemotherapy) do better than those who do not receive such treatments. It is also important, as mentioned above, to encourage patients to participate in well conceived clinical trials which may alter the generally guarded prognosis with this disease.

What if scenarios.

1. Difficulty tolerating adjuvant therapy: It is very important to do everything possible to palliate the side effects that the patient is experiencing and also, encouraging the patient and family that “sticking with” the treatment is very important since it has been shown to improve cure rates.

2. Unusual complications: For example, patients who develop headaches should be evaluated for leptomeningeal spread of tumors, which occurs occasionally with metastatic gastric cancer.

Follow-up surveillance and therapy/management of recurrences.

Patients resected with curative intent at high-risk for recurrence (stage IB or greater) need to be followed for the possibility of cancer recurrence. A reasonable regimen for follow-up is:

• History, physical, and blood work (CBC, complete chemistry and liver function panel such as a chem-24, CEA and CA19-9) every 3 months for the first two years, and then twice per year through the 5th year.

• CT of the chest, abdomen and pelvis should be performed every 4 months for the first 2 years and every 6 months between years 3 and 5. If the patient is a candidate for aggressive management of metastatic or locally recurrent gastric cancer, scanning may be performed more frequently to define if a symptom is secondary to recurrent cancer. Also, abnormal laboratory values or an abnormality on physical exam may lead to early scanning.

• Symptoms or laboratory abnormalities during follow-up may trigger endoscopy and/or PET/CT or chest films.

Relapse of stomach cancer after 5 years is uncommon.

Pathophysiology

As noted previously, roughly 95% of stomach neoplasms are adenocarcinomas and histologic diagnosis is straightforward. In a patient with poorly differentiated neoplasm immunohistochemical (IHC), staining can be helpful. Positive staining for cytokeratin will differentiate between a poorly differentiated carcinoma and a lymphoma. Neuroendocrine tumors and GISTs can also be confirmed with IHC for markers like neuron specific enolase and CD117 (C-Kit).

What other clinical manifestations may help me to diagnose gastric cancer?

Important symptoms are unexplained weight loss and early satiety and/or dysphagia. Asking the patient about “lumps” in the left axilla or around the umbilicus may yield evidence of Sister Joseph nodules or “Irish’s” nodes in the left axilla.

Skin rashes, particularly in the axillary areas are worth looking for, as gastric cancer is one of the tumors associated with Acanthosis Nigrans. Also, careful exam of the left supraclavicular area is important since the presence of Virchow’s nodes indicate distant lymphatic dissemination. Careful exam of the umbilicus (Sister Joseph Nodules) and a careful rectal exam (Blumer’s shelf) may show indication of peritoneal tumor spread.

What other additional laboratory studies may be ordered?

It is important to emphasize that a laparoscopy before gastrectomy can detect low volume peritoneal cancer spread not detectable by other diagnostic tests or scans. The finding of intraperitoneal carcinomatosis by the laparoscopy will spare the patient a full laparotomy.

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