Bartosz Chmielowski and Dennis A. Casciato
I. GASTROINTESTINAL (GI) BLEEDING
A. Etiology
1. Benign causes. GI bleeding in patients with active cancer is usually caused by acute gastritis, peptic ulcer disease, esophagitis, Mallory-Weiss tears, esophageal varices, ischemic colitis, diverticular disease, or angiodysplasia; only 10% to 15% is caused by direct tumor bleeding.
2. Malignant causes. The most common malignant causes of upper GI bleeding are esophageal cancer, gastric cancer, gastric lymphoma, gastrointestinal stromal tumors (GIST), and metastatic tumors involving the stomach. Lower GI bleeding is usually caused by colorectal cancer or metastatic cancer to the bowel. In order to diagnose bleeding from the small bowel, patients may require enteroscopy or capsule endoscopy; it is most commonly caused by GIST or metastatic cancer (i.e., melanoma).
3. Secondary to cancer treatments. Bleeding is a common complication of radiation therapy (RT), that is, radiation esophagitis, enteritis, or proctitis. Chemotherapy can induce enteric mucositis (cytarabine, fluoropyrimidines, taxanes). In addition, patients may suffer from superimposed infections (Candida or cytomegalovirus [CMV] esophagitis; CMV, Clostridium difficile, or gram-negative bacillus enteritis; typhlitis). Newer antiangiogenic cancer medications (bevacizumab, sunitinib, sorafenib, pazopanib) increase the risk of bleeding and the risk of hemorrhagic complications during surgery.
4. Secondary to supportive therapy in cancer patients. Cancer patients may bleed from erosive esophagitis secondary to oral bisphosphonate or potassium chloride or erosive gastritis secondary to steroids or nonsteroidal anti-inflammatory drugs (NSAIDs).
B. Management. In patients with cancer, the status of their malignancy may influence the aggressiveness of the management. The bleeding is most commonly caused by benign causes, and it is frequently reversible. Therefore, aggressive management should be applied in all patients with good performance status.
Initially, patients are resuscitated with intravenous fluids and blood products and then diagnostic efforts are concentrated on establishing the etiology. Surgical intervention is frequently required in cases of tumor bleeding; patients with persistent GI bleeding from unresectable tumors may be managed with RT. Long-term, successful systemic therapy against cancer is most helpful in the management of bleeding from the tumor.
II. BOWEL OBSTRUCTION
A. Etiology. Bowel obstruction is defined by the inability of intestinal contents to traverse through the bowel and can be divided into complete and partial, mechanical, or functional. In patients with a history of cancer, it is due to the original tumor or its metastases in 60% to 70% of cases. About 20% to 30% of patients have a benign cause of obstruction, and 10% to 20% have a new, and often resectable, primary lesion. Duodenal obstruction is most commonly caused by cholangiocarcinoma, pancreatic carcinoma, and gallbladder carcinoma; distal bowel obstruction is secondary mainly to colon and ovarian cancer.
1. Mechanisms of bowel obstruction in malignancy include the following:
a. External pressure on the intestine caused by mesenteric or omental masses
b. Obstructing masses in the bowel lumen
c. Intraluminal masses invading mucosa and impairing peristalsis (pseudo-obstruction)
d. Invasion of the intestine’s neural plexus, causing localized or diffuse ileus clinically indistinguishable from mechanical obstruction
e. Intussusception with certain tumors, notably melanoma
f. Pseudo-obstruction as a paraneoplastic syndrome (see Section IX)
g. Adhesions secondary to previous surgeries
h. Complications of RT or intraperitoneal chemotherapy
i. Use of cholinergic or sympathomimetic drugs (ileus, pseudo-obstruction)
2. Differential diagnosis. Diagnostic considerations in cancer patients include the following:
a. Vinca alkaloid neurotoxicity may produce constipation. Particularly in elderly patients, paralytic ileus or decreased bowel tone may lead to high fecal impaction with bowel obstruction. Impaction is better prevented than treated.
b. Radiation injury of small bowel (see Section VI.C) may be seen on small bowel radiographs or CT scan as mucosal effacement, ulcers, rigidity, narrowing, adhesions, bowel wall thickening, and bowel dilation.
c. Diverticulitis may produce tightly narrowed areas in the distal colon that are often radiologically indistinguishable from constricting carcinoma. In the absence of metastatic disease elsewhere, these lesions must be resected regardless of coexistent tumor.
d. Other nonmalignant causes of ileus and obstruction include adhesions, hernia, inflammatory bowel disease, volvulus, spontaneous intussusception, acute pancreatitis, and bowel infarction.
B. Management of bowel obstruction caused by cancer. The status of a patient’s cancer should be always included in decision making on the aggressive management of gastrointestinal obstruction. Patients with terminal cancer benefit from the aggressive symptom management, but not from surgical intervention, parenteral nutrition, or long-term nasogastric tube placement.
1. Fluid resuscitation. Intraluminal volume sequestration results in fluid depletion. In terminal patients, excessive hydration may worsen patients symptoms since it can increase intraluminal fluid secretion or lead to volume overload.
2. Decompression. Patients with evidence of intestinal obstruction should have decompression by placement of a nasogastric (NG) tube and intermittent suction. Complications of prolonged NG tube use include nasal erosion and sinusitis. The goal is to use decompression with other modalities listed later to minimize time with the NG tube. In refractory cases, venting gastrostomy/percutaneous endoscopic gastrostomy tube decompression is often the only palliative modality available when other measures fail.
3. Stents. Expandable metallic stents have been used to treat obstruction in nearly all portions of the GI tract, including the esophagus, gastric outlet, duodenum, proximal jejunum, terminal ileum, colon, and rectum. Although stent placement requires a trained endoscopist or interventional radiologist, this procedure palliates obstruction in >80% of patients and may obviate the need for surgery in patients who cannot be cured. Complication rates are low but include bleeding, stent migration, and tumor growth into stent. Stents can be used as a “bridge” to improve symptoms while awaiting definitive treatments for obstruction.
4. Operative intervention
a. A history of cancer or even the presence of active tumor is not necessarily a contraindication to surgery. About 75% of patients with a bowel obstruction resume normal bowel function after surgery. Function is maintained until death in 45% of patients. About 25% of these patients do not experience improvement of symptoms with surgery.
b. Surgical intervention should be considered if the obstruction does not improve after 4 to 5 days of decompression and if the following conditions are met:
(1) The patient’s medical condition, including nutritional status, makes the operative risk low.
(2) The patient does not have malignant ascites.
(3) The patient’s life expectancy would be >2 months if the bowel obstruction were relieved.
(4) The patient underwent no more than one surgical intervention for obstruction during the previous year and was significantly palliated by that operation for >4 months.
(5) The most recent operative intervention did not disclose multiple or widespread tumor sites causing obstruction.
5. Other modalities of management
a. Chemotherapy may be tried in patients with obstruction caused by carcinomatosis. In some tumors, such as lymphomas treated with chemotherapy or GIST and melanomas treated with targeted therapy, symptomatic improvement is seen within days after starting the therapy.
b. RT to relieve bowel obstruction may be beneficial in patients who have peritoneal carcinomatosis from ovarian carcinoma or extensive abdominal lymphoma that is resistant to chemotherapy. Abdominal irradiation produces severe side effects and is not recommended for other types of malignant bowel obstruction.
c. Treatment of preterminal patients with refractory obstruction caused by cancer
(1) NG suction is used to alleviate abdominal pain. Intravenous fluids are given to maintain hydration.
(2) Opioids are given SC or IV for pain control; they are appropriate for continuous abdominal pain but can aggravate colic.
(3) Anticholinergic agents, such as hyoscine butylbromide, 60 to 380 mg/d (Buscopan), or glycopyrrolate (Robinul), may alleviate pain, especially colic, and can also reduce nausea and vomiting. Nausea and vomiting can be treated with various drugs.
(4) Phenotiazines (prochlorperazine, promethazine, chlorpromazine) reduce nausea and vomiting.
(5) Metoclopramide can have its place in patients with functional or partial bowel obstruction; it should not be used with anticholinergics or in patients with colic or complete bowel obstruction.
(6) Haloperidol, 1 to 5 mg SC three times daily, is helpful in patients with nausea and delirium.
(7) Dexamethasone, 6 to 16 mg/d parenterally, can help decrease edema and possibly help decrease obstructive symptoms.
(8) Octreotide, 100 to 300 μg every 8 hours SC, is an effective drug that decreases GI secretions, decreases distention, and in many cases allows the NG tube to be taken out.
(9) Olanzapine (Zyprexa), in doses of 2.5 to 20 mg/d, can reduce vomiting in patients who failed other medications.
III. METASTASES TO THE LIVER AND BILIARY TRACT
A. Incidence and pathology
1. Liver. The liver is a common site of metastases. Liver metastases account for more than half of the deaths in certain malignancies, such as colorectal cancer.
a. The relative risks of tumor metastasizing to the liver during the course of advanced disease are as follows:
(1) Liver commonly involved: GI tract cancers (including carcinoids, pancreatic adenocarcinoma, and islet cell tumors), lung cancer (especially small cell), breast cancer, choriocarcinoma, melanoma, lymphomas, and leukemias
(2) Liver occasionally involved: carcinoma of the distal esophagus, kidney, prostate, endometrium, adrenal gland, and thyroid; testicular cancers, thymoma; angiosarcoma
(3) Liver rarely involved: carcinoma of the proximal esophagus, ovary, and skin; plasma cell myeloma; most sarcomas
b. Types of metastases
(1) Nodular metastases are the most common type and occur with all tumors capable of metastasizing to the liver, including lymphoma.
(2) Diffuse metastases most frequently occur with lymphomas. Breast cancer, small cell lung cancer, poorly differentiated GI tumors, and, rarely, other types of tumors can also produce diffuse metastases.
2. Extrahepatic biliary obstruction can occur from lymph node metastases in the porta hepatis, particularly from GI cancers and lung cancers (especially the small cell type).
B. Natural history. The clinical course of liver metastases depends on the tumor’s behavior and responsiveness to chemotherapy. In patients with solid tumors, death commonly occurs within 6 months with nodular metastases and more rapidly with diffuse metastases. A liver that appreciably increases in size in <8 weeks is typical in small cell lung cancer and high-grade lymphoma; both of these tumors respond well to treatment. Rapid liver enlargement in patients with other tumor types is less common.
C. Diagnosis
1. Symptoms and signs. Any combination of pain or discomfort in the right upper quadrant, weight loss, fatigue, anorexia, jaundice, or fever should raise the possibility of liver metastases, particularly in patients with a history of cancer. Symptoms are present in 65% of patients and hepatomegaly in 50% when liver metastases are discovered.
2. Laboratory studies
a. LFTs should be obtained in all patients suspected of having liver metastases. An elevation of the alkaline phosphatase level that is out of proportion to that of the transaminases suggests either a mass lesion or a biliary obstruction.
b. Liver imaging is obtained in all patients with history, physical findings, or laboratory values suggestive of hepatic metastases. Hepatic CT or MRI scans are the most sensitive techniques. Ultrasonography and99mTc colloid liver scans have lower diagnostic accuracy. Ultrasound may be useful in determining whether a lesion is solid or fluid. The evaluation of a single focal lesion in the liver is discussed in Chapter 9.
3. Selective hepatic angiography is the most predictive diagnostic test to assess the presence, number, and distribution of hepatic metastases but is usually unnecessary unless an embolization procedure is planned.
4. Liver biopsy should be performed to confirm the presence and type of tumor in the following circumstances:
a. There is no primary history of cancer, and the liver is the only obvious site of disease.
b. There has been a long disease-free interval (>2 years) since the removal of the primary tumor.
c. The liver abnormality is not typical of the natural history of the primary cancer. Suggestive evidence for hepatic metastases in patients with primary tumor type that does not usually metastasize to the liver indicates biopsy if the results are likely to affect therapeutic decisions.
d. Relative contraindications for liver biopsy include the following:
(1) Coagulation protein or platelet abnormalities
(2) Evidence of a vascular tumor (e.g., angiosarcoma)
5. Extrahepatic biliary obstruction. These patients must have special studies to exclude benign causes of obstruction, such as gallstones or bile duct strictures.
a. CT scan or DISIDA (diisopropyl iminodiacetic acid) scan of the liver is performed to look for parenchymal or porta hepatis masses and obstruction of the biliary tree.
b. Percutaneous transhepatic cholangiogram or retrograde contrast study of the biliary tree is performed, depending on the availability of experienced radiologists and gastroenterologists.
c. Laparotomy is indicated for both definitive diagnosis and treatment if the other studies suggest extrahepatic obstruction and if other sites of tumor are well controlled or not evident.
D. Management
1. Surgery
a. Resection of hepatic metastases has been used in highly selected patients and should be considered, especially in patients with colon cancer and metastasis only to the liver. Modern anatomic techniques have decreased surgical mortality to <6%. Overall, in properly selected patients (those with four or fewer metastases, absence of disease outside the liver, and good performance status), 20% to 40% of patients survive 5 years. Success is greater in patients with slow-growing tumors and with a disease-free interval of >1 year. Experience with hepatic resection is greatest in patients with colon cancer.
b. Extrahepatic biliary tract obstruction may be decompressed surgically if pruritus is severe. Jaundice per se is generally not an indication for surgery unless the patient must have a laparotomy for diagnosis. Biliary cirrhosis occurs only after 6 to 8 months of total obstruction, a period that exceeds the life expectancy of most patients with malignant obstructive jaundice.
(1) Percutaneous drainage through internal or external catheter placement offers reasonable palliation. Drainage is achieved in 60% to 85% of cases. This procedure has a 25% to 40% morbidity rate and a 2.5% to 5% mortality rate. The most frequent complication is cholangitis, which appears to relate to multiple sites of obstruction or inadequate drainage. Further intervention with tube manipulation, tube replacement, or surgery is required in 20% to 75% of patients. The success rate for palliation is about 80%, similar to that achieved with cholecystojejunostomy.
(2) Endoscopic placement of prostheses is another option that is successful in about 80% of patients. The difficulties of cholangitis from inadequate drainage result in a 2% to 5% mortality rate. Morbidity rates are similar to those associated with percutaneous procedures. Drainage is internal and more convenient for patients.
c. Hepatic artery ligation or hepatic dearterialization alone or in combination with perfusion produces no significant benefit.
2. RT in low doses (<2,400 cGy) is useful to palliate refractory pain from liver metastases. RT to portal masses may relieve biliary tract obstruction. External-beam therapy is best suited for patients with a good performance status, bilirubin <1.5 mg/dL, and no extrahepatic metastasis.
3. Chemotherapy
a. Oral and IV chemotherapy is useful for treating responsive tumors such as lymphomas, breast cancer, and small cell lung cancer. The primary tumor determines the selection of drugs. Dexamethasone (4 mg PO, IV, or SC twice daily) can reduce pain due to distention and inflammation of the hepatic capsule.
b. Direct perfusion of chemotherapy into the liver through hepatic artery cannulation is used by some physicians to treat isolated liver metastases when no other organs are involved. The most extensively used drugs are fluorouracil, floxuridine, and doxorubicin. Compared with systemic chemotherapy (including continuous peripheral venous infusion), hepatic artery infusion is associated with more responses, less systemic drug toxicity, significantly greater development of extrahepatic metastases, and no difference in survival. Complications of hepatic artery infusion include hospitalization for catheter placement and perfusion (if a portable pump is not used), hemorrhage, thrombosis of the perfused vessels, embolization, catheter displacement or breakage, catheter sepsis, GI bleeding, chemical hepatitis, acalculous cholecystitis, and biliary sclerosis.
4. Other options under investigation for hepatic metastases include selective chemoembolization, alcohol instillation, cryoablation, and radiofrequency ablation. Large randomized studies have not yet been conducted to determine whether these modalities affect survival.
IV. CANCER-ASSOCIATED ASCITES
A. Pathogenesis
1. Peritoneal carcinomatosis with malignant ascites but without liver metastasis is most often caused by ovarian and bladder cancer and mesothelioma. Malignant ascites in colon, gastric, and biliary tract carcinomas is usually accompanied by liver metastasis. The most common extra-abdominal malignancies to produce peritoneal carcinomatosis include breast and lung carcinomas. Except in patients with breast and ovarian cancer, it is usually a sign of the terminal phase of cancer. Malignant ascites is caused by increased production of fluid induced by the tumor, increased vessel permeability, and marked neovascularization of the peritoneum.
2. Massive liver metastasis
3. Hepatocellular carcinoma in a patient with cirrhosis is seen in patients with chronic hepatitis B, chronic hepatitis C, and alcoholic cirrhosis.
4. Chylous ascites may result from obstruction or rupture of the major abdominal lymphatic passages. It is usually caused by lymphoma.
5. Occlusion of the hepatic veins (Budd-Chiari syndrome) is seen in patients with hyperviscosity states, particularly polycythemia vera. Patients with hepatic venous obstruction have large, tender livers, and rapidly evolving ascites.
6. Peritonitis caused by Streptococcus bovis may be a presenting feature for right-sided colon carcinoma. Ascites from any cause may become infected.
B. Diagnosis
1. Differential diagnosis of ascites. Neoplastic diseases that cause ascites include liver metastases, peritoneal metastases, pseudomyxoma peritonei, and primary mesothelioma. The etiologies of ascites can be best classified by the serum–ascites albumin gradient, which is the difference between serum and ascitic fluid albumin concentration (Table 30.1). This gradient predicts the presence or absence of portal hypertension and, in parallel, the responsiveness to treatment with diuretics.
Table 30.1 Serum–Ascites Albumin Gradient
2. Paracentesis should be done in all patients with presumed malignant ascites for diagnosis and to rule out complicating infections. Ascites from carcinomatosis is usually exudative and often bloody. Ascitic fluid should be studied for the following:
a. Appearance. Clear fluid is seen in patients with cirrhosis and liver metassis; turbid/cloudy fluid is caused by the increased number of cells secondary to peritoneal carcinomatosis; milky fluid is typical for chylous ascites; pink/bloody ascites is secondary to the increased number of red blood cells in the fluid.
b. Culture for bacteria (including acid-fast bacilli) and fungi.
c. Albumin should be measured to calculate the gradient.
d. Exudates are associated with total protein values >2.5 g/dL, white blood cell count >250/μL (lymphocytosis suggests tuberculous peritonitis), and a lactate dehydrogenase level >50% of serum values.
e. Values in ascitic fluid significantly greater than in serum of amylase or triglyceride indicate a pancreatic etiology or chylous content, respectively.
f. Glucose level is often <60 mg/dL in carcinomatosis.
g. Cytology is positive in more than half of the cases of peritoneal carcinomatosis.
C. Management. With the exception of ovarian cancer–associated malignant ascites, which is treated with cytoreductive surgery and chemotherapy, management of malignant ascites is principally directed toward the palliation of symptoms.
1. Diuretics, such as furosemide and spironolactone, may be tried but are unlikely to be effective for ascites from peritoneal carcinomatosis. Diuretics may be beneficial for patients with a high albumin gradient.
2. Large-volume paracentesis is reserved for patients with symptoms of shortness of breath, anorexia, early satiety, nausea, vomiting, or pain. A 14- to 16-gauge plastic catheter or a peritoneal dialysis catheter can be used; the latter is preferred for removing a large volume of fluid. A single suture should hold the catheter in place.
a. Removal of large volumes of peritoneal fluid should not be done if a hepatic cause, such as cirrhosis or Budd-Chiari syndrome, is suspected.
b. If cancer is suspected, as much fluid as possible should be removed; nonpalpable abdominal masses may later become evident. Removal of large volumes of ascites fluid that is a result of peritoneal carcinomatosis does not usually cause dangerous fluid shifts.
3. Systemic chemotherapy is the treatment of choice for responsive tumors. The addition of bevacizumab, an antiangiogenic drug, may be especially important in women with ovarian cancer complicated by ascites.
4. Intraperitoneal chemotherapy. Instillation of chemotherapy directly into the abdomen may control some malignant effusions. The abdomen is drained to be as dry as possible, preferably using a peritoneal dialysis catheter. The chosen drug is dissolved in 100 mL of normal saline, injected into the catheter, and followed by another 100 mL of normal saline for flushing. The patient’s position is shifted every few minutes for an hour to disperse the drug. If treatment is effective, the dose may be repeated at intervals. Fever or abdominal pain or tenderness may develop after the procedure, may persist for up to 1 week, and may require paracentesis to confirm that the peritonitis is sterile.
a. Effective agents include cisplatin, paclitaxel, rituximab, mitomycin C, thiotepa, bleomycin, 5-fluorouracil, and bevacizumab. Hyperthermic intraperitoneal chemotherapy (HIPC) is sometimes used perioperatively in patients with peritoneal carcinomatosis. This method is more popular in Europe.
b. Catumaxomab is a trifunctional bispecific monoclonal antibody, binding epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3. The Fc-fragment of this antibody activates dendritic cells, macrophages, and natural killer cells. It is given intraperitoneally, and it is approved for the treatment of malignant ascites in the European Union.
c. Radioisotopes. Historically, radioactive gold was used in treatment of malignant ascites; the therapy was frequently complicated by bowel obstruction. Radioactive phosphorus may be tried, but leakage of the radioisotope through the needle tract is a major problem, and the treatment may be complicated by bowel necrosis in patients with significant intra-abdominal adhesions.
5. Peritoneovenous shunts (LeVeen and Denver) may be used to treat refractory cases if the patient has a life expectancy of >1 month and does not have significant cardiac or renal disease or disseminated intravascular coagulation (DIC). The ascitic fluid should not be hemorrhagic, infected, or loculated, and it should not contain large numbers of malignant cells. Complications of these shunts include primary fibrinolysis or clinically silent DIC (virtually 100%), sepsis (20%), pulmonary edema (15%), pulmonary emboli (10%), upper GI bleeding, fever without sepsis, superior vena cava thrombosis, pneumonia, shunt displacement, seromas around the catheter (10%), and neoplastic seeding to the superior vena cava on adjacent subcutaneous tissues. Thrombocytopenia is caused by both DIC and hemodilution. There is no evidence that shunts improve quality of life.
6. Pseudomyxoma peritonei. Mucinous adenocarcinomas, benign mucinproducing tumors, and appendiceal mucoceles can produce abundant gelatinous material that is impossible to remove by paracentesis. Recurrent bowel obstruction and progressive ascites develop. Laparotomy with removal of as much of the jelly-like substance as possible is indicated. The procedure may be repeated if there is recurrence, depending on the changing anatomy and formation of adhesions.
V. PANCREATITIS AND METASTASES TO THE PANCREAS
A. Etiology. Pancreatitis in patients with cancer is most commonly caused by the same conditions as in the general population (namely, gallstones and alcohol consumption), but hypertriglyceridemia and hypercalcemia may also contribute. Less commonly, it can be caused by malignancy itself, drugs, or iatrogenic injury.
Acute pancreatitis occurs in up to 16% of patients treated with L-asparaginase. It has been described also in patients treated with cytarabine, cisplatin, methotrexate, cyclophosphamide, doxorubicin, ifosfamide, steroids, and newer targeted agents such as sorafenib and sunitinib. Sunitinib and sorafenib cause asymptomatic elevation of lipase much more commonly than overt pancreatitis.
The list of procedures that can be complicated by pancreatitis includes ERCP and transarterial chemoembolization (TACE) of the liver. Small cell lung cancer metastasizes to the pancreas most commonly, but pancreatic metastasis of lymphoma, melanoma, and carcinomas of the breast, colon, and kidney also have been described.
Recently, chronic autoimmune pancreatitis has been identified that is associated with tissue infiltration by IgG4-positive plasma cells and increased levels of IgG4 in serum. This condition is treated with corticosteroids.
B. Diagnosis of pancreatitis depends on signs and laboratory findings. Blood work shows elevation of lipase and amylase, frequently accompanied by leukocytosis, hypo- or hyperglycemia, and hypocalcemia. CT scan of the abdomen is the best technique to demonstrate a mass in the pancreas.
C. Management. Pancreatitis complicating metastatic cancer should be treated with bowel rest, intravenous fluids, and analgesics. It is also important to remove the offending drug if only possible. Severe pancreatitis can be complicated by systemic inflammatory response syndrome (SIRS), and patients may require support with vasopressors and mechanic ventilation.
VI. ADVERSE EFFECTS OF RADIATION TO THE LIVER AND ALIMENTARY CANAL
A. Radiation-induced liver injury (RILD). The liver is not able to tolerate high doses of radiation. About 5% of patients treated with the whole-liver doses of 30 to 35 cGy develop RILD. Therefore, RT has a limited function in the treatment of hepatic metastasis. Acute hepatitis from radiation can be mild to severe and may result in cirrhosis.
1. Manifestations. Signs and symptoms become evident 2 weeks to 3 months after irradiation. Patients present with anicteric hepatomegaly, ascites, and elevation of liver enzymes. Alkaline phosphatase is usually elevated more than transaminases. Decreased uptake of 99mTc in the treatment portal is observed on liver scan. Liver biopsy demonstrates endophlebitis with thickening and obstruction of central veins and mild cellular necrosis or atrophy, findings similar to those seen with veno-occlusive disease (VOD) induced by chemotherapy.
2. Management is symptomatic. Corticosteroids and diuretics may help.
B. Radiation esophagitis
1. Acute esophagitis usually occurs within 2 to 3 weeks from the initiation of RT and presents with dysphagia, odynophagia, and mediastinal discomfort. Concomitant administration of chemotherapy increases the risk of esophagitis. These patients are treated with viscous lidocaine solution, analgesics (opioids, NSAIDs), proton-pump inhibitors, and promotility agents (metoclopramide). When symptoms occur, patients are advised to eat small, frequent, bland meals; the food frequently must be pureed. Occasionally, nutritional supplementation may be required through a gastrostomy tube.
2. Esophageal stricture is a rare late complication that is more common when chemotherapy, particularly doxorubicin or methotrexate, is given concomitantly. Endoscopy may be needed to distinguish stricture from cancer recurrence. Dilation is performed in patients with symptoms. Anti acids and promotility agents are usually prescribed to decrease the risk of restenosis.
C. Radiation gastritis
1. Acute radiation gastritis. Symptoms can begin as early as 24 hours after starting the treatment. It usually presents with anorexia, nausea, vomiting, and abdominal pain. Occasionally, it can be complicated by development of a gastric ulcer.
2. Late radiation gastritis presents as chronic atrophic gastritis, dyspepsia, or ulcerative gastritis. These patients are treated with proton-pump inhibitors, H2 blockers, or sucralfate.
D. Radiation enteritis
1. Acute radiation enteritis
a. Manifestations are usually related to the volume of the bowel irradiated and to the daily dose. Most injuries involve the terminal ileum. Patients treated with concomitant chemotherapy (oxaliplatin, irinotecan) or EGFR-blocking antibodies (cetuximab, panitumumab) are at higher risk for radiation enteritis.
(1) Nausea, vomiting, and anorexia usually do not persist >3 days after RT is stopped.
(2) Diarrhea is more severe in patients who have had laparotomies and have developed adhesions. Symptoms can occur after the second week of RT and usually disappear within 2 weeks after its completion.
b. Management
(1) Antiemetics are given regularly throughout the day for patients with persistent vomiting. If symptoms are severe, parenteral hyperalimentation and reduction of the daily dose of radiation may be necessary. The serotonin antagonists are excellent agents for the treatment of radiation-induced nausea and vomiting.
(2) Diarrhea is managed by eliminating alcoholic beverages, roughage, and milk products from the diet. Paregoric (tincture of opium), cholestyramine, or diphenoxylate–atropine (Lomotil) may be useful.
2. Chronic radiation enteritis. Abdominal pain syndromes, malabsorption, bowel strictures, hemorrhage, perforations, and fistulas usually occur with doses to the abdomen of >4,500 cGy and are more frequent in the presence of postsurgical adhesions. Symptoms may develop months to many years after completion of therapy. Parenteral hyperalimentation may be necessary while the bowel abnormality is being corrected.
a. Abdominal pain syndromes are treated with analgesics, bulk laxatives, and dietary modifications.
b. Perforations and fistulas indicate a poorer prognosis than strictures and hemorrhage; malignancy recurs in 70% of these patients.
c. Bowel obstruction. Tube decompression may lead to resolution. Laparotomy should be avoided if possible. If the obstruction progresses, intestinal bypass (10% mortality rate) rather than bowel resection should be performed in the absence of gangrenous bowel (75% mortality rate).
d. Chronic diarrhea with malabsorption is rare and is treated symptomatically. Anorexia, nausea, and vomiting may occur. Medium-chain triglycerides may be of help to decrease stool fat loss and to relieve radiation-induced intestinal lymphangiectasia with protein loss. Steatorrhea may result from bacterial overgrowth; tetracycline, 250 mg given four times daily, may be tried for 10 to 14 days on an empiric basis. Prednisone and sulfasalazine may also be used.
E. Radiation proctitis is most commonly seen as a complication of the treatment of prostate cancer, but it can also occur in patients with anal, rectal, cervical, uterine, urinary bladder, and testicular cancers.
1. Acute transient proctitis
a. Manifestations. Tenesmus, diarrhea, and, occasionally, minor bleeding develop. Symptoms usually resolve soon after RT is completed.
b. Management is usually not indicated. If symptoms are prolonged or severe, steroid enemas and suppositories, stool softeners, mineral oil, low-residue diet, paregoric, diphenoxylate–atropine, rectal sucralfate, hyperbaric oxygen, and metronidazole may be helpful.
2. Late radiation proctitis usually occurs 6 months to 2 years after RT, but occasionally it can develop many years after treatment.
a. Manifestations. Symptoms include tenesmus, diarrhea, and hematochezia. Proctoscopic examination reveals hemorrhagic, edematous mucosa with decreased pliability, and, occasionally, ulcers.
b. Management
(1) For severe inflammation, treat as described for acute proctitis.
(2) For rectal ulcers refractory to conservative management, surgery is advised.
(3) For late rectal narrowing, treat with dilation and stool softeners.
VII. HEPATIC SINUSOIDAL OBSTRUCTION SYNDROME (SOS)
SOS was previously known as veno-occlusive disease. Hepatic SOS is a nonthrombotic obliterative process of the central or sublobular hepatic veins characterized by rapid onset of hyperbilirubinemia, ascites, and painful hepatomegaly, and by varied clinical outcome.
A. Causes
1. The hepatotoxic pyrrolizidine alkaloids that occur naturally in plants (other implicated dietary contaminants include aflatoxin and nitrosamines) are the most common cause worldwide. Chemotherapy and irradiation, especially in patients who have had bone marrow, liver, or kidney transplantation and graft versus host disease, are important causes in the Western world.
2. Virtually any high-dose chemotherapeutic regimen can cause hepatic SOS. Azathioprine, 6-mercaptopurine (a metabolite of azathioprine), 6-thioguanine (a compound related to 6-mercaptopurine), and dacarbazine have been implicated as causes of hepatic vascular damage.
3. Other causes include postnecrotic cirrhosis, metastatic or primary hepatic malignancy, myeloproliferative disorders (particularly polycythemia vera), and a variety of other hypercoagulable states.
B. Diagnosis. The diagnosis of hepatic SOS is suggested by a typical clinical picture in a patient with risk factors. The reversal of flow in the portal vein by Doppler ultrasound is frequently seen. Liver biopsy can be helpful in establishing the diagnosis but is performed rarely. The transvenous approach is useful for patients with thrombocytopenia.
C. Management
1. Supportive care is indicated because most patients recover (70%). Management of fluid balance and diuretics are useful. In those with severe SOS, modalities such as dialysis and mechanical ventilation have little impact on outcome and the continued use of these modalities will have to be discussed based on the overall prognosis of the patient.
2. Defibrotide is a polydeoxyribonucleotide characterized by antithrombotic, fibrinolytic, and angiogenic activity. The study of defibrotide in patients with severe SOS after hematopoietic stem cell transplantation showed resolution of symptoms in 24% of patients at 100 days. Historically, resolution was seen only in 9% of patients. Defibrotide is awaiting FDA approval.
3. Thrombolytic therapy with tissue plasminogen activator (tPA). The use of tPA/heparin may have some efficacy but the benefit must be balanced against the significant risk of bleeding. The dose of tPA is 20 mg on 4 consecutive days along with heparin at 150 U/kg/d.
4. Liver transplant for severe SOS has been tried in patients where the underlying disease has a good chance of being cured with cytoreductive therapy.
5. Other surgical procedures, such as peritoneovenous or intrahepatic shunts, have had variable outcomes with SOS.
6. Ursodeoxycholic acid in divided doses of 600 to 900 mg a day is used in some transplant centers as SOS prophylaxis.
VIII. PARANEOPLASTIC GI TRACT SYNDROMES
The cause of paraneoplastic gastrointestinal tract syndromes is not known.
A. Esophageal achalasia may accompany gastric cancer and is reversible when the cancer is resected. Patients present with dysphagia for all foods and liquids.
1. Diagnosis. The barium esophagogram reveals a large, aperistaltic esophagus. Esophageal manometry shows weak contractions with a hypertensive lower esophageal sphincter.
2. Therapy. Patients with achalasia and unresectable cancer must have gastrostomy, an esophageal tube (e.g., Celestin tube), or forced pneumatic dilation.
B. Intestinal pseudo-obstruction occurs in patients with peritoneal carcinomatosis in the absence of mechanical obstruction. Signs of obstruction are cramping abdominal pain, absence of stools, nausea, vomiting, hyperactive bowel sounds, and nonlocalized air–fluid levels on abdominal plain films.
1. Diagnosis. Pseudo-obstruction and mechanical obstruction are clinically indistinguishable. Pseudo-obstruction, however, often remits spontaneously. Hypokalemia, hypomagnesemia, fecal impaction, history of vincristine use, and other causes of ileus should be sought.
2. Therapy is the same as for suspected bowel obstruction (see Section II).
IX. SYMPTOM CARE FOR ALIMENTARY CANAL PROBLEMS IS DISCUSSED IN CHAPTER 5
A. Oral problems, including stomatitis, xerostomia, abnormal taste, halitosis, caked material in the mouth, and dysphagia (see Chapter 5, Section II)
B. Nausea and vomiting (see Chapter 5, Section III)
C. Colorectal symptoms, including constipation and rectal discharge (see Chapter 5, Section IV)
D. Anorexia, including hyperalimentation (see Chapter 5, Section XII)
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