infectious - National Institutes of Health

COMMON EMERGENCIES IN CANCER MEDICINE: INFECTIOUS AND TREATMENT-RELATED SYNDROMES, PART II Charles R. Thomas, Jr, MD, Keith J. Steizer, MD, PhD, James G. Douglas, MD, Wui-jin Koh, MD, Lauren V. Wood, MD, and Ritwick Panicker, MD Seattle, Washington and Bethesda, Maryland

This article completes a summary of the common medical emergencies that can occur as a result of infectious processes (Part I) and antitumor treatment secondary to chemotherapy, biological response modifiers, or radiotherapy (Part 11). The use of high-dose cytotoxic agents, coupled with the common instillation of indwelling central venous access devices, have altered the spectrum of infectious etiologies that are appreciated in clinical practice. In addition, a myriad of cytotoxic agents and radiotherapeutic treatment schemes are used widely in clinical oncologic practice. While most of their related side effects are not considered life-threatening emergencies, they can be fatal if not recognized early and treated promptly. Moreover, some of these infectious and treatment-related sequelae can be prevented. This article highlights some of these clinical observations. (J Nati Med Assoc. 1 994;86:839-852.) Key words * cancer * cancer treatment * infectious complications * emergencies * radiation From the Division of Oncology and the Departments of Medicine and Radiation Oncology, University of Washington School of Medicine, Seattle, Washington; and the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland. Requests for reprints should be addressed to Dr Charles R. Thomas, Jr, Dept of Radiation Oncology, RC-08, University of Washington Medical Ctr, 1959 NE Pacific St, Seattle, WA 98195. JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

SELECTED SYSTEMIC THERAPY COMPLICATIONS Antifolates Methotrexate. This commonly used antifolate has a well-described history of multiorgan toxicities, mainly hematologic, hepatic, and marrow-related.'"3 While the latter two are most common, life-threatening neurological toxicity may occur with intrathecal methotrexate administration. An acute chemical arachnoiditis and a chronic demyelinating encephalopathic syndrome have been documented in children receiving intrathecal methotrexate.3 Inadvertent intrathecal overdose of methotrexate can lead to fatal necrotizing leukoencephalopathy.4 Emergency interventions include: immediate lumbar puncture and cerebrospinal fluid drainage, emergency ventriculostomy placement followed by ventriculolumbar perfusion, administration of high-dose dexamethasone, and the administration of intravenous folinic acid (50 mg every 6 hours) to prevent systemic methotrexate toxicity.5 Carboxypeptidase-G2 is an enzyme that hydrolyzes the C-terminal glutamate residue of methotrexate, thereby inactivating the latter. Primate studies have suggested that intrathecal methotrexate levels can be rapidly decreased following intrathecal instillation of this enzyme.6 High-dose methotrexate (>1 g/m2) can lead to serious nephrotoxicity and chemical hepatitis.2'3 The former may be prevented by routinely administering pretreatment hydration and sodium bicarbonate to maintain a urinary pH of >7 and an adequate urine

output.7 Patients with ascites, pleural effusions, and pericardial effusions may have methotrexate levels build-up 839

CANCER EMERGENCIES: INFECTIOUS & TREATMENT-RELATED

in third-space extravascular fluid compartments, thereby being retained for prolonged periods of time.

Edatrexate. Edatrexate, or 10-EDAM (10-ethyl-10deaza-aminopterin), is a methotrexate analog that competes for the folate-binding site of the enzyme dihydrofolate reductase.8 Edatrexate has not been administered intrathecally, but potentially would be more potent because of its enhanced polyglutamation within neoplastic cells compared to methotrexate.9 Folinic acid may also be useful in moderating severe toxicity to normal tissues. 0

Platinum Analogs Cisplatin. Cisplatin is used widely in chemotherapeutic regimens for a variety of solid tumors, most commonly for testicular, head and neck, ovarian, and lung cancers. It is imperative that potential toxicities are recognized early in order for this agent to be used successfully and safely. Nephrotoxicity is the doselimiting toxicity of cisplatin. Acute renal failure can result from its use, although it is to be mediated by several pathophysiological mechanisms.' 112 Compromise in renal function is initiated by an acute proximal tubular insult, followed by vasoconstriction of the renal vasculature. A reduced glomerular filtration rate ensues and can quickly lead to reduction in the resorptive capacities of both the proximal (pars recta) and distal tubules.'3 The resulting increase in vascular resistance may lead to azotemia, which may be reversible. This clinical syndrome can be prevented by vigorous intravenous hydration with normal saline both before and after administration of cisplatin.'3 Mannitol (12.5 g to 25 g) and furosemide will facilitate an osmotic diuresis and minimize the chance for toxic insults to the collecting tubules to occur. We have found that by diluting cisplatin in hypertonic (3%) normal saline, the incidence of clinically relevant nephrotoxicity is minimized further.14 Glycine has been shown to prevent acute renal failure in a rat model.'5 The possible mechanism of action could involve protection against hypoxic cell injury to proximal tubules. Life-threatening cation losses also can occur. Hypomagnesemia results from a defect in the thick ascending loop of Henle.'2 Persistent hypomagnesemia, lasting for several months after the last cisplatin dose, has been observed.'6 Magnesium replacement, in the form of intramuscular or intravenous magnesium sulfate, should be administered if early decreases in this cation are noted postplatinum therapy. Hypokalemia has been noted with high-dose cisplatin therapy. The decreased proximal tubule potassium resorption may lead to an 840

"overload" at the distal tubules. 12"17 Increased potassium loss from the kidney can be further aggravated by vomiting, a particularly frequent side effect of this class of antineoplastics. Potassium supplementation in posthydration intravenous fluids (10 to 20 mEq/L) is recommended strongly. Hyponatremia is observed with high-dose platinum administration and is very seldom life threatening. However, pronounced hyponatremia resulting from renal tubular wasting of sodium has been observed. I8 Neurotoxicity and ototoxicity are well documented but usually do not present as frank emergencies. Rarely, an acute demyelinating syndrome may develop, presenting with focal neurological signs.'9 Concomitant use of radiotherapy and etoposide with cisplatin occasionally has produced self-limiting Lhermitte syndrome, and seizures have been noted rarely.20 Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure have been reported as a consequence of cisplatin therapy. One report noted that while plasma exchange was ineffective, plasma perfusion with staphylococcal protein A produced a dramatic and permanent response in one patient.2' Carboplatin and ipraplatinum are analogs that have been developed with hopes of overcoming some of the aforementioned toxicities of cisplatin, mainly the dose-cumulative nephrotoxicity and ototoxicity. While a report of microangiopathic hemolytic anemia has been reported for carboplatin, most phase-2 trials have demonstrated less overall toxicity compared with the parent

compound.22'23

Alkylating Agents Cyclophosphamide. Cyclophosphamide is used in high doses (120 mg/kg) in many preparative regimens for bone marrow transplantation. Toxicity at standard doses consists of nausea and vomiting, alopecia, neutropenia, and rarely thrombocytopenia. A toxic metabolite, acrolein, produces hemorrhagic cystitis.24 Hemorrhagic cystitis remains the most important toxicity of this drug. It can occur up to 3 weeks after therapy and can be prolonged. Acrolein irritates the bladder wall, producing inflammation and bleeding. Therapy is largely preventive by way of aggressive hydration and continuous bladder irrigation via a three-way Foley catheter. Blood product support in the form of platelet and red cell transfusions may be required. Refractory hemorrhagic cystitis requires an immediate urological consultation and possibly cystoscopic intervention. Acute cardiomyopathy in the form of hemorrhagic myopericarditis is sometimes seen JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11


with high-dose cyclophosphamide used in the bone marrow transplant setting. It may be reversible and merits full supportive care. Acute syndrome of inappropriate antidiuretic hormone secretion and pulmonary fibrosis are other serious side effects of this drug.25

Ifosfamide. Bladder toxicity is an important side effect with the use of ifosfamide, similar to cyclophosphamide. Mesna, an agent that protects the bladder mucosa from this toxic effect, is routinely administered with ifosfamide.26 Central nervous system toxicity has been reported and includes seizures, mental status changes, cerebellar dysfunction, and focal motorsensory deficits. These are usually reversible. Nitrosoureas. Carmustine is the most commonly used compound in this class. At doses greater than 1000 mg/M2, there is a significant chance of the patient developing fatal interstitial pneumonitis.27 The risk of acute hepatic necrosis is less (about 3%).

Antitumor Antibiotics Anthracyclines. Significant neutropenia is more prominent than thrombocytopenia after administration of anthracyclines. Other toxicities of these vesicants include nausea and vomiting, alopecia, stomatitis, and radiation recall. There are three forms of cardiac toxicity produced by anthracyclines. Acute toxicity is manifested primarily by supraventricular arrhythmias and conduction delays and does not necessarily mandate against further administration of the drug. A pericarditis-myocarditis syndrome appearing 24 to 48 hours after administration results in congestive heart failure and requires that no further drug be given. Chronic cardiotoxicity is dose and schedule dependent. It is seen when the total cumulative dose exceeds 450 to 550 mg/M2 for doxorubicin and 900 to 1000 mg/M2 for daunomycin.28'29 The incidence of congestive heart failure is significantly less if doxorubicin is administered either by continuous infusion or on a weekly schedule.30 The presence of underlying cardiac disease (eg, hypertension) and prior cardiac irradiation increases the risk of cardiotoxicity. Clinical features are those of biventricular failure, with progressive decline in the left ventricular ejection fraction. Therapy includes diuretics, vasodilators, and digoxin. Preventive strategies include: early detection of declining cardiac contractility by serial measurements of left ventricular ejection fraction using radionuclide cardiography, the use of slow intravenous infusion, rather than boluses, as cardiotoxicity is a function of peak levels of the drug (antitumor effect is not compromised), and the use of "cardioprotective" JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

agents such as ICRF- 187.30 Uncommonly, angioedema, urticaria, and hypotension may occur after administration of anthracyclines. These reactions have been managed successfully by the use of corticosteroids and diphenhydramine. Because of their vesicant properties, extravasation of anthracyclines results in severe tissue necrosis. Therapeutic measures include: the application of cold compresses to the affected area; meticulous wound care and cautious debridement of dead tissue; and occasionally skin grafting.31

Bleomycin. The most important toxicity from use of bleomycin is an interstitial pneumonitis. This toxicity is increased with age with underlying pulmonary disease, previous pulmonary irradiation, and with cumulative doses >450 mg.32'33 Subsequent oxygen exposure may precipitate respiratory failure, and if patients who have received bleomycin require surgery, the fraction of inspired oxygen should be kept as low as possible. An acute hypersensitivity pneumonitis with eosinophilia may develop. Other side effects include fever, alopecia, and anaphylactic reactions. Hyperpigmentation, erythema, edema, and hyperkeratosis of the skin, as well as thickening of the nail beds, are frequent after bleomycin administration. Mitomycin C. One of the most well-recognized life-threatening toxicities of this agent is hemolyticuremic syndrome, which will be discussed later.

Topoisomerase Inhibitors Etoposide. Acute hepatitis is rare, but a potentially life-threatening side effect of etoposide, usually seen with high-dose therapy, although there are reports of this syndrome occurring with standard-dose therapy as well.34 Patients with malignant glioma treated with high-dose etoposide with autologous bone marrow. transplantation have shown a syndrome of acute neurological dysfunction.35 This is characterized by confusion, papilledema, somnolence, exacerbation of motor deficits, and sharp increases in seizure activity. These abnormalities have resolved after initiation of high-dose dexamethasone therapy.

Antimetabolites Cytosine Arabinoside. Life-threatening toxicity with this drug is seen primarily with high-dose cytarabine therapy.36 Acute cerebellar toxicity occurs in up to 14% of patients receiving high-dose cytarabine and is characterized by slurred speech, gait ataxia, and nystagmus.37 Patient age (above 60 years) appears to be the most 841


important risk factor, but cumulative drug dose, renal and hepatic dysfunction, and concomitant use of neuroleptic antiemetic agents also contribute. Acute cerebral dysfunction and seizures also can occur with high-dose cytarabine. Intrathecal therapy may cause reversible or partially reversible paresis, and when combined with cranial irradiation, necrotizing leukoencephalopathy may result. The drug should be discontinued, and the risk-benefit ratio critically assessed in a case-by-case basis. Noncardiogenic pulmonary edema is a potentially fatal complication of high-dose cytarabine therapy.38'39 It typically presents as adult respiratory distress syndrome without evidence of cardiac failure, fluid overload, electrolyte imbalance, or septicemia. Management includes vigorous supportive care with mechanical ventilation, high doses of corticosteroids, and exclusion of other known causes of adult respiratory distress syndrome. In a study of 13 such patients, four recovered with treatment, and the remainder died despite aggressive therapy.38 A fatal hepatorenal syndrome also has been described in association with high-dose cytarabine therapy.40 Hepatic toxicity with cytarabine therapy, as evidenced by elevated bilirubin, alkaline phosphatase, and transaminase levels is common but inconsequential from a clinical standpoint. Acute pancreatitis is a rare adverse effect of therapy.41 5-Fluorouracil. 5-fluorouracil (5-FU) is used extensively in the treatment of gastrointestinal and other neoplasms. Common side effects include nausea, vomiting, stomatitis, and diarrhea. Life-threatening diarrhea, though extremely rare, has been reported. An increasingly cited and potentially fatal side effect of 5-FU includes cardiotoxicity, mimicking myocardial ischemia.42'43 This is observed in patients receiving 5-FU by continuous infusion. It may manifest as dysrhythmias, anginal-like chest pain (with or without electrocardiogram changes), acute myocardial infarction, ventricular dysfunction, cardiogenic shock, and even sudden death.4445 This is a result of myocardial ischemia induced by 5-FU, as evidenced by the presence of classical chest pain, electrocardiogram abnormalities of ischemia, and the response to treatment with nitrates and calcium channel blockers. The incidence, contributing factors, and risk factors are unknown. Physicians should remain vigilant about this condition and institute prompt and emergent treatment should this occur. 5-FU should be discontinued. Neurotoxicity with 5-FU therapy occurs in 2% to 5% 842

of cases. It typically presents as a syndrome of acute cerebellar dysfunction, characterized by incoordination, gait ataxia, slurred speech, and nystagmus.46 This is usually reversible with temporary drug discontinuation. Less commonly, the patient may develop an acute organic brain syndrome, with confusion, disorientation, and other cognitive deficits. Thiamine deficiency has been implicated as the underlying mechanism.47 Administration of intravenous thiamine often results in prompt resolution of symptoms.47'48

Biological Response Modifiers Granulocyte/Macrophage Colony-Stimulating Factor. High doses of granulocyte/macrophage colony-stimulating factor (60 pug/kg/day) have been associated with pericarditis, thromboembolic phenomena, and a capillary leak syndrome. The latter usually is preceded by several days of hypotension, and thus, any patient who drops their mean arterial pressure by more than 20 mm should be followed carefully.

Interferon-a. Neurological toxicity, characterized by lethargy, disorientation, expressive aphasia, and seizures has been observed in patients receiving doses of interferon-ot greater than 108 units.4950 Full neurological evaluation, including computed tomography (CT)/magnetic resonance imaging (MRI), and discontinuation of the drug is indicated in these instances. Hyperpyrexia, mental status changes, severe hepatic dysfunction, and marked immune thrombocytopenia also have been observed. High-dose steroids may be of benefit in these situations.

lnterleukin-2. Interleukin-2 is a potent lymphokine used in treating metastatic renal cell carcinoma, melanoma, and increasingly as a part of "consolidative immunotherapy" after bone marrow transplantation for lymphoid malignancies. A capillary leak syndrome with noncardiogenic pulmonary edema is a well-known complication. Severe hepatic, renal, and cardiac dysfunction have been reported.5' The use of continuousinfusion interleukin-2, low-dose dopamine (2 ,g/kg/ min), and judicious diuretics has helped attenuate these toxicities. Nevertheless, life-threatening toxicities of interleukin-2 are well recognized, and patients on this medication warrant close medical supervision.

Miscellaneous Toxicities Vascular and Hepatic. Pulmonary veno-occlusive disease, leading to pulmonary arterial hypertension and pulmonary vasculitis, has been described in association with bleomycin and mitomycin therapy.52 Discontinuation of the offending drug along with immunosuppresJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11


sive therapy may be of benefit. Hepatic veno-occlusive disease is a well-recognized complication of high-dose chemoradiotherapy used in bone marrow transplantation.53 Additionally, the BuddChiari syndrome (occlusion of the large hepatic veins), as well as fatal hepatic necrosis with thrombosis of small hepatic veins, has been observed with dacarbazine therapy. The spectrum of hepatic complications, as well as offending agents, is wide.2'54 Intra-arterial cisplatin has been associated with sustained hypertension and cerebrovascular accidents.52 Acute myocardial infarction has been seen with therapy with Vinca alkaloids, etoposide, cisplatin, and 5-FU. The role of preexistent coronary artery disease and concomitant chest radiation, in such instances, is unclear.

Extravasation of Chemotherapeutic Agents Extravasation of chemotherapeutic agents should be treated as a medical urgency. The following agents are known to cause significant morbidity related directly to local extravasation: daunomycin, doxorubicin, mechlorethamine (nitrogen mustard), mithramycin, mitomycin, streptozotocin, vinblastine, vincristine, bleomycin, and actinomycin D.55 Of these, doxorubicin extravasation is the most commonly reported in the literature. Onset of pain during the infusion is common and should prompt an assessment of the patency of the vein in which the drug is being injected. Physical signs after extravasation include: nonblanching erythema followed by edema, brawny induration, skin necrosis, and ulceration. Extravasation is best prevented by confirming patency of the vein periodically throughout the infusion. Once erythema occurs, the infusion should be stopped and ice applied to the elevated affected area. A small pilot study has shown that topical 99% dimethyl sulfoxide applied every 6 hours for 14 days is effective in preventing skin necrosis and ulceration in cases of doxorubicin extravasation.56 It is also prudent to obtain an urgent surgical consultation, because if local measures fail, debridement with delayed skin grafting may be required.31

Treatment-Related Hemolytic-Uremic

Syndrome A syndrome of microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, and neurologic and cardiac dysfunction is known to occur in certain patients following chemotherapy. It typically occurs in patients with adenocarcinoma (especially gastrointestiJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

nal), who have been treated with mitomycin-C regimens.57 The risk of developing hemolytic-uremic syndrome after mitomycin treatment is 4% to 15%.58 It also has been reported in association with cisplatin and bleomycin-containing regimens.59 Conventional treatment with plasmapheresis, platelet inhibitors, and immunosuppressive agents has met with limited success. Plasma perfusion through a staphylococcal protein A column has shown significant, sometimes sustained, responses.60 Dialysis is often necessary. The pathogenesis of this syndrome is not known, but is felt to result from direct injury of endothelial cells leading to platelet aggregation, clot formation in microvessels, and decreased fibrinolysis.

SELECTED RADIOTHERAPY COMPLICATIONS Background Approximately 60% of cancer patients will undergo radiation therapy as a component of their treatment. These patients are at risk for a multitude of radiationrelated toxicities, most of which are transient and mild in severity. A small fraction of these patients, however, will suffer more significant degrees of toxicity. Although the need for truly emergent intervention for complications related to radiation therapy is unusual, there are some radiation sequelae that may warrant intervention with some degree of urgency. Some of these conditions may occur during or shortly after the course of radiation, but most occur months to years following completion of radiation. These late-occurring complications probably are related to endothelial cell injury with concomitant microvascular flow perturbation leading to parenchymal cell damage. This pattern of delayed radiation injury is- distinguished from the more commonly occurring acute radiation damage that is a result of stem cell depletion. The pathogenesis of these late complications is such that they often present at a time when local tumor recurrence is a concern. Furthermore, the symptoms resulting from damage to critical organs within a radiation treatment volume are similar whether this damage is secondary to tumor recurrence or radiation-induced damage. In fact, it is more likely that symptoms referable to significant organ damage within a previously radiated field are caused by tumor recurrence, and such recurrence must be ruled out before diagnosing radiation-induced toxicity. The incidence and magnitude of radiation-induced toxicity depends on several factors, including field size, radiation dose, dose per fraction, 843


patient-related risk factors, inherent organ sensitivity, and treatment with other modalities, such as chemotherapy and surgery Likewise, the incidence of tumor recurrence is dependent on such factors as tumor size, lymph node involvement, tumor type, and sensitivity to treatment. Therefore, the probability that symptoms in a particular patient are related to recurrent tumor versus radiation-induced toxicity is a complex function of multiple variables. In general terms, however, the incidence of severe late radiation sequelae is typically about 5%. Local recurrence, either alone or with distant failure, occurs in 6% to 54% of cases, depending on the primary cancer site.6' An average incidence of local recurrence is approximately one third of cancer cases. Even if only half of these local recurrences occurred in patients previously radiated to those sites, and half again of these recurrent sites were symptomatic, the majority of cases with symptomatic involvement in a previously radiated field would be the result of local recurrence rather than radiation toxicity. Additionally, tumor may recur synchronously with radiation toxicity. Therefore, evaluation for significant radiation toxicity should almost always include assessment for recurrent cancer. With this perspective, several of the more important types of radiation-induced toxicity requiring at least urgent intervention will be discussed here.

Gastrointestinal Late-bowel injury is the primary radiation doselimiting factor in the treatment of a number of malignancies, including those of gynecologic, urologic, and gastrointestinal origin. The incidence and severity of late radiation bowel toxicity is related to total dose, dose per fraction, length of bowel in the radiation field, and circumference of the bowel that is treated.62'63 Other contributing risk factors include those conditions predisposing to peripheral vascular disease, such as diabetes mellitus, hypertension, and inflammatory vasculitis.6364 Thin body habitus has been associated with radiation bowel toxicity, possibly because of an increased amount of small bowel, which is relatively immobile within the pelvis.65 Chemotherapy given concurrently with radiation also is a risk factor.63'66'67 Of 16 children with retroperitoneal rhabdomyosarcoma treated with vincristine, doxorubicin, dactinomycin, and cyclophosphamide concurrent with radiation (2700 to 5000 cGy), four patients developed intestinal obstruction, and three of four died. All were found to have severe intestinal fibrosis, and none had recurrent tumor.67 Abdominal 844

surgery prior to radiation has been identified as a risk factor for late toxicity caused by adhesion of segments of the small bowel within subsequent radiation fields.63'66 The use of whole abdominal radiation for epithelial ovarian cancer is pertinent to this issue. In patients undergoing a single debulking operation, the incidence of bowel obstruction was 3.1% after whole abdominal radiation.68 In patients undergoing salvage whole abdominal radiation after at least two celiotomies plus chemotherapy, the incidence of bowel obstruction related to tumor recurrence has ranged from 14% to 30%.69,70 Galland and Spencer66 reported a series of 70 patients with radiation enteritis, and 35 of these patients had previous abdominal surgery. Late radiation injury to the bowel has been attributed to progressive obliterative vasculitis, resulting in ischemic changes with fibrosis and mucosal ulceration.62'63'66'71 Grossly, the bowel may appear dull gray with thickened serosa, increased friability, decreased pliability, and attenuated peristalsis.63 The mesentery may appear short and thickened. The typical latency period for bowel toxicity is 4 months to 2 years following radiation, but latency greater than 10 years is not uncommon.66'71 Average latency periods have been reported as 4 months for rectosigmoid stenosis, 9 months for rectal necrosis, 10 months for colorectal obstruction, 28 months for rectovesicular fistula, 32 months for rectovaginal fistula, and 47 months for colorectal perforation.62 Rectal injury is most common, followed by injury to extrapelvic colon and small intestine. This order of frequency is a function of the types of cancer that are most commonly treated with radiation, determining the regions of the bowel included within the radiation field, rather than inherent sensitivity.63 Late radiation injury in the small intestine most commonly results in obstruction, but fistula occurs in up to 20% of patients.71 Large bowel injury usually presents as obstruction of a fistula in the rectosigmoid region.63 Intestinal perforation months to years after radiation has been characteristically described as occurring immediately proximal to a site of obstruction.66 Symptoms may start insidiously, but often progress relentlessly once established.66 Patients may present with cramping abdominal pain, nausea, vomiting, diarrhea, rectal bleeding, or tenesmus.63'71 Weight loss is common prior to presentation and may be secondary to atrophic intestinal villi with malabsorption.7' Severe abdominal pain is typically associated with obstruction or perforation, while rectal pain and bleeding is associated with ulceration or rectovaginal fistula.62 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11


Vaginal discharge is also suggestive of rectovaginal fistula. A large fixed abdominal or pelvic mass may be palpated and confused with recurrent cancer.63 Radiation injury of the rectum or colon may be diagnosed by endoscopy or barium enema.62 Colorectal mucosa may be smooth or show small ulcerations, and thickening of the presacral space greater than 1 cm is suggestive of rectal fibrosis. Rectovaginal fistula also may be diagnosed by sigmoidoscopy or barium enema, but biopsy should be done with care because of the risk of additional fistula formation. Signs of intestinal obstruction may be seen on plain abdominal radiation. Contrast studies of the small intestine may localize injury by pooling of the contrast agent, focal filling defects with narrowed lumen, proximal dilation, and a "saw-tooth" appearance of the bowel.63'71 A watersoluble contrast agent should be used if perforation is suspected. Enteroclysis allows serial examination of individual segments of the bowel and provides information on bowel motility, with hyperperistalsis often visible in segments proximal to the obstruction. While radiographic or endoscopic studies are indicated for progressive abdominal pain, diarrhea, tenesmus, or rectal bleeding, surgical exploration should be undertaken in the case of acute abdomen.63 Patients with radiation bowel injury may have multiple episodes of partial bowel obstruction, which may be managed conservatively with nasogastric decompression, intravenous fluids, and observation of electrolyte status. Total parenteral nutrition may improve clinical status.7' However, severe late radiation toxicity is generally refractory to medical management.63 If symptoms are unresponsive, or if acute abdomen occurs, then surgery is necessary.7' Simple lysis of adhesions is inadequate and often results in further damage.63 The issue of optimal surgical treatment with intestinal bypass versus excision and anastomosis has been controversial, with a recent trend toward excisional operations.7' Bypass procedures have been advocated because of high incidence of leakage and mortality with anastomosis.72 On the other hand, perforation, bleeding, and fistula are complications that may result from radiation-injured bowel left in situ following bypass.66 In 27 patients undergoing simple diverting colostomy for late radiation bowel injury, 44% had postoperative complications and 11% died.62 Galland and Spencer66 reviewed an initial 24 patients who underwent resection and anastomosis; 12 had leakage of the anastomosis and 10 died. These investigators hypothesized that the success of this procedure required the two ends of the anastomosis JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

not to be irradiated, providing relatively undamaged vascular supplies. Macroscopically, it is difficult to differentiate radiated and nonradiated bowel, and frozen section analysis is unreliable. For that reason, ascending, transverse, and descending colon (portions of bowel that are often outside of the radiation field) were used for anastomosis in their 14 most recently treated cases. In those 14 patients, there has been one anastomotic leak and no deaths.66 The treatment of radiation-induced bowel fistula deserves special attention. Small bowel fistula to skin or vagina should be treated by isolation and bypass without resection, as resection requires considerable dissection and is hazardous.66 Rectovaginal fistula repair may use grafting with vaginal fat, omentum, rectus muscle, or gracilis muscle. Few heal after simple colostomy, and they tend to recur even after aggressive resection or pull-through operation.62 The prognosis after late radiation bowel toxicity requiring surgery is poor. Risk of a subsequent episode of injury related to radiation is 23% to 39% and is greater after perforation or fistula than with bleeding or stricture.73'74 Life expectancy is shorter in patients presenting with perforation or fistula than with bleeding or stricture. Small-bowel injury carries a fourfold risk of mortality compared with colorectal injury.75

Lung The lung is relatively sensitive to radiation-induced injury. Injury to the lung may occur in the treatment of lung cancer, esophageal cancer, Hodgkin's and nonHodgkin's lymphoma, breast cancer, malignancies of the spinal cord, and metastatic disease. The incidence and severity of lung injury is related to total radiation dose, dose per fraction, volume of lung included within the radiation field, and use of chemotherapeutic agents.76 There is an increased incidence of bleomycininduced diffuse pulmonary fibrosis, including regions of lung outside the radiation field, when radiation therapy is used in combination with this drug, even in a nonconcurrent manner.77 Dactinomycin, cyclophosphamide, methotrexate, and doxorubicin have been associated with increased risk of lung injury when given with radiation.76-79 Idiopathic interstitial pneumonia occurred more frequently in bone marrow transplant patients receiving total body irradiation compared to patients receiving only chemotherapy.80 The risk of idiopathic interstitial pneumonia was increased with higher radiation dose, suggesting that radiation plays a role in the pathogenesis of idiopathic interstitial pneumonia in bone marrow 845


transplant patients. Lung toxicity may be classified as two progressive forms known as pneumonitis and fibrosis and has been considered a result of radiation injury to alveolar epithelium and capillary endothelium.81-84 Radiation pneumonitis is the earlier phase and reflects an alveolitis involving alveolar cells and capillary endothelium. Histologic changes have been well characterized in animals. From 1 hour through 1 week following single-dose radiation to the hemithorax of mice, electron microscopy reveals a decrease in the number of lamellar bodies in type II pneumocytes, suggesting perturbation of surfactant storage and secretion.81'84 At 7 weeks after radiation, surfactant in lung lavage is increased, and lethality has been correlated with the quantity of surfactant released.81'82 Eighteen weeks after radiation, alveolar and interstitial edema along with leukocyte infiltration is observed by light microscopy, while electron microscopy demonstrates increased intracellular lipid in type I pneumocytes and increased lamellar bodies in type II pneumocytes. At later times after radiation, there is a progression in interstitial fibrosis with thickening of alveolar septa. Pulmonary fibrosis is probably related to late vascular effects and is characterized by fibroblast proliferation, increased reticular fibers, and focal infiltration, predominantly with monocytes. Clinically, radiation pneumonitis is characterized by cough (usually nonproductive), dyspnea, increased respiratory rate, and fever. The typical latency period for onset of symptoms is 1 to 3 months after completion of radiation.76 The phase of pulmonary fibrosis begins 3 to 6 months after radiation. Although the histologic changes of pulmonary fibrosis can usually be observed in areas of lung receiving at least 4500 cGy, the clinical manifestations of pulmonary fibrosis require a critical volume of damage. Decreases in diffusion of carbon monoxide, lung compliance, and arterial oxygen levels may be documented, but pulmonary injury is typically irreversible at that point.82 The differentiation from recurrent tumor or infection is critical. The clinical diagnosis of radiation lung toxicity is radiographic and depends on the pulmonary density corresponding precisely with the geometry of the radiation field.81'84 Chest radiograph may be adequate for the diagnosis, but a CT scan is often helpful if the radiograph is not definitive. Treatment of radiation pneumonitis includes bed rest, bronchodilators, and oxygen. With marked symptoms, corticosteroids may be beneficial.85 Typical doses of prednisone for radiation pneumonitis are 40 to 60 mg 846

per day and must be tapered slowly over approximately 6 weeks to avoid relapse. In contrast to their efficacy in treating radiation pneumonitis, corticosteroids are not useful in the prevention or treatment of pulmonary fibrosis. If symptomatic pulmonary fibrosis occurs, it is irreversible and may result in chronic pulmonary disability, pulmonary hypertension, and death.86 Poor ventilation combined with continued perfusion of the affected lung results in arteriovenous shunting. This shunting limits the usefulness of supportive care with oxygen; however, pneumonectomy may be beneficial in rare cases.87 Prevention of pulmonary fibrosis is critical, and is done by limiting the volume of lung included in the radiation field to the degree possible.

Bone Bone injury following radiation therapy is rare, but may be serious if it occurs. Most commonly, osteoradionecrosis involves the mandible following radiation therapy for head and neck cancers. However, osteoradionecrosis may occur in other bones, such as the femoral head following treatment to the pelvic region. Risk factors for osteoradionecrosis of the mandible include higher doses of radiation, use of interstitial radioactive implants, larger size of radiation fields, poor oral hygiene, dental extractions, and oral trauma.88'89 The pathogenesis of mandibular osteoradionecrosis is related to endothelial cell death with vascular hyalinization and thrombosis. The periosteum becomes fibrotic. Osteocyte necrosis and fibrosis of bone marrow also are observed. The tissue becomes hypovascular, hypocellular, and hypoxic compared with undamaged regions of bone.89 The concept of oxygen supply and demand is important in understanding the evolution and treatment of osteoradionecrosis. At one time, trauma and infection were considered integral components of this process.88 However, culture of these lesions routinely failed to reveal microorganism involvement.89 Likewise, Marx reported that 35% of cases of mandibular osteoradionecrosis were not associated with trauma.89 The hypoxia associated with radiation damage to bone appears to result in a diminished ability to replace the normal collagen and cellular losses occurring in bone. Trauma may increase the demand on compromised oxygen supplies, thereby promoting osteoradionecrosis, but is not a prerequisite. Mandibular osteoradionecrosis has a median latency period of 5 months,88 but may be delayed in onset up to 16 years following radiation therapy.90 Symptoms consist of localized pain and swelling with occasional JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11


trismus.91 Examination frequently reveals ulceration of the overlying oral soft tissue lining with bone exposure.92 Radiolucent regions, bone destruction, and sequestrum formation may be seen on radiograph.91 Bone biopsy should generally be performed to differentiate from malignancy.93 Dental care is an important component of the radiotherapeutic management of head and neck cancer, and is essential to minimize the risk of mandibular osteoradionecrosis. Dental extractions taking place within a year following radiation therapy to the oral cavity region frequently lead to osteoradionecrosis. In one series, 6 of 10 patients who underwent dental extraction within a year following radiation developed osteoradionecrosis, while only 1 of 6 developed problems when extraction occurred at later posttreatment intervals.88 If extractions are performed prior to radiatioh therapy, it was recommended that the time interval between extraction and radiation be at least 10 days to 2 weeks. Conservative nonsurgical management has been unsuccessful and may delay treatment, leading to further advancement of osteoradionecrosis.94 Such conservative means have consisted of avoidance of irritants (such as hot beverages, tobacco, alcohol, and poorly fitting dentures), irrigation with salt and soda solutions, and administration of antibiotics.88 The failure of antibiotics is not surprising based on the lack of evidence for an infectious etiology. Conservative surgical treatment, such as the drilling of holes through nonviable cortex or repeated sequestrectomies, also has failed to resolve the problem consistently.94 More recently, hyperbaric oxygen treatments have proven to be important in the treatment of osteoradionecrosis, especially when combined with surgical intervention. Marx reported 58 patients with refractory osteoradionecrosis of the mandible who all had clinical resolution after participating in a protocol combining hyperbaric oxygen with surgical resection and reconstruction.94 Osteoradionecrosis of the femoral head may occur rarely after radiation therapy to the pelvis. Corticosteroid-containing chemotherapeutic regimens have been considered a risk factor for this complication in Hodgkin's disease patients treated with radiation using fields encompassing the hip joints.95 If hip joint pain occurs, a radiograph should be obtained. Radiographic findings may include wedge-shaped osteonecrosis, mottled osteoporosis, subchondral infarction, flattening of the femoral head, and joint space narrowing. Plain radiograph may be negative, in which case a bone scan should be obtained. Conservative treatment consists of JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

no weightbearing for 6 months, but most patients have progressive collapse of their femoral head, requiring hip replacement.95'96 Early surgical intervention with core decompression and grafting, along with electrical stimulation, has been reported to be successful.

Brain Radiation injury to the brain may occur in the treatment of primary brain neoplasms, brain and skull metastases, tumors of the orbit, and head and neck cancers, including those involving the scalp. Severe acute reactions will not be discussed here since they do not occur unless an unconventionally high dose per fraction, such as 750 to 1000 cGy, is used.97 The so-called early delayed radiation reaction is another less critical phenomenon that occurs a few weeks to months after radiation and is related to transient demyelination. It is characterized by somnolence and typically is self-limited. The major hazard, with respect to radiation injury to the brain, is late toxicity. The risk of late brain toxicity is greater with the use of higher radiation dose per fraction.97 A review of the literature estimated the incidence of brain necrosis to be 0.04% to 0.4% after doses having the biological equivalent less than or equal to 5200 cGy at 200 cGy per fraction.97 In another study of 139 patients receiving at least 4500 cGy for primary brain and pituitary tumors (180 to 200 cGy per fraction), pathologically confirmed radionecrosis was not observed in patients receiving less than the equivalent of 5400 cGy in 30 fractions.98 Larger radiation treatment volumes have also been associated with late brain toxicity.99 Chemotherapeutic agents, such as carmustine, procarbazine, methotrexate, and vincristine, may enhance radiation brain toxicity.97 Late radiation brain toxicity has a typical latency period of 4 months to 2 years, but has been reported to occur up to 7.5 years after radiation.97'98 Vascular damage is believed to be important in its pathogenesis.97100 Thickening and sclerosis of vascular walls occurs, which may lead to capillary occlusion and vasogenic edema.99"00 Parenchymal changes also are observed, consisting of reactive gliosis, focal demyelination, fibrosis, and coagulation necrosis. Necrotic debris may lead to severe edema with mass effect and increased intracranial pressure. There is a predilection for radionecrosis to occur in white matter for unknown

reasons.98 The clinical picture depends on the area of brain involved and often mimics that of an intracranial mass.97 Presenting features may include disorientation, personality change, headache, focal motor weakness, 847


visual loss, memory deficit, dysphasia, ataxia, diplopia, and seizure.98'101 Late radiation brain toxicity is a diagnosis of exclusion'°° and must be differentiated from the effects of recurrent tumor, incidental degenerative disease and surgery.99 Brain necrosis has been reported to be associated with tumor recurrence histologically. o Computed tomography may show an area of decreased radiodensity that is contrast enhancing, with edema, mass effect, atrophy, and white matter changes.98'99"101 Correlation between actual radiation dose distribution and pattern of damage seen on imaging is important. Often, the visible changes of radiation toxicity occur within the high-dose region, but they may be evident outside the high-dose region as related to the anatomy of the damaged vascular supply.99 Magnetic resonance imaging is more sensitive than CT for detecting radiation changes in brain tissue, with T2 signal enhancement caused by increased water content. Pronounced MRI changes occur more frequently in those patients with clinical evidence of radiation injury than in asymptomatic patients. However, some patients have high-grade lesions on MRI in the absence of neurologic deficits. Consequently, a change in clinical status cannot automatically be attributed to white matter abnormalities visible on MRI. Further investigation into clinical correlation with MRI abnormalities and evolution of lesions over time is needed. Recently, metabolic imaging using glucose analogs and positron emission tomography (PET) has shown promise for differentiating tumor recurrence from radionecrosis in patients with CT or MRI lesions.102 Using PET, focal hypometabolism was seen in areas of necrosis, while hypermetabolism was associated with recurrent tumor. Late radiation brain injury generally is irreversible, progressive, and often fatal.97 Spontaneous clinical and radiologic improvement is rare.101 Although steroids have been reported as useful to relieve symptoms in certain cases,97'98 others have found that steroids do not alter the clinical course.101 Surgical resection of a focal region of necrosis can be of benefit and may be lifesaving.97,98,101,103-105 A literature review revealed that 24% of cases of radiation brain necrosis benefited from surgery.97 It has been recommended that reoperation be performed in any patient who deteriorates neurologically within 3 years of high-dose radiation to the brain, especially if imaging studies show a lesion.98 Others suggest that patients may be treated symptomatically unless there is evidence of increased intracranial pressure at the time of presentation.101 With the 848

increased use of CT, MRI, and PET, milder cases of late brain toxicity from radiation may be detected that may benefit from conservative management.

Spinal Cord Radiation injury to the spinal cord has occurred in the treatment of primary central nervous system neoplasms, metastatic cancer involving the spine or spinal cord, head and neck cancer, and tumors involving the thorax or abdomen if the spinal cord is included in the radiation field. As with radiation toxicity in the brain, acute damage is essentially nonexistent with conventional fractionation schemes. Likewise, a transient myelopathy may occur an average of 16 weeks after radiation.'06"107 This is characterized by electric shock sensations down the spine and limbs upon neck flexion, a finding known as Lhermitte's sign. As is the case with the "early delayed" radiation reaction in the brain, transient myelopathy resolves spontaneously and does not herald late progressive toxicity. It has been reported to occur in 15% of Hodgkin's disease patients treated with a mantle field. Chronic progressive myelopathy is the primary concern with respect to spinal cord radiation toxicity. The risk of late radiation spinal cord toxicity is increased with higher total dose and dose per fraction. 108-110 Tolerance of the cervical spinal cord to radiation has been reported to be greater at doses per fraction in the range of 180 to 200 cGy in contrast to higher doses. Radiation treatment regimens reported as "safe" for the spinal cord include 2000 cGy in 5 fractions, 3000 cGy in 10 fractions, and 5000 cGy in 25 fractions.111 However, injury may occur sporadically even at typically "safe" doses.108 Increased length of spinal cord included within the radiation field appears to increase risk of chronic myelopathy.108'112 Other possible risk factors include hypertension,'13 age less than 20 years,"14 and some chemotherapeutic agents such as actinomycin D,"15 carmustine, vincristine, and intrathecal methotrexate." 6 Late radiation spinal cord toxicity appears to have a biphasic latency in humans and animals.14'117'118 The first peak of incidence occurs 12 to 14 months postradiation, and the second peak occurs 24 to 28 months postradiation. Histologic studies in rats demonstrated that the earlier phase of chronic spinal cord damage was associated with higher radiation doses and white matter necrosis.114 The later phase occurred with lower doses and was characterized by vascular damage in association with white matter injury. Similar biphasic changes have been confirmed in JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11


humans, and a dual mechanism has been proposed.1"8 The first type of damage involves extensive demyelination progressing to loss of axons, focal necrosis, and finally, liquifaction necrosis of white matter. The second type of damage is characterized by intramedullary vascular damage. This vascular damage consists of hyaline thickening of vessel walls, telangiectasia, fibrinoid necrosis, vascular occlusion, focal hemorrhage, and hemorrhagic necrosis. Severe damage results in cell loss, predominantly in white matter. The clinical presentation is one of focal neurologic deficit within a spinal cord segment submitted to radiation.119 Symptoms typically begin with paresthesias and sensory loss.112 Progression to involve other spinal cord functions often occurs, leading to pain radiating into extremities, gross sensory ataxia, paresis, incontinence of urine or feces, and paralysis.108'119"120 A well-demarcated, lateralized neurologic loss, such as Brown-Sequard syndrome, may be seen. Diagnosis of chronic radiation myelopathy is made after exclusion of metastatic disease, intramedullary tumor,121'122 and arthritic hypertrophy of the vertebral facets and laminae.123 Spinal cord dysfunction in patients with malignant disease usually indicates metastasis.119 Computed tomography, MRI, and myelogram are useful to rule out intramedullary and extramedullary tumor. Lumbar puncture should be included in the diagnostic evaluation. Cerebrospinal fluid usually is normal with chronic radiation myelopathy, but may contain mildly elevated protein.1 19 Imaging studies may reveal spinal cord atrophy or edema within the radiation field, but changes may occur beyond this region.124"125 Late radiation spinal cord toxicity occasionally arrests at an early stage,119 and temporary improvement has been observed with steroid therapy119"124 and hyperbaric oxygen.126 However, there is usually progression to a clinical picture of complete spinal cord transection.119 Typically, supportive care is instituted, but the clinical course is irreversible.1"2

SUMMARY The use of systemic antitumor agents can result in damage to both major and minor organ systems. Careful attention to the dose-limiting toxicities and early recognition of organ compromise may be lifesaving. Radiation complications requiring urgent intervention tend to occur months to years after radiation therapy. Damage to microvasculature appears to be important in the pathogenesis of late radiation injury. Recurrent or metastatic malignant disease must be excluded before radiation toxicity is diagnosed. AlJOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 86, NO. 11

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