Abeloff's Clinical Oncology, 4th Edition

Part II – Problems Common to Cancer and its Therapy

Section F – Local Effects of Cancer and Its Metastasis

Chapter 54 – Superior Vena Cava Syndrome

David H. Johnson,
Janessa Laskin,
Anthony Cmelak,
Steven Meranze,
John Robert Roberts

SUMMARY OF KEY POINTS

Etiology

  

   

Superior vena cava (SVC) syndrome is usually due to neoplastic process—predominantly primary lung carcinoma, with a disproportionate number of patients having small cell histology; non-Hodgkin's lymphoma and metastatic tumors are the next most common.

  

   

SVC syndrome can be iatrogenic—sometimes seen as a complication of central venous line or cardiac surgery.

Anatomy and Physiology

  

   

Junction of the brachiocephalic veins forms the thin-walled, low-pressure SVC, which is subjected to obstruction from a variety of mediastinal components.

  

   

External compression often precedes direct tumor invasion or thrombus formation.

  

   

The SVC has an extensive collateral network.

Clinical Features

  

   

Usual symptoms are head “fullness,” dyspnea, cough, and chest pain, typically with insidious onset.

  

   

More severe symptoms are infrequent, and life-threatening, neurologic symptoms are rare.

  

   

Diagnosis is based on clinical findings.

Evaluation

  

   

Chest radiograph typically shows mediastinal widening; a mass is often seen in the region of the SVC.

  

   

Small-dose cavagrams can be safely accomplished to define exact location and routes of collateral flow.

  

   

Computed tomography (CT) scanning identifies the mass and collateral flow and is the most helpful study to guide treatment.

  

   

Treatment of an identified mass before histologic diagnosis is rarely justified unless prior diagnosis is established.

  

   

Methods used to define histology are sputum cytology, bronchoscopy, lymph node biopsy, thoracentesis, percutaneous biopsy, mediastinoscopy, and thoracotomy; previously reported high risks associated with these procedures are not borne out in current data.

Treatment

  

   

Radiation therapy with or without chemotherapy is the preferred treatment in most malignant causes of SVC obstruction, particularly small cell lung cancer (SCLC) and non-Hodgkin's lymphoma.

  

   

Radiation therapy fractionation schedule depends on tumor histology, stage, prognosis, patient's general condition, and whether obstruction is acute or subacute.

  

   

Surgery is usually reserved for selective patients with benign causes of obstruction and consists of a bypass procedure.

  

   

Percutaneously placed, self-expanding intravascular wire stents provide an option or adjunct to other procedures in the palliative treatment of patients (usually with malignant disease).

INTRODUCTION

Obstruction of the superior vena cava (SVC) may occur as an acute or subacute process producing a syndrome with characteristic features including facial edema and plethora, dilation of chest wall and neck veins, mild to moderate respiratory difficulty, and, less commonly, conjunctival edema, central nervous system complaints such as headache, or, more rarely, visual disturbances and signs of altered states of consciousness. [1] [2] [3] [4] The first recorded description of SVC obstruction (SVCO) occurred in 1757 when William Hunter described the entity in a patient with syphilitic aortic aneurysm.[5] For nearly two centuries thereafter, nonmalignant processes such as aortic aneurysms, syphilitic aortitis, or chronic mediastinitis due to tuberculosis were the predominant etiologic factors. [1] [3] [6] [7] However, these diseases are now quite rare, and cancer has become the leading cause of SVCO primarily because of the rapid increase in the incidence of bronchogenic carcinoma after World War II. [1] [3] [6] [8] [9] [10]Although SVCO was once considered a medical emergency, it is now well established that patients with SVCO rarely experience immediate, life-threatening complications. [6] [11] [12] [13] Consequently, in cases in which a diagnosis is not known, it is appropriate to proceed with a biopsy to establish the underlying cause, because optimal management is dependent on etiology.[14]

ANATOMY AND PATHOPHYSIOLOGY

The SVC is formed by the junction of the brachiocephalic veins, which in turn are formed by the joining of the internal jugular and subclavian veins. Thus, the SVC represents the major drainage system of venous blood from the head, neck, arms, and upper thorax.[15] The right and left brachiocephalic veins join at about the level of the sternal angle to form the SVC. The SVC descends on the right side of the ascending aorta and empties into the right atrium, with its distal 2 cm lying within the pericardial sac ( Fig. 54-1 ).

 
 

Figure 54-1  Normal anatomy and drainage pattern of the superior vena cava.

 

 

Because of its mediastinal location surrounded by several rigid structures including the sternum, trachea, pulmonary artery, right main-stem bronchus, and numerous lymph nodes, the SVC is particularly vulnerable to obstruction. Despite being a relatively large vessel, its thin vascular walls and low intravascular pressure contribute to the ease with which the SVC can be obstructed.[15] SVCO can be caused by external compression due to tumor or by lymph nodes enlarged by inflammation or metastases ( Fig. 54-2 ). SVCO also can be caused by direct tumor invasion or by a thrombus. Secondary thrombus is reported to occur in up to 50% of cases[2] and may contribute to the lack of response to appropriate therapeutic maneuvers.

 
 

Figure 54-2  Lateral view of the thorax with superior vena cava obstruction.

 

 

The azygous vein represents an important collateral system of the SVC and is formed by the junction of the right subcostal and right ascending lumbar veins. Additional routes of collateral flow include the mammary, vertebral, lateral thoracic, paraspinous, and esophageal vessels. The azygous vein ascends through the posterior and superior mediastinum, arches over the hilum of the right lung, and ends in the SVC. Fortunately, extensive anastomoses are formed between the SVC, azygous, and vertebral systems, providing multiple routes of collateral blood flow. Therefore, an obstruction of the SVC above the orifice of the azygous vein is better tolerated than is blockage below this level, because blood can be diverted through chest-wall veins into the thoracic and iliac veins and enter the heart by way of the inferior vena cava and azygous systems. [9] [15] [16] Blood from the head and neck also can return to the heart via the vertebral plexus. If the SVC is obstructed between the azygous vein and the heart, the only route of blood return is via the inferior vena cava.

ETIOLOGY

Since the middle part of the 20th century, cancer has been the principal cause of SVCO, with bronchogenic carcinoma accounting for up to 85% of cases ( Table 54-1 ). [1] [2] [3] [8] [11] [17] [18] [19] [20] [21] The two most frequent lung cancer histologic types associated with SVCO are small cell and squamous cell carcinoma. [1] [15] [22] [23] [24] Although small cell lung cancer (SCLC) accounts for just 15% to 20% of newly diagnosed lung cancers, it is the underlying cause of up to 65% of all cases of SVCO. [6] [9] [22] [25] [26] The tendency of SCLC to occur centrally within the lung, as well as its high incidence of mediastinal lymph node metastases, most likely accounts for this consistent observation. Although lung cancer is the leading cause of SVCO, the incidence of this syndrome in patients with lung cancer ranges from 3% to 30%, with most series tending toward the lower figure. [4] [12] [27]


Table 54-1   -- Causes of Superior Vena Cava Syndrome

 

Parish et al

Yellin et al

Lochridge et al

Davenport et al

Bell et al

Armstrong et al

Scarantino et al

Little et al

Total patients

86

63

66

35

159

125

60

42

Lung cancer

45

30

52

26

129

99

36

35

 Non-small cell

33

26

44

6

64

57

23

28

 Small cell

12

4

8

20

65

42

13

7

Lymphoma

8

13

8

1

3

18

8

3

Metastases

12

4

4

4

4

8

4

3

Thymoma/Thyroid

2

4

1

1

Benign

19

11

2

2

Biopsy not done

3

21

12

Data compiled from references 1–3, 11, 17–19, and 21. [1] [2] [3] [11] [17] [18] [19] [21]

 

 

Non-Hodgkin's lymphoma is the second most common cause of SVCO. [3] [6] [28] [29] Perez-Soler and colleagues[29] identified 36 cases among 915 lymphoma patients treated at the M.D. Anderson Cancer Center (University of Texas, Houston). SVCO was most commonly observed with diffuse large cell and lymphoblastic lymphomas.[29] The frequency of mediastinal presentations with the latter histologic types may account for this association, because up to 65% of patients with lymphoblastic lymphomas are first seen with a mediastinal mass. The incidence of SVCO in these categories of non-Hodgkin's lymphoma is reported to be 7% and 20%, respectively.[29]

Metastatic cancers account for approximately 5% to 10% of SVCOs (see Table 54-1 ). [1] [3] [8] [11] [18] [21] [30] [31] [32] The most common primary tumor sites are, in approximate order of frequency: breast cancer, germ cell malignancies, and gastrointestinal cancers. Less common primary sites include sarcomas (including primary sarcomas of the great vessels), [33] [34] [35] transitional cell carcinoma, prostate cancer, and melanomas.[32] However, virtually any cancer capable of metastasizing to the mediastinum can result in SVCO.

Nonmalignant causes of SVCO account for up to 5% of cases. An increasingly common benign cause of SVCO is central venous catheter-induced thrombosis, which may occur with cardiac pacemakers, LaVeen shunts, hyperalimentation lines, and Swan-Ganz catheters, as well as those used for chemotherapy administration. [8] [36] [37] [38] [39] [40] [41] [42] [43] SVCO seems to be more common when the tip of the catheter is placed in the left subclavian vein in the upper part of the vena cava.[40] The incidence of catheter-related thrombosis may be reduced with the administration of very-low-dose warfarin (1 mg/day) before insertion of the catheter and continuation afterward. [44] [45] Additional rare benign causes of SVCO include chronic mediastinitis secondary to histoplasmosis, retrosternal goiters, Nocardiainfection, and congestive heart failure. [3] [46] [47] [48] [49] [50]

In children, SVCO is most frequently related to iatrogenic causes secondary to cardiovascular surgery for congenital heart disease or ventriculoatrial shunts for hydrocephalus. [51] [52] [53] The most common malignant causes of SVCO in children are non-Hodgkin's lymphoma, acute lymphoblastic leukemia, Hodgkin's disease, neuroblastomas, and yolk sac tumors. [51] [53]

CLINICAL FEATURES

Although the duration of symptoms may range from a few days to several weeks, a majority of patients have symptoms of 4 weeks’ duration or less.[1] The physical findings accompanying SVCO are diagnostic ( Fig. 54-3 ). Patients frequently complain of a sense of head “fullness,” mild dyspnea, cough, chest pain, and occasionally dysphagia ( Table 54-2 ). [1] [3] [13] [21] [25] [53] Less frequently arm edema, stridor, upper body cyanosis, and neurologic symptoms (e.g., headaches or lethargy) may occur. All symptoms may be aggravated by positional changes, particularly those associated with lowering of the head, for example bending to put on shoes.

 
 

Figure 54-3  A patient with characteristic venous dilation and facial edema.

 

 


Table 54-2   -- Signs and Symptoms of Superior Vena Cava Obstruction

 

Parish et al

Yellin et al

Lochridge et al

Maddox et al

Bell et al

Armstrong et al

Scarantino et al

Little et al

Total patients

86

63

66

56

159

125

60

42

Suffusion

69

54

55

49

62

56

55

35

Dyspnea

54

19

55

112

69

47

22

Cough

47

13

46

11

29

11

26

Pain

17

4

20

19

Dysphagia

10

4

1

16

6

3

Syncope

6

2

6

Arm edema

3

20

19

13

49

Stridor

1

22

1

Neurologic

2

23

0

0

Hemoptysis

5

5

Data compiled from references 1, 3, 11, 17–19, 21, and 31 [1] [3] [11] [17] [18] [19] [21] [31].

 

 

The prospect of catastrophic neurologic events has led to the characterization of SVCO as an “oncologic emergency.” [4] [9] [53] However, experimental studies in dogs as well as several recent reviews have conclusively demonstrated that life-threatening neurologic symptoms such as seizures, syncope, or coma rarely occur. [6] [8] [13] [14] [16]

RADIOGRAPHIC FINDINGS AND DIAGNOSTIC STUDIES

Imaging Studies

A standard chest radiograph is the first radiographic procedure performed when SVCO is suspected, with the most common abnormality being mediastinal widening. Typically, a mass is found in the superior mediastinum, right hilum or perihilar region, or right upper lobe [3] [4]; however, a normal chest radiograph is not inconsistent with the diagnosis of SVCO.[3]

A contrast-enhanced chest computed tomography (CT) scan provides visualization of extravascular and intravascular tumor, as well as thrombus formation within the SVC, and also demonstrates collateral flow. [54] [55] [56] [57] [58] [59] [60] [61] A CT diagnosis depends on diminished or absent contrast opacification of central venous structures such as the innominate vein or the SVC inferior to the obstruction, and opacification of collateral venous routes,[59] especially anterior subcutaneous collaterals ( Fig. 54-4 ).[54] Because dilution of the contrast medium by unopacified blood or the displacement of blood by laminar flow may simulate an intraluminal filling defect, both criteria must be present for the diagnosis of SVCO to be made.[59] The anatomy defined by CT scan may help to guide a fine-needle aspiration biopsy or another diagnostic procedure if a histologic diagnosis has not been previously established. The current-generation helical CT scans also have been used to diagnose SVCO with results that correlate well with regular contrast CT scans.[58] In addition, helical scans can potentially reveal more information regarding the site and extent of disease and the collateral pathways involved, as well as define soft-tissue abnormalities.

 
 

Figure 54-4  Chest computed tomography venogram scan of a patient with superior vena cava obstruction. Note the abrupt blockage of contrast dye indicative of the superior vena cava obstruction.

 

 

Contrast venacavograms may still play an occasional role in determining management strategy, particularly when surgical bypass or stenting is being considered.[62] Current techniques using low-osmolarity contrast involve the positioning of a small catheter in the desired vascular location under fluoroscopic guidance with injection of only small amounts of contrast dye necessary to define the pattern of venous flow and degree of SVCO.[62] Collateral circulation is usually identified readily, and complications are uncommon. Cavography also is possible by using nuclear medicine techniques. [63] [64] [65] [66]

In the majority of cases of SVCO, a contrast CT scan will be the most useful radiographic study; noncontrast studies are of limited value, because the vessels are difficult to distinguish. However, occasionally other imaging studies may also provide helpful data. [56] [57] For example, transesophageal echocardiography can be used to distinguish thrombus formation from extrinsic compression of the SVC.[67] Single-photon emission CT has been used to identify obstruction of the SVC by an intravascular metastasis from an adenocarcinoma.[68]

DIAGNOSTIC APPROACH

In the absence of a known cause of SVCO, every effort should be made to obtain a histologic diagnosis before the initiation of any therapy ( Box 54-1 ) for two reasons. [6] [8] [13] [14] First, a definitive diagnosis is necessary to plan therapy, and second, even a brief course of radiation therapy before establishing a diagnosis can make histologic diagnosis difficult or even impossible. [14] [69] [70]

Box 54-1 

HISTOLOGIC CONFIRMATION OF UNDERLYING CAUSE OF SUPERIOR VENA CAVA OBSTRUCTION

In most cases the distinction between carcinoma and lymphoma is readily accomplished with routine hematoxylin and eosin stains. Special studies sometimes required to distinguish these entities include the following:

  

1.   

Immunoperoxidase stains

  

a.   

Common leukocyte antigen; positive in lymphoma, negative in carcinomas

  

b.   

Epithelial membrane antigen or keratin; positive in carcinomas, negative in lymphomas

  

c.   

Surface immunoglobulins; positive in B-cell lymphomas, negative in carcinomas

  

2.   

Electron microscopy

  

a.   

Desmosomes and intracellular junctions typical of carcinomas

  

b.   

Microvilli typical of adenocarcinomas

  

c.   

Dense-core granule (neurosecretory) present in neuroendocrine tumors (e.g., small cell lung cancer)

  

d.   

Transformed lymphocytes, identified from a paucity of organelles, abundant free ribosomes, prominent nucleoli, and occasional presence of nuclear blebs

Immunoperoxidase studies can usually be obtained relatively quickly and are most helpful in distinguishing a lymphoma from a carcinoma. However, expensive pathology studies are avoided unless necessary to help guide therapeutic decisions.

The least invasive diagnostic technique should be performed initially, followed by more invasive procedures as necessary ( Box 54-2 ). Procedures commonly used to establish a tissue diagnosis includesputum cytology, bronchoscopy, lymph node biopsy, thoracotomy, and mediastinoscopy, although the diagnosis is sometimes obtained through other means such as thoracentesis and percutaneous lung biopsy with or without ultrasound guidance. [6] [17] [71] [72] [73] The complication rate of invasive procedures in the face of SVCO is fairly modest. Schraufnagel and associates[13] reviewed the outcome of 93 invasive procedures in 62 patients with diagnostic problems, and none of the procedures, including bronchoscopies and mediastinoscopies, was associated with a fatal outcome. Yellin and coworkers[21]performed 27 invasive diagnostic procedures in 63 patients with SVCO. No mortality or major bleeding episodes were observed, and diagnostic material was obtained in 89% of patients. Ahmann[6]reported that complications of bronchoscopy and lymph node biopsies are virtually nonexistent and that contrast studies, such as nuclear medicine venography, are remarkably safe in the presence of SVCO. Of the various invasive procedures used to obtain tissue in patients with SVCO, mediastinoscopy seems to be the most risky. However, even this procedure has a relatively low complication rate. Mineo and colleagues[73] reviewed the outcome of 80 patients who underwent diagnostic mediastinoscopy for SVCO by a single surgeon over a 23-year period. Five patients had significant bleeding, but only one required an urgent sternotomy, and no perioperative mortality was recorded. A definitive diagnosis was made in all of the patients; therefore, mediastinoscopy should be considered if less invasive procedures are unsuccessful at determining a diagnosis ( Table 54-3 ). [17] [72] [74] [75]

Box 54-2 

APPROACH TO PATIENTS WITH SUPERIOR VENA CAVA OBSTRUCTION

Diagnosis is established by physical examination and clinical presentation (see text).

  

   

Respiratory status should be assessed promptly. Only patients in extremis should be treated urgently with radiation without a histologic diagnosis. Emergency radiation therapy is necessary in fewer than 5% of all SVCO cases. Stent insertion can also be considered as first-line therapy for patients with malignant cases of SVCO.

  

   

Diagnostic evaluation should proceed with least invasive procedures performed initially followed by more invasive procedures as needed to obtain histologic diagnosis:

  

   

Chest radiograph

  

   

Sputum cytology

  

   

Thoracentesis with cytologic evaluation of fluid

  

   

Node biopsy if palpable node is present, avoid fine-needle aspiration if lymphoma suspected

  

   

Fiberoptic bronchoscopy

  

   

Mediastinoscopy

  

   

Thoracostomy

  

   

Evaluation may vary depending on the age and sex of the patient.

  

   

In older adults (i.e., ≥50), the most common cause of SVCO is lung cancer; lymphoma or metastatic cancer are less common and benign processes are uncommon.

  

   

In young adults (<50 years old), the most common cause of SVCO is lymphoma (usually large cell lymphoma or lymphoblastic lymphoma; rarely Hodgkin's disease); lung cancer or rare thoracic malignancy are less common, and germ cell cancer (almost never in females) and benign causes all uncommon. The preceding evaluation should be modified to include the following studies before more invasive procedures:

  

   

Serum tumor markers (i.e., β-human chorionic gonadotropin, α-fetoprotein, lactate dehydrogenase)

  

   

Bone marrow aspiration and biopsy


Table 54-3   -- Diagnostic Procedures, Yield, and Complication Rate in Superior Vena Cava Obstruction

Procedure

No. Performed

No. Diagnostic

Complications

Sputum cytology

30

8

0

Bronchoscopy

84

39

1

Thoracotomy

22

21

0

Mediastinoscopy

132

124

13

Lymph node biopsy

44

30

0

Bone marrow

13

3

0

Data compiled from references 13, 21, 31, 55, 73, 75, and 147 [13] [21] [31] [55] [73] [75] [147].

 

 

Special pathologic studies may be needed to establish a diagnosis when routine histologic assessment is unclear or available tissue is scant. Other laboratory studies such as serum tumor marker (e.g., β-human chorionic gonadotropin and α-fetoprotein) determination may be useful in selected cases. For example, the presence of an elevated β-human chorionic gonadotropin and/or an abnormal α-fetoprotein in a young male patient with SVCO is virtually diagnostic of an underlying germ cell malignancy. In the latter situation, no further workup is needed before initiation of chemotherapy.

The diagnostic yield from various noninvasive and invasive procedures ranges from approximately 20% for cytologic studies to virtually 100% with thoracotomy and mediastinoscopy (see Table 54-3 ). [73] [75] Although these findings may reflect publication bias, the existing data argue against the need for immediate irradiation without a histologic diagnosis in most cases. In rare circumstances, a definitive tissue diagnosis cannot be made in a timely manner. In such cases it is appropriate to proceed with radiotherapy or placement of an endovascular stent, because either therapy is effective for most underlying causes of SVCO. Prudence dictates that prolonged attempts to establish a histologic diagnosis should be discouraged in the presence of severe dyspnea due to tracheal compression or rapidly progressive neurologic symptoms. Furthermore, in circumstances in which SVCO occurs in an individual with an established diagnosis of cancer or other known cause, an attempt to reestablish the histology of the underlying cause clearly is not a productive exercise.[13]

TREATMENT

Radiotherapy

Radiotherapy is the most commonly used treatment modality for SVCO after a malignant etiology has been established. Three factors must be considered before radiation delivery: (1) dose fractionation (fraction size and timing), (2) total dose to be delivered, and (3) volume to be irradiated, or “field size.”[9]

Dose Fractionation

Considerable controversy is found in the radiation oncology literature over the past 40 years regarding fractionation in patients with SVCO. Before 1960, treatment of SVCO generally consisted of low-dose (i.e., 50–100 cGy) fractions to avoid inducing “radiation edema,” which was assumed to cause further compromise of SVC patency and worsen associated symptoms.[76] In reality, however, the fear of producing further SVC compromise by radiation-induced edema was largely unfounded, and symptoms previously ascribed to radiation edema were predominantly due to inadequately treated tumor, causing progressive obstruction.[23]

Rubin and associates[23] undertook a retrospective comparison of a high-fraction regimen (400 cGy/day) with historical controls treated with lower fraction schedules (200 cGy/day). They noted more prompt relief of facial swelling after an initial high-dose-per-fraction schedule. The apparent superiority of high-dose-per-fraction regimens in providing faster symptom relief has been corroborated in several other retrospective nonrandomized studies. [1] [2] [13] [14] [16] [19] [22] [77] In contrast, Perez and colleagues[4] found the high-dose-per-fraction regimen only slightly better than conventional fractions. It is our belief that for the management of potentially curable patients, 300-cGy fractions for the first 2 to 3 days is reasonable therapy for those experiencing rapidly progressive and distressing SVCO. Thereafter, the daily fraction size can be safely reduced, and the total dose adjusted to compensate for the number of initial high-dose fractions. Patients with subacute SVCO treated with curative intent should be managed with conventional (e.g., 200 cGy) fractions throughout their treatment course. Effects on surrounding normal tissues treated to tolerance doses are more predictable with standard fractions. Appropriate oblique fields with spinal cord shielding can later be used to boost the target volume.

In patients with extrathoracic disease who are treated with palliative intent, total radiotherapy doses will probably be lower, and the use of higher fraction sizes (e.g., ≥300 cGy) for the entire course of radiation is appropriate. With two hypofractionated regimens with 8-Gy fractions, Rodrigues and associates[77] concluded that 24 Gy given once weekly in 8-Gy fractions using spinal cord sparing after the first fraction produced better relief of symptoms, more durable responses, and better median survival than did 16 Gy given in 1 week.

Total Dose

In the individual with SVCO, the planned total radiation therapy dose should take into account the specific type and extent of underlying malignancy and normal tissue tolerance. Other considerations include prognosis and performance status, the speed at which SVCO symptoms developed, and whether chemotherapy is to be included in the treatment program. The radiation oncologist must also decide if the goal of treatment is curative or palliative and treat accordingly. If radiation alone is to be used for the curative treatment of lymphoma in adults, 3600 to 4400 cGy is commonly recommended. [78] [79]More commonly, however, combined-modality treatment is given, and total radiation dose can then be reduced.[80] In SCLC, typically 4500 cGy twice daily or 6000 cGy given daily with concomitant chemotherapy is recommended, [81] [82] and for non-SCLC, 6000 cGy to 7000 cGy is usually used sequentially or, more commonly, simultaneously with chemotherapy. [83] [86]

Field Size

Radiation field size is determined by the extent of disease, baseline pulmonary reserve as determined by pulmonary function tests and split perfusion-ventilation scans, and the type of chemotherapy, if any, the patient will receive. Toxicity of treatment, in particular radiation pneumonitis, pericarditis, and fibrosis, can carry significant morbidity and mortality if severe. Mortality from severe radiation pneumonitis approaches 50% in some reports.[87] Therefore, efforts to minimize radiation field size carry considerable importance in the treatment of SVCO. Risk of pneumonitis is a function of many patient- and treatment-related factors: pretreatment performance status, gender (women more likely than men), forced expiratory volume in 1 second, low PaO2 (<80 torr), mean lung dose, and volume of lung irradiated to 20 Gy. [88] [89] [90] To reduce the risk of pulmonary and cardiac toxicity, some groups have used induction chemotherapy followed by thoracic irradiation with a reduced treatment volume. With bronchogenic carcinoma, retrospective and prospective studies have shown that the postchemotherapy tumor volume can be treated without significantly compromising local control or survival. [91] [92] In addition, CT scan-based treatment planning, particularly with intensity-modulated radiation therapy, provides better assurance of the target volume and allows a reduction in the lung volumes irradiated. [93] [94] [95] [96] Volumes should be constricted if high total doses are used (>4000 cGy) or if methotrexate, mitomycin C, doxorubicin, or bleomycin is used concomitantly.

Patients with lymphoma will need chemotherapy for control of systemic as well as local disease. Fraction size and total dose to the spinal cord should be carefully considered in these patients who may subsequently undergo a bone marrow transplant requiring total body irradiation.

Response to Radiotherapy

Clinical response of SVCO signs and symptoms to various radiotherapeutic dose-fractionation schedules is high ( Table 54-4 ). [2] [11] [19] [21] [31] Radiographic and postmortem pathologic studies, however, indicate that reestablishment of vena cava patency is rare, and therefore collateral flow rather than therapeutic intervention may be responsible for symptomatic improvement. Ahmann[6] reported the response to radiation therapy for SVCO based on a literature review of more than 90 publications since 1934. Overall, approximately 50% to 70% of treated patients achieve symptomatic improvement within 2 weeks of initiation of therapy. In circumstances in which serial venograms were obtained, normal venous flow through the SVC was rarely observed after completion of radiation therapy. [19] [24] [97] In some instances, complete obstruction remained despite clinical improvement in the patient's signs and symptoms. [19] [24] [97]


Table 54-4   -- Clinical Response of Superior Vena Cava Obstruction to Radiation Therapy

Author

No. of Patients

Response Rate (%)

Recommendation

Yellin et al[20]

23

78

SVCO not emergency; obtain biopsy before RT

Armstrong et al[11]

125

78 to 83

Use initial 4-Gy fractions

Maddox et al[29]

14

64

Chemotherapy and RT are equally effective

Scarantino et al[18]

60

86

Use initial high-dose RT fractions

Davenport et al[1]

35

91

Use initial 4-Gy fractions

Howard[23]

253

86

Use 30-Gy total dose

Data compiled from references 2, 11, 19, 24, and 31 [2] [11] [19] [24] [31].

RT, radiation therapy; SVCO, superior vena cava obstruction.

 

 

 

SVC patency after radiation also has been assessed in autopsy studies. [6] [12] After radiotherapy, the SVC usually is not sufficiently patent to allow adequate blood flow through the vessel. Ahmann's literature review[6] found that among 99 postmortem examinations of which most patients had achieved symptomatic relief after radiation therapy, only 14 patients had complete or partial SVC patency. Although autopsy studies may be less reliable than venography obtained in living patients, these results are entirely consistent with reported radiographic data. Although radiotherapy is associated with improvement or relief of clinical signs and symptoms in most patients, the majority of patients do not actually achieve any measurable increase in vena cava blood flow. The development of collateral blood flow probably contributes to the clinical improvement in some patients and is the sole reason for improvement in others. Thus, the literature does not support the traditional dogma that emergency irradiation is needed in all patients with SVCO.

Chemotherapy

Small Cell and Non-Small Cell Lung Cancer

SVCO has been reported to occur in 7% to 12% of SCLC patients at diagnosis. [26] [31] [98] [99] [100] [101] With rare exception,[31] the literature indicates that the presence of SVCO has little impact on the prognosis of SCLC patients, provided that therapy is appropriately instituted. [26] [98] [101] [102] Even in the presence of SVCO, chemotherapy (with or without thoracic radiotherapy) is the preferred initial treatment of SCLC.[103] The choice of treatment is dictated by the patient's stage and performance status. Those with limited-stage disease, good performance status, and no contraindication to cisplatin are best treated with cisplatin plus etoposide and concurrent chest irradiation.[82] In extensive-stage disease, it is reasonable to proceed with chemotherapy alone—either cisplatin-based therapy or a cyclophosphamide-based regimen in those in whom excessive hydration is to be avoided. [26] [98] [99] [101] [102] Alternatively, carboplatin can be substituted for cisplatin if there is a need to avoid aggressive hydration.[104] A majority of patients will experience partial or complete resolution of signs and symptoms within 7 days of initiation of treatment, and in most series, complete resolution of symptoms has occurred within 2 weeks. Although the rapidity of symptom resolution suggests that a direct treatment effect on tumor regression is the principal cause of symptom improvement, the development of collateral drainage undoubtedly plays an equally significant role, as noted earlier. Thoracic radiotherapy does not cause transient worsening of symptoms. Although SVCO reoccurs in approximately 25% of patients, reinstitution of therapy with salvage chemotherapy alone, radiotherapy alone, or a combination of these modalities has resulted in the prompt resolution of symptoms in most cases.[24]Unfortunately, sequential thoracic radiotherapy on completion of chemotherapy has not resulted in a reduction in the incidence of SVCO relapse.[105]

Chemotherapy alone also has been used for the treatment of SVCO in non-SCLC with positive results.[106] However, because of their innate chemotherapy resistance this approach is less effective with non-small cell tumors, and thus radiotherapy or combined-modality therapy remains the preferred initial treatment.[90] Unlike SCLC, the presence of SVCO in non-SCLC seems to have a negative impact on the prognosis of patients with locally advanced disease.[106]

Non-Hodgkin's Lymphoma

Although symptoms can be well controlled with radiotherapy, chemotherapy alone also can effectively palliate the symptoms of SVCO in non-Hodgkin's lymphoma.[29] However, because lymphoma is usually a systemic process and death is rarely due to localized disease, radiotherapy should never be used in isolation except when dealing with recurrent disease. Local recurrences tend to occur primarily in patients with large mediastinal masses and large cell histologic types.[29] Therefore, local consolidation with radiotherapy after a few cycles of chemotherapy can be justified in patients with large cell lymphoma and mediastinal masses larger than 10 cm.[29] Conversely, in lymphoblastic lymphoma, recurrences are uniformly systemic, obviating the need for radiotherapy in this histologic type of non-Hodgkin's lymphoma.[29] As in SCLC, the optimal chemotherapy regimen for treatment for lymphoma-associated SVCO has not been determined and is dictated to a much greater degree by the underlying histologic type, further underscoring the need to establish a tissue diagnosis before institution of therapy. It should be noted that a fine-needle aspiration is insufficient for a complete diagnosis and characterization of a lymphoma and should not be relied on as the sole diagnostic procedure. Lymphoblastic lymphoma is more aggressive than large cell lymphomas and generally requires more aggressive chemotherapy. [54] [107] [108]

SURGERY

Surgery generally plays a limited role in the management of the patient with SVCO, although reconstruction of the obstructed SVC may be indicated in highly selected patients. [58] [109] [110] [111] [112]Surgical intervention is reserved most often for patients with SVCO due to a benign cause such as granulomatous disease, aortic aneurysm, or retrosternal goiter.[113] When symptomatic malignant obstruction is refractory to radiotherapy, chemotherapy, or both, and when anticipated survival approaches 6 months, operation may be considered. Surgical intervention also may prove beneficial in the setting of recurrent SVCO after chemotherapy and radiation, and when caval thrombosis is the primary problem and fails to improve symptomatically with anticoagulants or thrombolytic therapy. [95] [114] [115] [116]

Surgical bypass of the obstructed SVC may be accomplished with synthetic grafts (Dacron or Goretex), autologous pericardium, or autogenous vein graft, with preference for the later because of a betterpotential for long-term patency. [109] [110] [111] [112] [117] [118] The spiral vein graft, initially described by Doty and associates, [110] [119] is constructed by using the saphenous vein, which is slit longitudinally and wrapped around a stent (usually a chest tube) of the desired diameter. The edges of the vein are joined by using continuous suture, resulting in a large-bore conduit. The bypass is constructed between the brachiocephalic or left internal jugular vein and the right atrial appendage. Long-term relief of symptoms may be achieved. [112] [119] [120] When SVCO is the result of a primary tumor of the SVC or right atrium, resection (with cardiopulmonary bypass) and reconstruction is recommended. These tumors may be relatively slow-growing sarcomas (angiosarcomas or leiomyosarcomas), and long-term palliation is sometimes possible. [33] [34] [35] [121]

Stents

Percutaneously placed, self-expanding intravascular wire stents can offer an attractive adjunct to other procedures in the palliative treatment of patients with SVCO in the presence or absence of an underlying malignant disease.[122] These devices have been placed before radiotherapy, during the course of radiotherapy or chemotherapy, and after maximum-tolerance radiation therapy. [20] [123] [124] [125] [126] [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] [139] [140] This percutaneous treatment option offers the ability to increase the lumen diameter of the SVC and does not usually require general anesthesia ( Fig. 54-5 ). Complete symptom relief is often obtained within 24 to 48 hours in 75% to 95% of patients, depending on the underlying cause of SVCO and type of stent deployed. Dyspnea seems to be the least likely symptom to improve, whereas facial and upper body edema improve within 48 hours in virtually all patients.[123] Possible complications include acute thrombosis, retroperitoneal hemorrhage, and death due to cardiac arrhythmias, and reocclusion may occur (especially in the absence of anticoagulant therapy). [126] [127] [128] Because all currently available expandable stents have a metallic composition, their presence may preclude or limit serial follow-up with magnetic resonance imaging. This point should be taken into account before this course of treatment is chosen.

 
 

Figure 54-5  A, A 60-year-old man after radiotherapy for lung cancer with recurrent superior vena cava obstruction. B, Placement of a Wallstent resulted in immediate relief of symptoms. Radiograph at 6-month follow-up.

 

 

Venous access is accomplished through a femoral, jugular, or subclavian vein. It is necessary to traverse the obstruction with a guide wire to allow deployment of the stent, and in many cases, a preplacement venous angioplasty is indicated. The presence of acute thrombosis superimposed on the chronic SVCO may indicate the need for preprocedure thrombolytic therapy. Although thrombolytic therapy is associated with a known risk of hemorrhage, it may minimize the risk of thromboembolization and permit greater accuracy of stent placement. [122] [139] Careful consideration should be given to a preprocedure cerebral CT scan to help rule out the presence of cerebral metastases before the use of thrombolytic therapy.[139]

Whereas a variety of metallic stents is currently available, most reports address one or more of three general device designs, the Gianturco-Rösch (sometimes referred to as the “Z-stent”; Cook, Bloomington, IN), Wallstent (Schneider, Plymouth, MN), and Palmaz stent (Johnson & Johnson Interventional Systems, Warren, NJ). No rigorous comparisons of outcomes have been made among the various stent designs. Each has particular qualities with respect to flexibility and radial strength, which may make one or another particularly well suited under certain clinical circumstances. Although the Wallstent and Z-stent are “self-expanding” devices, balloon dilatation may be required after stent insertion to provide a clinically adequate effect.[141]

Technical and clinical success and long-term venous patency have been demonstrated by several trials summarized in Table 54-5 . [122] [134] [135] [136] [137] [138] [139] [140] [142] The overall complication rate is relatively low, although considerable variation is found in the reporting of complications, in that some studies include reocclusion as a complication.[136] The majority of the more serious complications involve graft migration. Many patients require more than one stent either to maintain SVC confluence with adjacent vessels or because the vascular lesion is too extensive to be covered by a single stent. Close follow-up is required to monitor venous patency, and stent occlusion can generally be alleviated by a second procedure.


Table 54-5   -- Evaluation of Intravascular Stents

Author

No. of Patients

Primary Patency Rate (%)

Clinical Success (%)

Overall Complication Rate (%)

Kee et al[128]

51

95

78

10

Smayra et al[141]

30

74

100

7

Chatziioannou et al[147]

18

100

89

0

Lanciego et al[142]

52

92

100

25

De Gregorio Ariza et al[146]

82

93

95

0

Miller et al[143]

23

100

83

13

Thony et al[144]

26

83

90

4

Nicholson et al[145]

76

100

90

9

Urruticoechea et al148

52

100

90

10

Data compiled from references 122, 134–140, and 142 [122] [134] [135] [136] [137] [138] [139] [140] [142].

 

 

A discrepancy exists in the literature regarding balloon dilation before stent placement. Some studies advocate routine balloon dilation before stent insertion, whereas others limit such dilations to situations necessitated by very tight stenoses. [122] [134] [135] [137] The suggestion is that immediate stenting without dilation traps endothelial clots, thus helping to prevent distant embolic events.[135] Other series reported improved patency rates with balloon angioplasty after stent placement.[140] Some believe that this variation in practice may relate to the type of stent used.

Considerable variation also exists regarding routine anticoagulation after stent placement. Chatziioannou and coworkers[136] recommend oral anticoagulation therapy with coumarin “for life.” Kee and colleagues[122] recommend continuous oral anticoagulation for all of their patients with an underlying malignancy. In both the studies of Lanciego and associates[134] and Chacon Lopez-Muniz and coworkers,[123] patients were initially given anticoagulation with heparin and warfarin; however, over time their standard of practice changed to recommend antiplatelet agents alone, with seemingly no adverse effects. Thony and colleagues[140] treated a few selected patients with heparin for up to 3 days after the procedure and otherwise recommend aspirin therapy for 3 months after stent placement. This shift in practice may reflect parallel studies of anticoagulation for coronary artery stents. As no standard recommendations exist now, the risks and benefits of full anticoagulation versus antiplatelet agents must be weighed for individual patients.[143]

Although no randomized trials have been done, two studies directly compared the results of endovascular stenting with radiation with or without chemotherapy for malignant SVCO. Tanigawa and associates[144] reported the results of 33 patients treated with radiation therapy or stents. These patients were selected for a specific therapy and not randomized. Of the 23 patients who underwent a stenting procedure, 11 had undergone ineffective radiation therapy for their obstructions. The majority of patients in the stent group and all 10 of the patients who received radiation therapy had a primary lung cancer. Symptom relief was seen in 78% of the stent group overall: 75% of those who had not had previous therapy and 82% of those who had received prior radiation. Although the rate of improvement (80%) in clinical signs and symptoms in patients who were treated with radiation therapy was similar, the median time to respond was longer at 5.5 days compared with 24 to 48 hours after stenting. No difference was found in the overall survival between the two treatment groups. These authors suggested that stenting be considered first-line therapy and certainly indicated after an ineffective trial of radiation. Nicholson and colleagues[139] reported their experience with malignant SVCO of 76 patients treated with stent insertion and compared the results retrospectively with those of 25 similar patients who had been treated with radiation therapy for malignant SVCO. Of the 76 patients, 26 were treated with stents alone, and the remainder were treated with chemotherapy or radiation before or after stent placement. The report of Nicholson and colleagues confirms the more rapid resolution of clinical symptoms in the stent group versus the radiation-alone group; however, it should be noted that the radiation group was examined retrospectively. The mean asymptomatic time was significantly longer in the stent group at 21.8 weeks compared with 11.7 weeks in the radiation-only group. Although 83% of patients treated with a stenting procedure continued to have minor symptoms of swelling or venous distention, major symptoms were relieved in all 76 patients. In addition, more than 90% of patients in the stent group died without a recurrence of their SVCO symptoms compared with only 12% in the radiation-only group. The figures for the stent group include the patients who were treated with additional therapy, although the trends are the same for the 26 patients who were only stented. Poststent venography was performed on 19 patients. Interestingly, although they were all asymptomatic, seven of these patients had a reoccluded SVC, suggesting that collateral vessels play a significant role in symptom relief. This finding is consistent with the reocclusion after radiation therapy noted in autopsy studies. [6] [13]

Although a definite role exists for stents in malignant SVCO, the results of endothelial stent placement for benign causes are more mixed, and few long-term follow-up data are available.[141] Life expectancy for patients with malignant disease is often limited, but the same may not be true with benign SVCO, and therefore in these patients, long-term patency is a critical consideration. The underlying cause of the initial SVCO and the likelihood of recurrence may be more relevant in these situations. Technical success and symptom relief have been reported, primarily for venous catheter-induced SVCO.[137] The gold standard for benign SVCO remains surgical bypass, although, given the variability and rarity of this condition, no studies have been done comparing these two modalities.

Although endovascular stents may provide more rapid relief of symptoms, they are not designed to treat the underlying cause of the obstruction, whereas radiation, chemotherapy, and surgery may function both palliatively and therapeutically. No randomized trials are likely to compare treatments for SVCO, because the goals of each therapeutic modality are somewhat different. However, many studies report that stented patients experience a rapid and almost complete resolution of the symptoms associated with SVCO. [123] [126] [134] [135] [137] [138] [140] [144] For this reason, several recent studies advocated stent placement as first-line therapy for patients with malignant causes of SVCO. [138] [142] [143] [144] [147] Stent insertion should not interfere with subsequent radiation or chemotherapy and may allow symptom relief while further therapy is being planned and initiated.[145]

SUPPORTIVE MEASURES

Few medical measures are of proven benefit in the management of SVCO, other than therapy directed at the underlying cause. General recommendations include bedrest, head-of-the-bed elevation, and oxygen administration. [9] [21] These therapies are designed to reduce venous pressure and cardiac output. Diuretics also have been advocated without clear evidence of efficacy, although they are thought to lessen edema.[9] Steroids also are sometimes administered without good documentation as to their efficacy. These agents have been advocated for their putative benefit in lessening the likelihood of radiation-induced edema. However, in experimental systems, little inflammation or edema has been observed with irradiation.[74] Anticoagulation and thrombolytic therapy may be of benefit when the underlying cause is an indwelling catheter, but otherwise they have not been shown to alter the course of recovery. [32] [37] [39] [109] Furthermore, because anticoagulation may impair diagnostic efforts, it should be avoided until a clear indication for its use is identified.

Survival in the face of SVCO is dependent on the underlying cause and proper treatment. [1] [11] [29] [146] Overall, median survival is around 6 months and is clearly related to the underlying cause. One-year survival may range from as little as less than 1% in non-SCLC to more than 40% in patients with non-Hodgkin's lymphoma. [1] [11]

SUMMARY

SVCO is usually not a true oncologic emergency, except in rare situations in which a patient experiences respiratory compromise secondary to tracheal obstruction. Administration of irradiation before histologic confirmation of the underlying cause can lead to inappropriate therapy and should be discouraged. Excessive concern about the risk of invasive procedures in the face of SVCO is likewise without foundation. Numerous reports have demonstrated the relative safety of bronchoscopy, thoracentesis, lymph node biopsy, and similar invasive procedures. In the past 5 years, numerous studies have demonstrated the palliative benefit of endovascular stent placement, particularly for malignant causes of SVCO. Stent placement does not preclude the use of additional therapy such as chemotherapy or radiation. In experienced hands, the procedure has a low rate of complications and often provides rapid and lasting relief of symptoms. Depending on availability, endovascular stenting should be considered early in the treatment of SVCO and certainly when a different primary therapy has failed. In many institutions, radiotherapy remains the treatment of choice, with exceptions made for those causes known to be relatively sensitive to chemotherapy (e.g., SCLC or non-Hodgkin's lymphoma).

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