cancercomps

Pleural effusions are caused principally by malignancy, and infection. Pets commonly present with the symptoms of cough, dyspnea, decreased exercise tolerance, and chest pain. While larger effusions may be detected on physical examination, chest radiographs or ultrasound of the chest may detect effusions as small as 100 mls. A diagnostic thoracentesis should be performed early in the course of investigation. In markedly symptomatic pets, removal of pleural fluid can provide immediate, albeit temporary, relief; generally 250-500 mls or more must be removed to improve symptoms. Pleural fluid analysis should include protein, pH determinations, cell counts, cytology, and cultures for bacteria, fungi, and mycobacteria. At least 50 milliliters of pleural fluid is necessary for adequate cytologic examination.

Pleural effusions are classified as transudative or exudative. Most often, transudative effusions are caused by congestive heart failure, cirrhosis, nephrotic syndrome, or occasionally by lymphatic blockade produced by cancer. Exudative effusions are caused by infection or malignancy. In the absence of infection, an exudative pleural effusion, especially if it is bloody, strongly suggests a malignant etiology. The cancer very likely causes an exudative pleural effusion in a pet with a current or past cancer. Effusions due to lymphoma or mediastinal involvement by any tumor may be chylous and cytologically negative. About half of effusions ultimately diagnosed as malignant will have a positive cytology from the initial thoracentesis.

Diagnostic Approach

Two different approaches can be used to attempt to diagnose the etiology of pleural effusions if the initial cytologic examination does not show malignant cells. Repeat thoracentesis and pleural biopsy will confirm malignancy in 80% to 90% of malignant effusions. The pleural biopsy has a higher complication rate but a higher yield than thoracentesis. Despite thoracentesis and pleural biopsy, 10%-20% of pets with malignant pleural effusions will still not have a diagnosis.

In such pets, thoracoscopy or thoracotomy will be needed for diagnosis.

Although thoracoscopic biopsy requires local or general anesthesia, it increases the diagnostic yield greatly compared to thoracentesis.

The alternative diagnostic approach to pets with pleural effusions whose initial cytologic examination does not show malignant cells is to go directly to thoracoscopy or thoracotomy with biopsy of visually identified abnormal areas of the pleura. The diagnostic yield of a malignancy using this approach exceeds 90% if the effusion is caused by cancer.

Treatment Considerations

Once the diagnosis of malignant pleural effusion has been made, treatment depends on the tumor type and prior, if any, antineoplastic therapy.

About 25% of effusions do not require immediate therapy; the effusions are small and stable. Malignant effusions caused by lymphomas may respond to systemic chemotherapy. Repeated percutaneous draining of effusions may lead to tumor growth along the needle track and through the chest wall. Pets who have received extensive prior systemic therapy and those with chemotherapy-resistant tumors are not likely to respond to systemic therapy. Palliative approaches to the management of malignant pleural effusions are necessary in such pets.

Pets with symptomatic malignant pleural effusions whose underlying cancer is unlikely to respond to systemic treatment should have their pleural fluid drained. Pets with relatively large (>1,000 mls) recurrent effusions whose symptoms resolve with drainage and whose lung can fully expand are candidates for palliation. Two general approaches to the palliative management of symptomatic pleural effusions are chest tube drainage with installation of a sclerosing agent and thoracoscopic drainage of the pleural effusion under local or general anesthesia with intraoperative sclerosis of the pleural space.

Historically, many chemical agents have been instilled into the pleural space and shown to have some effectiveness in controlling effusions, including tetracycline, doxycycline, minocycline, bleomycin, cisplatin, doxorubicin, mitoxantrone, interferon, Corynebacterium parvum, methylprednisolone, and talc.

Chest tube drainage should be done by inserting the chest tube into the pleural cavity and draining the fluid. When the drainage reaches less than 50-100 milliliters in a 24-hour period, a sclerosing agent can be instilled.

Information on the recommended sclerosing agent is currently inconclusive. Small numbers and relatively short follow-up plague the few randomized studies on this topic. Some comparative studies suggest advantages for talc as the sclerosing agent compared to tetracycline and others.

In humans with breast cancer, thoracoscopy and insufflation of talc controlled the pleural effusions in twice as many patients as tetracycline (>90% versus 50%, respectively).

Another approach that is appropriate for pets with a symptomatic malignant pleural effusion and good performance status who are capable of undergoing a procedure under local, regional, or general anesthesia is to perform thoracoscopy with biopsy of suspicious pleural lesions, lyse any adhesions, evaluate to see if the lung re-expands, and instill the sclerosing agent during the same procedure.

This potentially shortens the hospitalization because the whole procedure can be done in the operating room in a single day.

Since tetracycline is no longer available and similar efficacy has been shown for doxycycline, doxycycline has been substituted for tetracycline in human clinical trials.

Pleural stripping (pleurectomy) via thoracotomy or thoracoscopy is nearly 100% effective in controlling malignant pleural effusions, but the morbidity is so severe that this procedure is rarely used in veterinary medicine.

Prognosis

The prognosis for dogs and cats with malignant pleural effusions is poor (median survival time with treatment about 6 months) and in those with chemotherapy-resistant tumors that are not likely to respond to systemic therapy, the prognosis is grim.

ONCOLOGY EMERGENCIES

Cancer itself can present as an emergency. Internal blood loss from a ruptured abdominal mass or a pericardial effusion due to a bleeding heart based tumor may present as shock. General and emergency veterinarians who are able to recognize these signs early and institute appropriate shock therapy can give these patients and their owners time, a tissue diagnosis and treatment options for extended quality time. Other examples of oncologic emergencies include metabolic derangements (hypercalcemia, hypoglycemia and hyponatremia).

The treatment of cancer can also lead to many unique yet predictable complications. The administrations of many chemotherapeutic agents are associated with known side effects. Many of these agents are irritating to tissues and extravasations can and will occur even to the most experienced oncologist. Some agents are associated with hypersensitivity reactions and even anaphylaxis. Many side effects are predictable. Bone marrow suppression and gastrointestinal disturbances are just some common complications of these agents.

Metabolic Complications

Hypercalcemia is the most common metabolic disturbance associated with neoplasia. Most commonly the result of parathyroid-related peptides produced by some tumors, hypercalcemia is usually caused by lymphoma. Other tumors frequently implicated include anal sac adenocarcinoma, mammary adenocarcinoma and primary hyperparathyroidism.

Emergency care for the hypercalcemic patient involves a diuresis with 0.9% NaCl for enhanced calciuresis. Furosemide (2-4 mg/kg BID) will also enhance calcium elimination. Other drugs used to treat hypercalcemia include intravenous biphosphonates (etridronate, disodium palmidroate), gallium nitrate, mithramycin, and salmon calcitonin. Corticosteroids prevent bone reabsorption, intestinal absorption and increase urinary calcium excretion. However, because of their rapid antitumor effects, corticosteroid use should be withheld until a tissue diagnosis is made. Identification and treatment of the primary disease becomes the highest priority. Lymph node aspiration/biopsy, chest radiographs, abdominal ultrasound and bone marrow evaluation should follow physical examination including lymph node palpation and perianal examination. Every effort should be made to rule out lymphoma and anal sac adenocarcinoma.

Hypoglycemia associated with neoplasia may be the result of an insulin-secreting tumor, the result of destruction of normal gluconeogenic tissues or glucose consumption associated with such systemic complications as bacterial sepsis. The most common tumors associated with hypoglycemia are insulinoma, hepatoma and carcinoma. Insulinomas are diagnosed by demonstrating inappropriately high levels of insulin in the face of hypoglycemia. Animals showing clinical signs of hypoglycemia (stupor, coma, seizures) can be treated with parenteral dextrose and dextrose containing fluids. Prednisone (0.5-2 mg/kg divided BID) will increase hepatic gluconeogenesis and antagonize the effects of insulin on peripheral tissues. Diazoxide (10-40 mg/kg divided BID) can directly inhibit insulin secretion and may be useful in the medical management of insulin secreting tumors. Surgical excision and medical management of metastatic lesions can lead to the temporary resolution of clinical disease.

Shock

Animals with large intraabdominal tumors may appear normal to the owner until such time that these vascular tumors rupture and lead to acute blood loss, collapse and hypovolemic shock. Acute collapse can also be seen with pericardial tamponade secondary to vascular tumors on the heart or at the heart base. Both cases will present with cool extremities, a rapid heart rate, decreased mentation and hypotension. It is important to differentiate pericardial tamponade from hypovolemia as aggressive fluid therapy may actually worsen the patient’s condition. Jugular pulsation, elevated central venous pressure (distension of the lateral saphenous vein when held above the heart), decreased amplitude electrocardiogram and a rounded cardiac silhouette are often seen with tamponade. Tamponade is best treated immediately with pericardiocentesis. Internal blood loss from a ruptured vascular tumor should be treated with shock doses of crystalloid fluids. Frequent rechecks of heart rate, blood pressure and packed cell volume are mandatory. If the packed cell volume drops precipitously, whole blood, packed red blood cells or cell free hemoglobin should be used to improve blood oxygen content. Patients should be carefully evaluated to identify the source of the hemorrhage. When a patient's condition allows, radiographs of the chest and abdomen will help stage the disease and provide the veterinarian and owner with more information on the extent of the disease. Exploratory surgery will be necessary to remove the source of blood loss and fully evaluate the extent of the disease. The acute nature of these cases requires compassion and understanding from the veterinarian. The diagnosis of "cancer" when the only finding is an intraabdominal mass can be overwhelming for owners. Clients need to be informed and given every option. Surgical exploration and biopsy are the only ways to definitively diagnose and treat these cancers. Sepsis and septic shock are not uncommon in cancer patients. Sepsis can be the result of the disease itself or a complication of treatment. Intestinal neoplasia can lead to bacterial translocation and even rupture of a hollow viscus. These animals will present with signs of acute abdominal distress and evidence of peritonitis on plain radiographs (free air, decreased abdominal detail). The diagnosis can be confirmed with a diagnostic peritoneal lavage. Animals with diffuse intestinal neoplasia may have a more chronic course of weight loss, panhypoproteinemia and non-specific gastrointestinal symptoms that may lead to weakened immunity and septic complications. Septic shock is characterized by fever or hypothermia, leukocytosis or leukopenia and hypotension associated with the systemic release of local inflammatory mediators. Emergency management of these cases centers around the quick identification and removal of the septic focus, appropriate antibiotic therapy, and cardiovascular support with fluids, colloids, and if necessary, positive inotropes.

Extravasation

Some of the more common chemotherapeutic agents used in veterinary medicine can cause significant tissue injury when they extravasate into perivascular tissues. Some of the more serious compounds include the vinca alkaloids (vincristine and Vinblastine) and doxorubicin. Other agents causing some tissue damage include mithramycin, mitoxantrone and cisplatin. Every effort should be made to prevent extravasation. Veins used for chemotherapy should not be used for blood sampling. Multiple attempts to catheterize one vein or recent venipunctures make it unsuitable for administration of any cytotoxic drugs. A careful "first-stick" approach using a small (22-23 g) catheter should be used to administer large volumes of drugs like cisplatin and doxorubicin. Small volumes (less than 1cc) can be given through a small (23-25 g) butterfly catheter. Saline should be flushed before and after administration of the chemotherapeutic to assess catheter placement and insure vessel integrity. The earliest sign of extravasation is pain. Animals will become extremely agitated, even to the point of self-trauma as these vesicants leak into surrounding tissues. Erythema may develop quickly or over several days ultimately resulting in tissue necrosis and open draining wounds. When extravasation is suspected, do not remove the catheter. Instead, use the catheter to remove as much drug as possible.

Apply WARM compresses to enhance systemic absorption. Then apply COLD compresses to affected area for up to 10 hours to inhibit cytotoxicity.

Keep in mind that even with the use of good first aid, intense wound management may be required.

Anaphylaxis

Allergic complications are uncommon side effects of chemotherapy. Reactions range from potentially lethal anaphylaxis to mild delayed type hypersensitivity reactions. Serious anaphylaxis has been associated with L-asparaginase. Because L-asparaginase associated anaphylaxis usually occurs within minutes, it is advisable to observe the patients for no less than 30 minutes after administration. Giving the drug by intramuscular injection can minimize the risk of anaphylaxis. Intravenous and intraperitoneal administration is associated with higher incidence of anaphylactic reactions. Anaphylaxis causes acute collapse and hypotension. Emergency management of these patients involves quick shock therapy. Intravenous access and shock volumes of crystalloid fluids (up to 90 ml/kg/hour) are given along with 0.1- 0.3 ml of a 1:1000 dilution of epinephrine given IV or IM. Delayed type hypersensitivity can be seen with any drug but has been most commonly associated with doxorubicin, etoposide and paclitaxel. These reactions typically result in erythema and swelling of the ears, face and paw. Delayed hypersensitivity reactions can be minimized by diluting drugs such as doxorubicin with 250-500 ml of 0.9% NaCl and administering slowly over 30 minutes. Hypersensitivity reactions can be treated with rapid acting corticosteroids (Dexamethasone sodium phosphate (2 mg/kg IV) and an antihistamine (Diphenhydramine 2-4 mg/kg IM).

Acute Tumor Lysis Syndrome

Acute (hours to days) collapse and even death can be seen with the treatment of extremely chemosensitive tumors. The destruction of large tumor volumes can lead to massive release of inflammatory cellular debris. The resulting inflammatory cascade can mimic sepsis and septic shock, and can best be described as a systemic inflammatory response. Electrolyte disturbances caused by the release of intracellular potassium and phosphorous also contribute to cardiovascular problems. Tumors most frequently associated with acute lysis include lymphoma and leukemia. Fast recognition of tumor lysis with appropriate cardiovascular support is required if the patient is to survive. Bradycardia in the face of shock should alert the clinician to possible hyperkalemia. Hypocalcemia may result from high phosphorous levels and can result in impaired cardiac conduction and reduced cardiac output. Aggressive fluid resuscitation, normalization of electrolytes and support of cardiac output and vascular tone are necessary to see the patient through the crisis.

Neutropenia

Bone marrow suppression is an expected complication of many chemotherapeutic protocols. In addition, diseases like leukemia and lymphoma can invade the bone marrow causing primary granulopoiesis and even pancytopenia. Drugs that are highly myelotoxic include doxorubicin, cyclophosphamide, cisplatin and carboplatin. Doxorubicin and cyclophosphamide usually cause myelosuppression in 7-10 days. Recognizing the neutrophil nadir and taking steps to prevent bacterial colonization should help prevent serious complications. Patients should be closely monitored during this period. Changes in appetite, attitude, body temperature, mucous membrane color and pulse quality warrant closer examination. Every effort should be made to prevent bacterial colonization during periods of neutropenia. Signs of bacterial colonization will also be affected by neutropenia. Bacterial colonization of lungs and bladder can result in infection without suppurative inflammation. Culture of urine, blood and bronchial fluid can result in the identification of causative organisms without cellular evidence of inflammation. Treatment of neutropenia and septic complications is directed at maintaining perfusion through the use of crystalloid and colloid solutions, and antibiotic therapy with bactericidal drugs effective against likely organisms. Recombinant human granulocyte-colony stimulating factor (5 ug/kg/day SQ) can be administered to neutropenic patients to decrease the duration and severity of chemotherapy induced neutropenia.

Gastrointestinal Ulceration

Upper GI inflammation can be managed with antacids and GI protectants. Symptoms of inflammatory colitis can be managed with sulfasalazine 10-30 mg/kg TID. Many chemotherapeutics stimulate the chemoreceptor trigger zone to cause a central nausea. Secondarily, the primary disease can cause stimulation to the gastrointestinal tract and peritoneal cavity resulting in nausea and vomiting. Early antiemetic therapy should be considered in anorectic nauseous patients. Chemotherapy induced emesis is mediated by 5-HT3 -serotonergic receptors. Antiemetic drugs, which antagonize this receptor, seem work the best. Metoclopramide (1- 2 mg/kg/day) has some partial 5-HT3-antagonist properties and can be given by continuous infusion. Specific 5-HT3 receptor antagonists such as ondansetron (0.5 - 1.0 mg/kg) though expensive, work even better.

Diarrhea

Simplified, diarrhea is the result of increased fecal water. A number of different pathophysiologic mechanisms can account for increased fecal water. Acute diarrhea is most often caused by malabsorption (osmotic diarrhea), abnormal fluid secretion (secretory or inflammatory diarrhea), and altered intestinal motility. Mucosal or submucosal diseases that impair absorption in either the small or large bowel result in malabsorptive diarrhea. Impaired absorption of dietary substances interferes with water resorption by altering osmotic gradients. Mucosal diseases also may directly impair sodium resorption, in effect inhibiting water resorption resulting in diarrhea. Enhanced intestinal secretion of water and electrolytes can be induced by several stimuli, most notably bacterial enterotoxins. Bile acids and dietary fatty acids also incite intestinal secretion, as does intestinal obstruction. Damage to the intestinal mucosa can result in transudation of water and electrolytes. If the injury is severe, plasma proteins and blood may also be lost. It is unclear whether there is a diarrhea that is caused specifically and only by abnormal motor function. Most diarrheal diseases that have been studied have been shown to alter intestinal fluid and electrolyte transport as well as smooth muscle function. Intestinal motility, most notably segmental contractions, is reduced in most diarrheic conditions. Decreased segmental contractions result in transport of ingesta at a rate too fast for digestive and absorptive processes to occur. Diarrhea may result from one pathophysiologic mechanism, however, in most patients with diarrhea, more than one pathophysiologic mechanism is probably simultaneously operative.

Mild diarrhea causes few metabolic consequences, however, moderate or severe diarrhea may lead to profound hydration, electrolyte and acid-base disturbances. Diarrhea most often results in loss of fluids isotonic to plasma. Loss of isotonic fluid decreases circulating plasma volume, and if severe, precipitates hypovolemic shock. The major solutes lost with diarrhea are sodium, chloride, and potassium. Initially, serum electrolyte concentrations remain normal because isotonic fluids are lost. Hypokalemia is the most common electrolyte disturbance. Renal loss secondary to aldosterone released in response to fluid volume depletion is the most important source of potassium loss. Significant losses of potassium may also occur through the feces if the diarrhea is severe or protracted. Metabolic acidosis may develop secondary to loss of intestinal bicarbonate and the production of lactic acid by anaerobic metabolism in response to hypovolemia.

As with any medical problem, treatment for acute diarrhea is best based on knowledge of the cause. In many cases, however, the cause of acute diarrhea is not ascertained because of the anticipated brevity of the diarrhea, financial constraints of the owners or the elusive nature of the disease process. As a result, symptomatic therapy of diarrhea is often utilized. Symptomatic therapy is also of importance in the adjunctive supportive therapy in patients with acute diarrhea in which the primary cause is known. The routine use of nonspecific antidiarrheal drugs in all patients with acute diarrhea is unnecessary and in many situations these agents are contraindicated.

Opiates stimulate segmental contractions and decrease peristalsis. The net effect is prolonged intestinal transit that allows additional time for fluid and electrolyte absorption. Opiates actions are attributed to direct effect on intestinal smooth muscle. Additional antidiarrheal effects are attributable to stimulation of absorption, and inhibition of secretion, of fluid and electrolytes. The two most common opiates used are loperamide (0.1 mg/kg PO q8h) and diphenoxylate hydrochloride (0.1 mg/kg PO q8h). Although structurally similar, loperamide appears to be more potent, have a more rapid onset of action, a longer duration of effect. These properties may be attributable to loperamides prostaglandin synthetase inhibiting, calmodulin antagonizing, and calcium channel blocking actions. Side effects of these two drugs are most often noted when inappropriate dosages are used and include depression, vomiting, and excessive salivation. Opiates should not be used to treat acute diarrhea in which a bacterial cause is suspected. Increasing intestinal transit time prolongs residence time of the bacteria, allowing further proliferation of the organism, mucosal invasion, and the absorption of toxins. If diarrhea is not controlled within 48-72 hours, opiates should be discontinued.

Bismuth subsalicylate (0.5-1 ml/kg q6-8h PO) appears to be an effective agent for the treatment of enterotoxigenic diarrhea. The salicylate moiety is felt to decrease intestinal secretion by interfering with prostaglandin production and by a more direct, but undetermined, effect on the enterotoxin. In addition, this drug appears to be antiinflammatory, possess some bactericidal activity, and may bind enterotoxin. Salicylate intoxication can result from overdosage, particularly in cats. It is a useful and practical therapy for acute nonspecific diarrhea. Silicates, such as kaolin, may bind enterotoxins but have no proven efficacy for the treatment of diarrhea.

Anticholinergics inhibit Cl^- and water secretion by crypt epithelial cells and stimulate Na⁺, Cl^-, and water absorption by villus epithelial cells by antagonizing muscarinic (M₁ and M₂) cholinergic receptors. Unfortunately, available muscarinic antagonists are non-selective and also inhibit smooth muscle contraction, causing a major reduction in resistance to flow in the intestinal tract. For this reason, the effectiveness of these drugs is questionable and their use can precipitate ileus by further reducing intestinal motility in an animal with diarrhea whose intestine is already hypomotile.

Other drugs that might be of benefit in the treatment of severe, unexplained acute diarrhea would include 5-HT₃ antagonists (ondansetron or granisetron 0.5-1.0 mg/kg q12h PO), a₂-adrenergic antagonists (clonidine 5-10 mg/kg q8-12h SC, PO), calmodulin antagonists (chlorpromazine 0.2-0.4 mg/kg q8h SC, IM or prochlorperazine 0.25-0.5 mg/kg q8h PO, SC, IM) and calcium channel blockers (verapamil or diltiazem 0.5-1.0 mg/kg PO). Because of limited clinical experience with the use of these drugs and their potential side effects, these drugs should be used with caution.

Complications in pets with cancers.

MALIGNANT EFFUSIONS