Oncologic emergencies and paraneoplastic syndromes

April 21, 2009

Superior vena cava syndrome (SVCS) is a common occurrence in cancer patients and can lead to life-threatening complications such as cerebral or laryngeal edema. Although most commonly resulting from external compression of the vena cava by a tumor, SVCS can also stem from nonmalignant causes in cancer patients.

SUPERIOR VENA CAVA SYNDROME

Superior vena cava syndrome (SVCS) is a common occurrence in cancer patients and can lead to life-threatening complications such as cerebral or laryngeal edema. Although most commonly resulting from external compression of the vena cava by a tumor, SVCS can also stem from nonmalignant causes in cancer patients.

Etiology

Malignant causes

Primary intrathoracic malignancies are the cause of SVCS in approximately 87%–97% of cases. The most frequent malignancy associated with the syndrome is lung cancer, followed by lymphomas and solid tumors that metastasize to the mediastinum.

Lung cancer SVCS develops in approximately 3%–15% of patients with bronchogenic carcinoma, and it is four times more likely to occur in patients with right- versus left-sided lesions.

Metastatic disease Breast and testicular cancers are the most common metastatic malignancies causing SVCS, accounting for > 7% of cases. Metastatic disease to the thorax is responsible for SVCS in ~3%–20% of patients.

Nonmalignant causes

Thrombosis The most common nonmalignant cause of SVCS in cancer patients is thrombosis secondary to venous access devices (see chapter 43).

Other nonmalignant causes include cystic hygroma, substernal thyroid goiter, benign teratoma, dermoid cyst, thymoma, tuberculosis, histoplasmosis, actinomycosis, syphilis, pyogenic infections, radiation therapy, silicosis, and sarcoidosis. Some cases are idiopathic.

Signs and symptoms

Classic symptoms Patients with SVCS most often present with complaints of facial edema or erythema, dyspnea, cough, orthopnea, or arm and neck edema. These classic symptoms are seen most commonly in patients with complete obstruction, as opposed to those with mildly obstructive disease.

Other associated symptoms may include hoarseness, dysphagia, headaches, dizziness, syncope, lethargy, and chest pain. The symptoms may be worsened by positional changes, particularly bending forward, stooping, or lying down.

Common physical findings The most common physical findings include edema of the face, neck, or arms; dilatation of the veins of the upper body; and plethora or cyanosis of the face. Periorbital edema may be prominent.

Other physical findings include laryngeal or glossal edema, mental status changes, and pleural effusion (more commonly on the right side).

Diagnosis

It is important to establish the diagnosis and underlying etiology of SVCS, since some malignancies may be more amenable to specific treatment regimens than others. In the majority of cases, the diagnosis of SVCS is evident based on clinical examination alone.

The following diagnostic procedures may aid in establishing the diagnosis of SVCS and its etiology: chest x-ray, bronchoscopy, limited thoracotomy or thoracoscopy, contrast and radionuclide venography, Doppler ultrasonography, CT (especially contrast-enhanced spiral CT), and MRI.

Prognosis

The prognosis of SVCS depends on the etiology of the underlying obstruction. A review by Schraufnagel showed the average overall survival after the onset of SVCS to be 10 months, but there was wide variation (± 25 months) depending on the underlying disease, with an average survival of 7.6 months. This duration was not significantly different from the survival duration of 12.2 months in patients presenting with SVCS as the primary manifestation of the disease. Thoracic malignancy, the most common cause of SVCS, had a poor prognosis of < 5 months.

Treatment

Treatment includes radiotherapy, chemotherapy, thrombolytic therapy and anticoagulation, expandable wire stents, balloon angioplasty, and surgical bypass.

Most patients derive sufficient relief from obstructive symptoms when treated with medical adjuncts, such as diuretics and steroids (see section on “Adjunctive medical therapy”), so they can tolerate a work-up to determine the etiology of SVCS. In some instances, it is appropriate to delay treatment for 1–2 days if necessary to establish a firm tissue diagnosis.

Radiotherapy and chemotherapy

Both radiotherapy and chemotherapy are treatment options for SVCS, depending on the tumor type. The specific drugs and doses used are those active against the underlying malignancy.

Life-threatening symptoms, such as respiratory distress, are indications for urgent radiotherapy. A preliminary determination of the treatment goal (potentially curative or palliative only) is necessary prior to the initiation of treatment, even in the emergent setting.

Radiation therapy is the standard treatment of non-small-cell lung cancer (NSCLC) with SVCS. Recent studies suggest that chemotherapy may be as effective as radiotherapy in rapidly shrinking small-cell lung cancer (SCLC). Chemoradiation therapy may result in improved ultimate local control over chemotherapy alone in SCLC and non-Hodgkin lymphoma. Retrospective reviews of patients with SCLC have reported equivalent survival in patients with or without SVCS treated definitively with chemoradiation therapy.

Reasonable palliative courses can range from 2,000 cGy in 1 week to 4,000 cGy in 4 weeks. Curative regimens can range from 3,500 to 6,600 cGy based on histology. If indicated, more rapid palliation may be achieved by delivering daily doses of 400 cGy up to a dose of 800–1,200 cGy, after which the remainder of the appropriate total dose can be given in more standard daily fractions of 180 to 200 cGy. Some European investigators have used doses as high as 600 cGy 1 week apart in elderly patients.

Anticoagulation and thrombolysis

Anticoagulation for SVCS has become increasingly important due to thrombosis related to intravascular devices. In certain situations, the device remains in place. Both streptokinase and urokinase have been used for thrombolysis, although urokinase has been more effective in lysing clots in this setting. Urokinase is given as a 4,400-U/kg bolus followed by 4,400 U/kg/h, whereas streptokinase is administered as a 250,000-U bolus followed by 100,000 U/h. The use of thrombolytic therapy is controversial for catheter-related thrombosis, however.

Stenting

Placement of an expandable wire stent across the stenotic portion of the vena cava is an appropriate therapy for palliation of SVCS symptoms when other therapeutic modalities cannot be used or are ineffective. Use of stents is limited when intraluminal thrombosis is present. The Institut Catala d’Oncologia in Barcelona, Spain, published its results using endovascular stent insertion for the treatment of malignant SVCS. Stenting was performed in all 52 patients with lung cancer. Phlebographic resolution of the obstruction was achieved in 100% of cases, and symptomatic improvement was achieved in more than 80% of patients. There was one major complication due to bleeding during anticoagulation. Reobstruction of the stent occurred in 17% of cases, mostly due to disease progression. Improvement of the obstruction allowed for delivery of full-dose systemic therapy for patients for whom this approach was indicated.


 

Other interventional treatments

Balloon angioplasty and surgical bypass have also been used in appropriate patients but are rarely indicated. Balloon angioplasty may be considered in patients with SVCS, significant clinical symptoms, and critical superior vena cava obstruction demonstrated by angiography. Surgical bypass is usually limited to patients with benign disease; however, for a select group of patients with SVCS, bypass may be an important aspect of palliative treatment. Other palliative efforts may be considered prior to bypass in this patient population.

Adjunctive medical therapy

Medications that may be used as adjuncts to the treatments described above include diuretics and steroids.

Diuretics may provide symptomatic relief of edema that is often immediate although transient. The use of diuretics is not a definitive treatment, and resulting complications may ensue, such as dehydration and decreased blood flow. Loop diuretics, such as furosemide, are often used. Dosage depends on the patient’s volume status and renal function.

Steroids may be useful in the presence of respiratory compromise. They are also thought to be helpful in blocking the inflammatory reaction associated with irradiation.

Dosage depends on the severity of clinical symptoms. For severe and significant respiratory symptoms, hydrocortisone, 100–500 mg IV, may be administered initially. Lower doses every 6–8 hours may be continued. Tapering of the steroid dosage should begin as soon as the patient’s condition has stabilized. Prophylactic gastric protection is advised during steroid administration.

VENOUS THROMBOEMBOLIC COMPLICATIONS OF CANCER

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common and potentially serious clinical challenges. In the United States, the estimated incidence of DVT and PE is approximately 450,000 and 355,000 cases per year, respectively. The actual incidence is likely much higher than presently documented due to often vague complaints and symptoms. PE may be associated with increased mortality and contributes to approximately 240,000 deaths annually in the United States.

Armand Trousseau noted the association between thrombosis and cancer more than 125 years ago. The risk of venous thromboembolism (VTE) in cancer patients depends upon the type and extent of the malignancy, the type of cancer treatment, the existence and nature of comorbidities, and changes in hemostasis of the blood, which have been noted in more than 90% of cancer patients. The prevalence of clinically noted venous thrombosis in cancer patients is 15%; patients undergoing surgery, hormonal therapy, and chemotherapy have the highest risk. Venous thrombosis is the second leading cause of death in cancer patients.

Etiology of VTE in cancer patients

The etiology of VTE in cancer patients may be attributed to several factors, including hypercoagulable states, surgical interventions, chemotherapy, in-dwelling central venous catheters, and prolonged immobilization.

The mechanisms by which tumors cause a hypercoagulable state are not completely understood, but they may be attributed to abnormalities of blood composition (increased plasma levels of clotting factors, cancer procoagulant A, tissue factor, and cytokines) and increased release of plasminogen activator. Postoperative VTE was more common in patients with malignant disease (36%) than in those patients with benign disease (20%), according to recent analyses of several clinical trials in surgical patients.

Patients undergoing chemotherapy are at increased risk of venous thrombosis secondary to endothelial cell damage from drug toxicity. In the recent ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the aromatase inhibitor anastrozole (Arimidex) was compared with tamoxifen for 5 years in 9,366 postmenopausal women with localized breast cancer. Forty-eight patients (1.6%) receiving anastrozole developed DVT events, compared with 74 patients (2.4%) in the tamoxifen arm (P = .02). Anastrozole was associated with significant reductions in DVT events and should be considered for initial treatment in this population.

Indwelling central venous catheters predispose patients to upper extremity thrombosis and thrombosis of the axillary/subclavian vein. The catheters are also prone to occlusion. Increased venous stasis owing to immobility also promotes blood pooling into the intramuscular venous sinuses of the calf and may lead to thrombosis formation.

TUMOR TYPE ASSOCIATED WITH VTE

Several tumor types have been associated with higher rates of VTE, including those arising from the pancreas, lungs, and other mucin-secreting tumors. In general, tumor types associated with an increased incidence of thromboembolic events reflect the frequency of the tumors in the general population: In women, the most common tumors are breast, lung, gynecologic, and GI tumors; in men, prostate, lung, and GI tumors are most common. However, hematologic malignancies (multiple myeloma, lymphoma, and leukemia) also have significant rates of VTE.

Treatment

Several classes of agents have been used for prevention and treatment of VTE. Nonpharmacologic approaches to prophylaxis may include intermittent pneumatic compression, elastic stockings, and inferior vena cava filters. Commonly used pharmacologic agents for thromboprophylaxis and treatment of VTE include unfractionated heparin (UFH; standard, low-dose, or adjusted-dose), oral anticoagulants such as warfarin, and low molecular weight heparin (LMWH).

Initial treatment of DVT and PE includes inpatient UFH or LMWH and, more recently, outpatient LMWH for low-risk patients with DVT. (Although patients with PE have been treated with LMWH as outpatients, it is not the standard of care in the United States.)

UFH generally is administered as a bolus of 5,000 U followed by a continuous drip, usually initiated between 750–1,000 U/h. A baseline partial thromboplastin time (PTT) and prothrombin time (PT) are drawn prior to the initiation of treatment. PTT is then rechecked approximately 4–6 hours after treatment is begun, and the UFH is titrated to approximately 1.5 to 2 times control in most patients.

Warfarin is usually begun on day 1 or 2 of treatment; therapy is monitored to maintain an international normalized ratio (INR) between 2.0 and 3.0. (Patients with prosthetic valves require a higher INR.) It is standard practice to maintain UFH for 4–5 days while the warfarin is titrated to therapeutic levels. Most patients are maintained on warfarin for 3–6 months depending upon underlying risk factors. There is controversy regarding the duration of anticoagulation, and some investigators maintain that patients with active cancer should continue anticoagulation for as long as the cancer remains active. Patients with recurrent VTE are usually maintained on anticoagulants for the rest of their lives.


 

Patient response to warfarin depends on numerous factors, such as age, diet, alcohol consumption, and liver and GI function, as well as concomitant medications.

Recent studies have demonstrated the safety and efficacy of LMWH in the treatment and management of VTE. Several studies have demonstrated no appreciable differences in recurrent thromboembolism and an increased risk of bleeding with UFH and LMWHs. Because LMWHs do not require a continuous drip and frequent serum testing, some low-risk patients are now treated as outpatients. Studies are ongoing in the cancer patient population.

In the United States, enoxaparin (Lovenox) has received US Food and Drug Administration (FDA) approval for prevention and treatment of DVT. Tinzaparin (Innohep) also has FDA approval for the treatment of DVT. Dalteparin (Fragmin), another LMWH agent indicated for prophylaxis, has been approved by the FDA for cardiac use and for treatment of DVT/PE.

LMWH doses vary by product and are not equivalent. Enoxaparin is generally administered once or twice a day for treatment of VTE, whereas the indications for tinzaparin and dalteparin are for once-daily dosing. The commonly administered dose for treatment of DVT with enoxaparin is 1 mg/kg SC (subcutaneous) every 12 hours. Tinzaparin is given via SC injection at a dose of 175 IU/kg body weight once daily, and the dalteparin dose is 200 IU/kg SC once daily for the first month, followed by 150 IU/kg SC daily thereafter. Therapy with LMWH is continued for a minimum of 5 days during the acute phase of treatment. Generally, laboratory monitoring is unnecessary, although for individuals with renal insufficiency or those with < 50 kg body weight or obesity, plasma antifactor Xa concentrations may need to be monitored.

In an international study comparing the long-term treatment benefits of dalteparin versus warfarin in cancer patients with VTE, long-term dalteparin substantially reduced the rate of recurrent VTE, compared with warfarin therapy, without an increase in bleeding. Based on this trial, cancer patients requiring VTE treatment should continue dalteparin (or possibly another LMWH) during the chronic phase of treatment instead of switching to warfarin. Cost issues may require patients to remain on warfarin.

DIFFICULTIES IN ANTICOAGULATION

Often, therapeutic challenges arise in patients on anticoagulation therapy for VTE who require surgical interventions and, therefore, temporary discontinuation of their anticoagulation treatment.

Preoperative guidelines The timing of discontinuation of anticoagulation depends upon the type of treatment and the surgical intervention planned. For patients on continuous-drip heparin, the drip may be discontinued 4–6 hours prior to the procedure. A PTT should be drawn prior to the procedure to check for total reversal of the treatment. In cases where only partial reversal is noted or an emergency arises, fresh frozen plasma may be administered for rapid reversal.

Patients on warfarin may be advised to discontinue their medication 3–5 days prior to the planned procedure. This approach allows for a gradual reduction in the anticoagulation effect. An INR should be checked prior to the procedure. If partial reversal is noted or an emergency arises, vitamin K and/or fresh frozen plasma may be administered for acute reversal.

Postoperative guidelines Timing of postoperative therapy depends on the type of procedure undertaken and its associated risk of bleeding. Direct communication between the surgeon and the physician managing the anticoagulation treatment is necessary. When the surgeon believes that the risk of bleeding is at an acceptable level, anticoagulation should be restarted. It may be prudent to utilize UFH or LMWH prior to the initiation of warfarin, especially if a substantial risk of bleeding remains.

High-risk patients For high-risk patients (prosthetic valve, recurrent VTE), it may be reasonable to switch from warfarin to either UFH or LMWH, with appropriate discontinuation prior to the procedure. Both UFH and LMWH have shorter reversal times than does warfarin, although LMWHs are not fully reversible. Another option is to continue warfarin until shortly before the procedure, reversing treatment with vitamin K and/or fresh frozen plasma. The risk/benefit ratio should be considered when reviewing the options for the individual patient.

Surgery has long been known to be a risk factor for VTE. The nature of surgery in part determines the relative risk: Patients undergoing orthopedic surgery are at a particularly high risk. The risk is modified by the presence of other factors, such as underlying malignancy, age, obesity, and history of previous thromboembolism. Recent meta-analyses of clinical trials have shown there is a high overall risk of DVT during general surgery, based on rates observed in control subjects; there is a confirmed incidence of DVT of 25% noted by the fibrinogen uptake test. The risk is even higher (29%) in surgical patients with malignancy. Risk is also increased in those individuals with multiple risk factors (eg, age > 65 years, obesity, bed rest > 5 days). A comparison of commonly used prophylaxis in 160 clinical trials indicates that overall, low-dose UFH and LMWH are the most effective agents in reducing the incidence of DVT after general surgery. A higher dosage of the prophylactic agent may be needed for adequate prevention in patients with malignant disease.

Treatment alternatives for recurrence There are several treatment options for patients with recurrent VTE. Patients who develop recurrence of thrombosis while on therapeutic doses of anticoagulation should be considered for inferior vena cava filter placement. The filter will not prevent new clots from forming, but it does provide a physical barrier to prevent propagation of clots to the pulmonary bed. Alternatively, an inferior vena cava filter can be placed to avoid the need for long-term anticoagulant therapy if there are contraindications to anticoagulation. Or, another LMWH may be utilized prior to placement of an inferior vena cava filter, since there may be other complications related to filter placement (ie, postphlebitis syndrome, clotting of the filter).

Depending upon patient prognosis and tumor factors, other comorbidities, and propensity for bleeding, continued therapy with warfarin or LMWH may also be considered in addition to filter placement.

SPINAL CORD COMPRESSION

Spinal cord compression develops in 1%–5% of patients with systemic cancer. It should be considered an emergency, as treatment delays may result in irreversible paralysis and loss of bowel and bladder function.

Etiology

Compression of the spinal cord is due predominantly to extradural metastases (95%) and usually results from tumor involvement of the vertebral column. A tumor may occasionally metastasize to the epidural space without bony involvement.

Site of involvement The segment most often involved is the thoracic spine (70%), followed by the lumbosacral (20%) and cervical spine (10%).


 

Most common malignancies Spinal cord compression occurs in a variety of malignancies; the most common are lung, breast, unknown primary, prostate, and renal cancers.

Signs and symptoms

Early signs More than 90% of patients present with pain localized to the spine or radicular in nature (ie, not due to bony involvement but rather to neural compression). Pain, which is usually secondary to bony involvement, is often exacerbated with movement, recumbency, coughing, sneezing, or straining. The majority of patients experience pain for weeks to months before neurologic symptoms appear.

Intermediate signs If cord compression goes untreated, weakness often develops next. It may be preceded or accompanied by sensory loss.

Late signs Symptoms of autonomic dysfunction, urinary retention, and constipation are late findings. Once autonomic, motor, or sensory findings appear, spinal cord compression usually progresses rapidly and may result in irreversible paralysis in hours to days if untreated.

Physical findings may include tenderness to palpation or percussion over the involved spine, pain in the distribution of the involved nerve root, muscle weakness, spasticity, abnormal muscle stretch reflexes and extensor plantar responses, and sensory loss. Sensory loss occurs below the involved cord segment and indicates the site of compression. In patients with autonomic dysfunction, physical findings include a palpable bladder or diminished rectal tone.

Diagnosis

The first step in the diagnosis of spinal cord compression is an accurate neurologic history and examination.

X-rays More than 66% of patients with spinal cord compression have bony abnormalities on plain radiographs of the spine. Findings include erosion and loss of pedicles, partial or complete collapse of vertebral bodies, and paraspinous soft-tissue masses. Normal spine films are not helpful for excluding epidural metastases.

MRI The standard for diagnosing and localizing epidural cord compression is MRI. Gadolinium-enhanced MRI has been especially helpful in assessing cord compression secondary to spinal epidural abscesses, as gadolinium enhances actively inflamed tissues and defines anatomic boundaries. An abnormal signal within the disk space suggests the possibility of infection.

Primary or secondary neoplasms involving the vertebral bodies generally demonstrate a long T1, resulting in decreased signal intensity on a T1-weighted image, and a long T2, with increased signal intensity on the T2-weighted image.

CT and myelography If MRI is unavailable, a CT scan and/or myelogram may be used to diagnose and localize epidural cord compression.

Prognosis

Treatment outcome correlates with the degree and duration of neurologic impairment prior to therapy. In a prospective analysis of 209 patients treated for spinal cord compression with radiotherapy and steroids, Maranzano and Latini reported that of patients who were ambulatory, nonambulatory, or paraplegic prior to treatment, 98%, 60%, and 11%, respectively, were able to ambulate following therapy. Treatment outcome in the most radiosensitive malignancies (eg, lymphoma) was superior to that in the less sensitive cancers (renal cell carcinoma). Almost all ambulatory patients treated with either irradiation alone or laminectomy followed by postoperative irradiation remained ambulatory after treatment, whereas ~10% of patients whose lower extremities were paralyzed could walk after treatment.

Treatment

The goals of treatment of spinal cord compression are recovery and maintenance of normal neurologic function, local tumor control, stabilization of the spine, and pain control. Choice of treatment depends on clinical presentation, availability of histologic diagnosis, rapidity of the clinical course, type of malignancy, site of spinal involvement, stability of the spine, and previous treatment.

In general, radiation therapy has been the treatment of choice for these patients. This is based upon the belief that radiotherapy is as effective as surgery in terms of pain relief and maintaining neurologic function. In other words, the potential complications and convalescence associated with surgery can be avoided in this group of patients with a limited life expectancy.

This approach has been further investigated in a randomized clinical trial reported by Patchell et al. A total of 101 patients with spinal cord compression caused by metastatic cancer were randomized to undergo either surgery followed by adjuvant radiation therapy (n = 50) or radiation therapy alone (n = 51). Radiotherapy for both groups consisted of 10 fractions of 300 cGy each. The primary endpoint was the ability to walk.

The study was stopped after an interim analysis of the 101 patients revealed that 42 of 50 patients (84%) in the surgery group were able to walk after treatment, compared with 29 of 51 patients (57%) in the radiotherapy group (P = .001). Additionally, patients treated with surgery retained the ability to walk significantly longer than those patients treated with radiation therapy alone (median, 122 days vs 13 days; P = .003). Of the 32 patients who entered the trial unable to walk, 10 of 16 (62%) in the surgery arm regained the ability to walk, compared with 3 of 16 (19%) in the radiotherapy arm (P = .01). Based on the results of this trial, decompressive surgery followed by adjuvant radiation therapy should be considered in the treatment of patients with spinal cord compression.

The ability to regain ambulatory function after surgery had been recognized prior to this study. This finding represented the rationale for strong consideration of surgery in this group of patients. The authors advocated the wider use of surgery in most patients with spinal cord compression. Still, there are reasons to consider radiotherapy alone as appropriate initial treatment. They include the disappointing results in the radiotherapy-alone arm in this study compared with the experiences of previous studies and the possible reluctance to consider spinal surgery by patients and/or physicians (based upon limited life expectancy). These issues should, of course, be thoroughly reviewed during the process of informed consent.

Steroids

Dexamethasone should be administered if the patient’s history and neurologic examination suggest spinal cord compression. There is controversy as to whether an initial high dose of intravenous (IV) dexamethasone (100 mg) followed by 10 mg of dexamethasone every 6 hours is necessary. Some studies have suggested lower doses are just as effective.


 

Radiation therapy

Radiation therapy alone is still usually the standard initial treatment for most patients with spinal cord compression due to a radiosensitive malignancy. Treatment outcome is contingent upon both the relative radiosensitivity of the malignancy and the neurologic status of the patient at the time radiotherapy is initiated.

Radiation portal In general, the treatment volume should include the area of epidural compression (as determined by MRI or myelography) plus two vertebral bodies above and below. Consideration should be given to including adjacent areas of abnormalities if feasible. Careful matching techniques should be employed in patients treated to adjacent vertebral levels, a situation that is not uncommon.

Radiation dose and fractionation The chosen regimen should take into account such factors as field size and normal tissue tolerance. Smaller fields are appropriately treated to 2,000–3,000 cGy over 1 or 2 weeks, respectively. Larger fields may occasionally necessitate longer courses, such as 4,000 cGy over 4 weeks, to minimize side effects.

The University Hospital Hamburg has reported their results on five fractionation schemes of radiation therapy for spinal cord compression. In this retrospective review, 1,304 patients were treated from January 1992 through December 2003. Radiation schedules included 1 x 8 Gy (n = 261), 5 x 4 Gy (n = 279), 10 x 3 Gy (n = 274), 15 x 2.5 Gy (n = 233), and 20 x 2 Gy (n = 257). Improvement in motor function was noted in 26% (1 x 8 Gy), 28% (5 x 4 Gy), 27% (10 x 3 Gy), 31% (15 x 2.5 Gy), and 28% (20 x 2 Gy). Motor function improvement and post-treatment ambulatory rates were not significantly different throughout all groups.

On multivariate analysis, age, performance status, pretreatment ambulatory status, and length of time motor deficits were present prior to the initiation of radiotherapy were all significantly associated with improved functional outcome, whereas the schedule of radiation therapy was not a significant indicator. Recurrence rates at 2 years were 24%, 26%, 14%, 9%, and 7%, respectively. There was mild acute toxicity and no late toxicity. The authors concluded that shorter fractionation schemes should be considered for those patients with poor predicted survival.

In another study, the University Hospital Hamburg reported its prospective evaluation of 10 versus 20 fractions of radiation therapy for metastatic spinal cord compression. A total of 214 patients were irradiated with 30 Gy in 10 fractions (n = 110) or 40 Gy in 20 fractions (n = 104). Motor function improved in 43% of patients treated with 30 Gy and in 41% of patients treated with 40 Gy (P = .799). There was no significant difference in post-treatment ambulatory rates (60% and 64%, respectively; P = .708). As expected, being ambulatory prior to the initiation of treatment was associated with better functional outcome after irradiation (P = .035). Acute toxicity was mild, and no late toxicity was observed during the 12-month follow-up.

Retreatment may be entertained, particularly when no effective alternative exists. Usually, doses of 2,000 cGy over 2 weeks can be used for retreatment. It is important, however, to counsel the patient regarding the risk of radiation neuropathy. Furthermore, only those patients who had a lasting response to the initial treatment should be reirradiated, as tumors that were refractory to the first course or that recur within 3 months are unlikely to respond to subsequent courses.

Surgery

Vertebral body resection for a tumor anterior to the cord and posterior laminectomy for a tumor posterior to the cord may be appropriate treatment options for relieving spinal cord compression in patients who require spinal stability, have undergone previous radiotherapy in the area of the compression, require a tissue diagnosis of malignancy, or experience progression of the cord compression despite optimal treatment with steroids and irradiation.

In general, surgical decompression should be strongly considered in patients whose cord compression is caused by a relatively radioresistant cancer and who have a severe neurologic deficit (such as bowel or bladder dysfunction). Unfortunately, many patients in this situation are not candidates for aggressive surgery. In these cases, radiotherapy is offered, albeit with limited expectations for neurologic recovery.

Chemotherapy

Chemotherapy may be an effective treatment of spinal cord compression in select patients with a chemosensitive metastatic tumor. It also may be considered in combination with other treatment modalities, such as radiotherapy, or as an alternative if those modalities are not suitable options for relieving spinal cord compression.

HYPERCALCEMIA

Hypercalcemia is the most common metabolic emergency seen in individuals with cancer, occurring in an estimated 10%–20% of patients.

Etiology

The malignancies most commonly associated with hypercalcemia include myeloma, lung cancer (epidermoid tumors more often than small-cell tumors), and renal cancer. In some cases, the pathogenesis of hypercalcemia may relate to the release of parathyroidlike hormones, prostaglandins, and osteoclast-activating factor.

Signs and symptoms

Symptoms of hypercalcemia may involve various organ systems, including the central nervous, cardiac, GI, and renal systems (Table 1).

Bony metastasis versus paraneoplastic syndrome The signs and symptoms of hypercalcemia secondary to bony metastases are often indistinguishable from those of hypercalcemia as a paraneoplastic syndrome. The laboratory findings may vary. A tumor secreting an immunoreactive parathyroid hormone (iPTH)-like substance will have increased levels of cyclic adenosine monophosphate (cAMP), low levels of serum phosphorus, and variable levels of iPTH, depending on the specificity of the assay. Many patients with bony metastases also exhibit features consistent with “ectopic” hyperparathyroidism.

Diagnosis

An accurate history and physical examination are often the most helpful diagnostic tools to exclude correctable nonmalignant causes of hypercalcemia. Hypercalcemia in association with occult malignancies is rare. The presence of weight loss, fatigue, or muscle weakness should increase clinical suspicion of malignancy as the cause of hypercalcemia.

Laboratory findings In patients with hypercalcemia of malignancy, serum iPTH levels, determined by a double-antibody method, are extremely low or undetectable; levels of inorganic phosphorus are low or normal; and levels of 1,25-dihydroxyvitamin D are low or normal.

Use of additional tests to identify the underlying malignancy responsible for the hypercalcemia often depends on the history and physical findings.

Treatment

Asymptomatic patients with minimally elevated calcium levels (< 12.0 mg/dL) may be treated as outpatients, with close monitoring of calcium levels and symptoms. Encouragement of oral hydration, mobilization, and elimination of drugs that contribute to hypercalcemia are essential. Patients who are symptomatic or have calcium levels ≥ 12.0 mg/dL should be considered for inpatient management if medically appropriate. An algorithm for the acute and chronic treatment of hypercalcemia of malignancy is shown in Figure 1.

Volume expansion (eg, lactated Ringer’s solution, 0.9% NaCl) Volume expansion and natriuresis increase renal blood flow and enhance calcium excretion secondary to the ionic exchange of calcium for sodium in the distal tubule. The volume required depends on the extent of hypovolemia, as well as the patient’s cardiac and renal function. Often, infusion rates of 250–500 mL/h are needed. Typically, the onset of action is 12–24 hours.

Loop diuretics There is much controversy over the effectiveness of loop diuretics in the treatment of hypercalcemia. In theory, furosemide-induced natriuresis should enhance urinary calcium excretion. However, in most cases of significant hypercalcemia, hypovolemia is present. Thus, once euvolemia has been achieved with saline infusion, diuretics may be useful in preventing hypervolemia. Diuretic dosages depend on the patient’s underlying renal function, and the dosing frequency should be based on hourly urine output. In patients with normal renal function, furosemide, 20–40 mg IV, may be initiated after volume expansion is achieved, with subsequent doses given when urine output is < 150–200 mL/h.


 

Bisphosphonates (etidronate, clodronate, pamidronate, and zoledronic acid [Zometa]) bind avidly to hydroxyapatite crystals and inhibit bone resorption. Their antiresorptive effects may be mediated by the inhibition of osteoclasts and activation by cytokines. Bisphosphonates also inhibit recruitment and differentiation of osteoclast precursors. They are poorly absorbed from the GI tract, have a very long half-life in bone, and appear to accumulate at sites of active bone turnover.

Pamidronate has been shown to be effective in restoring normocalcemia in 60%–100% of patients with hypercalcemia secondary to malignancy. The recommended dose is 90 mg IV over 4 hours. The single IV dose over
4 hours, lack of renal toxicity, and superiority over etidronate make pamidronate a logical choice for bisphosphonate therapy for hypercalcemia of malignancy. Side effects include low-grade fever and mild hypocalcemia and hypomagnesemia. Clodronate, another bisphosphonate indicated for cancer-associated hypercalcemia, is dosed at 300 mg IV daily for 5 consecutive days (infused over at least 2 hours) or 800–3,200 mg/d orally. Zoledronic acid
(4 mg IV) is a newer bisphosphonate that can be infused quicker and has fewer systemic side effects than other bisphosphonates.

Corticosteroids In certain malignancies, such as lymphomas and hormone-sensitive breast cancers, corticosteroids may be of some value in producing a direct antitumor effect. In the majority of solid tumors, however, steroids are of limited or no value.

The onset of action is 3–5 days. Doses of prednisone (or its equivalent) may range from 10 to 100 mg/d.

Calcitonin inhibits bone degradation by binding directly to receptors on the osteoclast. It has few serious side effects (rare hypersensitivity) and can be given to patients with organ failure.

Calcitonin’s onset of action is 2–4 hours, but its hypocalcemic effect is of short duration and peaks at 48 hours. There is little response to continued treatment. Doses range from 2 to 8 U/kg SC or IM (intramuscular) every 6–12 hours.

Plicamycin (Mithracin) has direct osteoclast-inhibitory effects and may also block the effects of vitamin D or parathyroid hormone. It reportedly is effective in ~80% of patients with hypercalcemia secondary to malignancy.

The onset of action of plicamycin is 24–48 hours. The duration of normocalcemia varies, but retreatment is required in 72–96 hours in most patients. The usual dose is 25 µg/kg (range: 10 to 50 µg/kg).

Significant toxicity increases with multiple injections and includes renal and liver toxicity. Thrombocytopenia is a common side effect.

Gallium nitrate (Ganite) directly inhibits osteoclasts and increases bone calcium without producing cytotoxic effects on bone cells. It successfully restores normocalcemia in 75%–85% of patients.

Gallium nitrates’s onset of action is 24–48 hours. The dose range is 100–200 mg/m2 given by continuous IV infusion for 5 days.

A study by Bertheault-Cvitkovic et al suggested that gallium nitrate may be superior to pamidronate for the acute normalization of cancer-related hypercalcemia. In other comparative trials, gallium nitrate proved to be more effective than both calcitonin and etidronate in patients with hypercalcemia that is secondary to malignancy.

There are some disadvantages to gallium nitrate therapy, including the need for inpatient care and daily IV infusions and potential nephrotoxicity. It has been recommended that the drug not be used in patients with creatinine levels > 2.5 mg/dL.

HYPERURICEMIA

Compared with hypercalcemia, hyperuricemia is a less common metabolic emergency in cancer patients.

Etiology and risk factors

Hyperuricemia occurs most often in patients with hematologic disorders, particularly leukemias, high-grade lymphomas, and myeloproliferative diseases (polycythemia vera). It may occur secondary to treatment of the malignancy.

Drugs Hyperuricemia is also associated with certain cytotoxic agents (eg, tiazofurin and aminothiadiazoles). Various other drugs can contribute to hyperuricemia by increasing uric acid production or decreasing its excretion. Diuretics (thiazides, furosemide, and ethacrynic acid [Edecrin]) cause acute uricosuria, and hyperuricemia may occur secondary to volume contraction. Antituberculous drugs, such as pyrazinamide and ethambutol (Myambutol), as well as nicotinic acid (niacin) are also associated with hyperuricemia.

Extensive or aggressive tumors Patients with extensive, anaplastic, or rapidly proliferating tumors are at greatest risk for hyperuricemia. These patients include those with bulky lymphomas and sarcomas, those with chronic myelocytic leukemia or chronic lymphocytic leukemia and extreme leukocytosis, and those undergoing remission-induction chemotherapy for acute leukemia.

Renal impairment Individuals with preexisting renal impairment are also at risk of becoming hyperuricemic.

Signs and symptoms

Patients with clinical syndromes caused by hyperuricemia present with significant elevations of serum uric acid. Gouty arthritis may be seen occasionally, but the most significant complication is renal dysfunction, particularly acute renal failure. Clinical symptoms associated with renal dysfunction vary depending on the degree of dysfunction and the timing of its development. In patients with acute renal failure, clinical symptoms may include abnormal mental status, nausea and vomiting, fluid overload, pericarditis, and seizures.

Diagnosis

The diagnosis of hyperuricemia is based on laboratory findings of high serum uric acid levels, hyperuricosuria, and increased serum creatinine and urea nitrogen levels.

Prognosis

Prognosis often depends on the etiology of the hyperuricemia.

Treatment

Prophylactic measures against the development of hyperuricemia should be undertaken prior to the initiation of chemotherapy. Drugs that increase serum urate levels or produce acidic urine (eg, thiazides and salicylates) should be discontinued if possible. Alkalinization of the urine should be initiated to maintain a urine pH > 7.0. Usually, sodium bicarbonate solution (50–100 mmol/L) is added to IV fluids and then adjusted so that an alkaline urinary pH is maintained. The carbonic anhydrase inhibitor acetazolamide (Diamox) may be used to increase the effects of alkalinization. It is important to remember that alkalinization is secondary to the overall goal of decreasing urinary uric acid concentration by increasing urinary volume.

Allopurinol, a xanthine oxidase inhibitor, is the mainstay of drug treatment and may be started 1–2 days prior to cytotoxic treatment. Dosages range from 300–600 mg/d, and therapy is usually continued for 1–2 weeks or until the danger of hyperuricemia has passed.


 

Rasburicase (Elitek) is an antihyperuricemia drug. It has been approved by the FDA for malignancy-associated hyperuricemia in pediatric patients but is also used in adults. The usual pediatric dose is 0.15 or 0.2 mg/kg IV over 30 minutes for 5 days. The usual adult dosage is 0.15–0.2 mg/kg/d in limited studies.

Acute oliguria In patients who develop acute oliguria, ureteral obstruction by urate calculi should be considered. This condition should be evaluated by ultrasonography or CT. Administration of IV contrast agents for pyelography should be avoided, as they may increase the risk of acute tubular necrosis.

Dialysis Patients with advancing renal insufficiency and subsequent renal failure may benefit from peritoneal dialysis or hemodialysis. Dialysis has been shown to be effective in reversing renal failure caused by urate deposition.

TUMOR LYSIS SYNDROME

Tumor lysis syndrome occurs due to the rapid release of intracellular contents into the bloodstream, leading to life-threatening concentrations. If the resulting metabolic abnormalities remain uncorrected, patients may develop renal failure and sudden death.

Etiology and risk factors

Tumor lysis syndrome most commonly develops during the rapid growth phase of high-grade lymphomas and leukemia in patients with high leukocyte counts; it is less common in patients with solid tumors. The syndrome is often iatrogenic, caused by cytotoxic chemotherapy. Because of clinicians’ increased awareness of the tumor lysis syndrome during the past decade and the use of adequate prophylaxis prior to the initiation of chemotherapy, there are fewer cases currently. Occasionally, the syndrome occurs following treatment with irradiation, glucocorticosteroids, tamoxifen, or interferon.

Patients at risk The typical patient at risk for tumor lysis syndrome tends to be young (< 25 years of age) and male and has an advanced disease stage (often with abdominal disease) and a markedly elevated lactic dehydrogenase level.

Other predisposing factors include volume depletion, concentrated acidic urine pH, and excessive urinary uric acid excretion rates.

Signs and symptoms

The syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and, often, oliguric renal failure.

Diagnosis

The diagnosis of tumor lysis syndrome is based on the development of increased levels of serum uric acid, phosphorus, and potassium; decreased levels of serum calcium; and renal dysfunction following chemotherapy.

Prognosis

Prognosis varies depending on the adequate correction of metabolic abnormalities and the underlying etiology of tumor lysis.

Treatment

Prophylactic measures Patients at risk for tumor lysis syndrome should be identified before the initiation of chemotherapy and should be adequately hydrated and given agents to alkalinize the urine. Treatment with allopurinol (IV or oral) may be instituted to minimize hyperuricemia. The recommended dosage of IV allopurinol ranges from 200 to 400 mg/m2/d. This regimen should be started 24–48 hours before the initiation of cytotoxic treatment. The dose may be equally divided into 6-, 8-, or 12-hour increments, but the final concentration should not exceed 6 mg/mL. (For oral dosages of allopurinol and IV doses of rasburicase, see the section on “Hyperuricemia, treatment” earlier in this chapter.)

Serum electrolytes, uric acid, phosphorus, calcium, and creatinine levels should be checked repeatedly for 3–4 days after chemotherapy is initiated, with the frequency of monitoring dependent upon the clinical condition and the risk profile of the patient.

Established tumor lysis Once tumor lysis is established, treatment is directed at vigorous correction of electrolyte abnormalities, hydration, and hemodialysis (as appropriate in patients with renal failure).

SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a paraneoplastic condition that is associated with malignant tumors (particularly SCLC), CNS disease (eg, infection, intracerebral lesions, head trauma, and subarachnoid hemorrhage), and pulmonary disorders (eg, tuberculosis, pneumonia, and abscess).

Signs and symptoms

Hyponatremia is the most common presenting sign of SIADH. Patients who experience a rapid fall in plasma sodium levels are usually the most symptomatic.

Other presentations Patients with SIADH can also experience malaise, altered mental status, seizures, coma, and, occasionally, death. Focal neurologic findings can occur in the absence of brain metastases.

Diagnosis

To make a diagnosis of SIADH, certain criteria must be met (Table 2). In addition to those criteria, patients should have normal renal, adrenal, and thyroid function, along with normal extracellular fluid status.

Drug history It is important to obtain a full list of the medications that the patient is taking, since certain drugs can impair free water excretion either by acting on the renal tubule or by inducing pituitary arginine vasopressin (AVP). These drugs include morphine, cyclophosphamide, vincristine, chlorpropamide (Diabinese), amitriptyline, and clofibrate (Atromid-S).

Treatment

The major focus of treatment for SIADH related to malignancy is successful treatment of the underlying cancer.

Acute treatment is indicated in patients who are symptomatic and who have severe hyponatremia (eg, serum sodium level < 125 mEq/L). The goals of therapy in these patients are to initiate and maintain rapid diuresis with IV furosemide (1 mg/kg body weight) and to replace the sodium and potassium lost in the urine. Usually, the latter goal can be achieved by administering 0.9% saline with added potassium.


 

This rapid correction should not exceed a 20-mEq/L rise in serum sodium concentration during the first 48 hours. Patients who experience too rapid a rise in serum sodium concentration may suffer neurologic damage and central pontine myelinolysis.

Chronic treatment The mainstay of chronic therapy is water restriction to 500–1,000 mL/d. When this measure alone is unsuccessful, demeclocycline (Declomycin), 300–600 mg orally bid, may be used in patients without liver disease. The onset of action may be > 1 week.

LAMBERT-EATON SYNDROME

The Lambert-Eaton syndrome is strongly associated with SCLC. It is caused by antibodies that interfere with the release of presynaptic acetylcholine at the neuromuscular junction.

Signs and symptoms

Fatigue/muscle weakness This syndrome is characterized by fatigue and proximal muscle weakness, particularly of the pelvic girdle and thighs.

Autonomic symptoms Many patients with this disorder have autonomic symptoms, one of the most common of which is dry mouth.

Other symptoms Other possible symptoms include diplopia or blurred vision, ptosis, dysarthria, dysphagia, and paresthesias.

Diagnosis

Patients with the Lambert-Eaton syndrome show an improvement in muscle strength with exercise.

Electromyographic (EMG) studies are helpful in making the diagnosis. These studies reveal an increase in the muscle action potential with repeated nerve stimulation at rates faster than 10 per second.

Edrophonium test In addition, in contrast to individuals with myasthenia gravis, patients with the Lambert-Eaton syndrome have a poor response to the edrophonium test.

Treatment

Chemotherapy is the first line of treatment, since 90% of patients with SCLC will respond to this measure. In fact, recovery from the Lambert-Eaton syndrome has been noted in some patients treated with chemotherapy.

Other therapies For patients in whom chemotherapy fails to improve symptoms or control the tumor, guanidine has been reported to be useful, as has 3,4-diaminopyridine.

Guanidine is taken orally beginning with a dosage of 5–10 mg/kg/d divided throughout the waking hours. The dosage may be increased to a maximum of 30 mg/kg/d on the basis of the patient’s clinical response. However, side effects may be severe at dosages > 1 g/d. Also, the dose of guanidine should not be increased more often than every 3 days, since the maximum response to a dose may not be seen for 2–3 days. At dosages of 5–25 mg 3–4 times per day, 3,4-diaminopyridine can significantly improve symptoms. Side effects of this drug include perioral and acral paresthesias, insomnia, and epigastric distress.

In addition, plasmapheresis, steroids, immunosuppression, and IV gamma globulin are all of potential benefit.

POLYMYOSITIS/DERMATOMYOSITIS

The relationship between polymyositis/dermatomyositis and malignancy was established long ago. The most commonly associated malignancies are breast, lung, and ovarian cancers. An increased incidence of cancer patients with dermatomyositis (10%) has been observed, but the association of cancer with polymyositis is less clear.

Signs and symptoms

Muscle weakness Patients with this syndrome typically experience proximal muscle weakness that progresses over weeks to months. Weakness in the hips, thighs, and shoulder girdle may cause patients to have difficulties in getting out of a chair, climbing stairs, or combing their hair. Patients also may experience dysphagia as well as weakness of the flexor muscles of the neck.

In the majority of cases, the distal muscles of the extremities are not involved. Also, most patients do not have involvement of the extraocular muscles.

Rashes Patients with dermatomyositis can have involvement of the eyelids, forehead, cheeks, chest, elbows, knees, and knuckles with the classic heliotrope rash. A more diffuse rash may also occur.

Diagnosis

Muscle enzymes and erythrocyte sedimentation rate Patients with polymyositis/dermatomyositis usually have an elevation in their serum muscle enzyme levels and erythrocyte sedimentation rate (ESR).

EMG studies and muscle biopsies In addition, EMG tracings are abnormal, and muscle biopsies reveal minimal inflammatory changes, along with muscle fiber necrosis, in patients with polymyositis/dermatomyositis.

Treatment

Steroids In addition to treatment of the underlying malignancy, patients with polymyositis or dermatomyositis are treated with high-dose oral steroids (eg, prednisone, 60–80 mg/d). Other supportive measures, such as range-of-motion exercises, are also prescribed.

Immunosuppressives In patients who do not respond to steroid therapy, immunosuppressive therapy is often added. This type of therapy needs to be tailored to the individual patient, and consultation with a rheumatologist should be considered.

Therapy for skin disease The skin disease of dermatomyositis can be treated with a variety of measures, such as topical corticosteroids, antimalarials, photoprotection, and, at times, low-dose methotrexate.

SUGGESTED READING

ON SUPERIOR VENA CAVA SYNDROME

Mose S, Stabik C, Eberlein K, et al: Retrospective analysis of the superior vena cava syndrome in irradiated cancer patients. Anticancer Res 26:4933–4936, 2006.

Rice TW, Rodriguez RM, Light RW: The superior vena cava syndrome: Clinical characteristics and evolving etiology. Medicine (Baltimore) 85:37–42, 2006.

ON VENOUS THROMBOEMBOLIC COMPLICATIONS

Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62, 2005.

Chew HK, Wun T, Harvey DJ, et al: Incidence of venous thromboembolism and the impact on survival in breast cancer patients. J Clin Oncol 25:70–76, 2007.

ON SPINAL CORD COMPRESSION

Patchell RA, Tibbs PA, Regine WF, et al: Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: A randomised trial. Lancet 366:643–648, 2005.

Rades D, Stalpers LJ, Veninga T, et al: Evaluation of five radiation schedules and prognostic factors for metastatic spinal cord compression. J Clin Oncol 23:3366–3375, 2005.

Rades D, Veninga T, Stalpers LJ, et al: Outcome after radiotherapy alone for metastatic spinal cord compression in patients with oligometastases. J Clin Oncol 25:50–56, 2007.

ON HYPERCALCEMIA

Cvitkovic F, Armand JP, Tubiana-Hulin M, et al: Randomized, double-blind, phase II trial of gallium nitrate compared with pamidronate for acute control of cancer-related hypercalcemia. Cancer J 12:47–53, 2006.

ON HYPERURICEMIA/TUMOR LYSIS SYNDROME

Jeha S, Kantarjian H, Irwin D, et al: Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: Final results of a multicenter compassionate use trial. Leukemia 19:34–38, 2005.

ON SYNDROME OF INAPPROPRIATE SECRETION OF ANTIDIURETIC HORMONE

Flombaum CD: Metabolic emergencies in the cancer patient. Semin Oncol 27:322–334, 2000.

Raftopoulos H: Diagnosis and management of hyponatremia in cancer patients. Support Care Cancer 15:1341–1347, 2007.

ON LAMBERT-EATON SYNDROME

Dropcho EJ: Remote neurologic manifestations of cancer. Neurol Clin 20:85–122, 2002.

Wirtz PW, Smallegange TM, Wintzen AR, et al: Differences in clinical features between the Lambert-Eaton myasthenic syndrome with and without cancer: An analysis of 227 published cases. Clin Neurol Neurosurg 104:359–363, 2002.

ON POLYMYOSITIS/DERMATOMYOSITIS

Sparsa A, Liozon E, Herrmann F, et al: Routine vs extensive malignancy search for adult dermatomyositis and polymyositis: A study of 40 patients. Arch Dermatol 138:885–890, 2002.

Wakata N, Kurihara T, Saito E, et al: Polymyositis and dermatomyositis associated with malignancy: A 30-year retrospective study. Int J Dermatol 41:729–734, 2002.