Radiation Oncology/Palliation/SVC Syndrome

Superior Vena Cava Syndrome

Histologic diagnosis is essential for choosing appropriate therapy

Epidemiology

• ~15,000 cases in US per year
• Caused by invasion/compression of SVC by mass in right lung, lymph nodes, mediastinal structures, or thrombosis within the SVC
• Historically syphilitic thoracic aortic aneurysms, fibrosing mediastinitis (histoplasmosis) and other untreatable infections were frequent causes
• Currently (since 1980s) malignancy is the most common cause ~ 70-90%
• Non-malignant causes (10-30%): Thrombosis (indwelling vascular devices), fibrosing mediastinitis, postradiation fibrosis
• Of all SVC cases related to malignancy
  • Presenting symptom in previously undiagnosed malignancy in 60% of cases
  • NSCLC in 50%, SCLC in 25% and NHL in 10%
• 2-4% of Lung cancers cause SVC
• 2-4% of NH Lymphomas (DLBCL and Lymphoblastic lymphoma) cause SVC
• Hodgkins lymphoma is rarely a cause, in spite of its predilection for mediastinum
• Prognosis on average is 6 months life expectancy
• But approximately 10% to 20% survive longer than 2 years
• Survival of malignant SVC patients similar to survival of comparable tumor type/stage patients without it

Etiology

• Malignancy (~65%)

Tumor Type	Proportion
NSCLC	50%
SCLC	22%
Lymphoma	12%
Metastatic cancer	9%
Germ cell	3%
Thymoma	2%
Mesothelioma	1%
Other cancers	1%

• Intra-vascular devices (~33%)
• Infections (rare)

Anatomy

• Collateral veins arise from the azygos, internal mammary, lateral thoracic, paraspinous, and esophageal venous systems

Clinical Presentation

• Symptoms may develop over weeks to months
• Dyspnea is most common presenting symptom
• Increased venous pressure
  • Edema in torso, arms, neck, and head (exacerbated when lying down)
  • Laryngeal edema, leading to cough, hoarseness, dyspnea, stridor, dysphagia
  • Cerebral edema, leading to headaches, confusion, and coma
• Decreased venous return
  • Hemodynamic compromise
  • Development of collateral venous return

Proposed grading system for superior vena cava syndrome (See PMID 18670297)

Grade	Category	Incidence %	Definition
0	Asymptomatic	10	Radiographic superior vena cava obstruction in the absence of symptoms
1	Mild	25	Edema in head or neck (vascular distention), cyanosis, plethora
2	Moderate	50	Edema in head or neck with functional impairment (mild dysphagia, cough, mild or moderate impairment of head, jaw or eyelid movements, visual disturbances caused by ocular edema)
3	Severe	10	Mild or moderate cerebral edema (headache, dizziness) or mild/moderate laryngeal edema or diminished cardiac reserve (syncope after bending)
4	Life-threatening	5	Significant cerebral edema (confusion, obtundation) or significant laryngeal edema (stridor) or significant hemodynamic compromise (syncope without precipitating factors, hypotension, renal insufficiency)
5	Fatal	< 1	Death

Workup

• CXR, CT Scan
• Consider: sputum cytology, pleural fluid cytology, bronchoscopy, mediastinoscopy, VATS

Treatment

Medical Management

• Elevate head to decrease hydrostatic pressure and cerebral edema
• Remove indwelling catheter (if secondary to thrombosis)
• Consider glucocorticoids (decadron 4mg q6), although risk is that it will obliterate existing histology in case first biopsy is insufficient
• Consider loop diuretics
• Anticoagulation benefit not clear, although some recommend thrombolysis followed by anticoagulation

Radiation Therapy

• Emergent RT is no longer considered necessary if patient is stable and diagnosis is not established (PMID 7234887)
  • RT prior to biopsy can obscure histologic diagnosis (PMID 3701390)
  • Endovascular stents in severely symptomatic patients provide more rapid relief
• Consider Emergency RT (and endovascular stent) if
  • Stridor from severe laryngeal edema
  • Coma from cerebral edema
• RT dose/schedule
  • Start RT as soon as possible. Initially use high-dose fractions (3-4 Gy) for 2 or 3 days if treating curatively to 60-70Gy, followed by standard 1.8-2 Gy/fx
  • Not unusual to palliate with 3Gy x 10, or 4Gy x 5 or 2.5Gy x 15
• Symptomatic relief can be apparent in 72 hours, complete relief can be seen by 2 weeks (78% SCLC, 63% NSCLC)
• However, SVC patency improvement only in 31%, so some symptom relief probably due to development of collateral circulation over time
• Many patients will recur symptomatically prior to death
• Consider Chemotherapy before or with RT if:
  • SCLC, NHL & germ cell tumors
• In the absence of distant metastasis, aggressive management is indicated
• Symptomatic relief within the first 30 days might be a good prognostic factor

Endovascular Stent

• Stent can be placed before tissue diagnosis (unlike RT)
  • Results in rapid relief of symptoms
  • ~ 90% patients report symptomatic relief (PMID 17546400)
• Indications to consider:
  • Significant respiratory distress, although lymphomas and germ cell tumors respond rapidly to chemo and/or RT
  • Post-RT recurrence
  • Mesothelioma, since they don't respond well to chemo or RT
• Recurrence post-stent is < 40% (average is 13%)
• No evidence for durable benefit of angioplasty alone

Chemotherapy

• Chemotherapy is initially preferred for SVC in
  • SCLC, NHL & germ cell tumors with ~75% response
• Addition of RT can reduce recurrence of symptoms
• Review of 2 randomized trials and 44 single institution series showed no difference in symptom relief, DFS, and OS between RT only, chemo only, or chemo-RT

Literature

• Meta-analysis, 2002 PMID 12555872 -- "Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review." (Rowell NP, Clin Oncol (R Coll Radiol). 2002 Oct;14(5):338-51.)
  • 2 randomized and 44 nonrandomized studies reviewed. SVC present in 10% of patients with SCLC and 2% of patients with NSCLC
  • Relief of SVCO: SCLC chemo 77% vs. RT 78%; NSCLC chemo 59% vs. RT 63%. Not related to RT fractionation schedule or chemo regimen
  • Conclusion: Chemotherapy and RT are effective in some patients, stent may provide relief in higher proportion and more rapidly. Effectiveness of steroids uncertain

• Sao Paolo, 1999 (Brazil) Abstract "Neoadjuvant chemotherapy vs radiotherapy alone for superior vena cava syndrome (SVCS) due to non-small cell lung cancer (NSCLC): preliminary results of randomized phase II trial." (Pereira JR, Eur J Cancer 1999;35(Suppl 4):260.
  • Randomized. Terminated early due to larger number of treatment-related deaths in chemo arm. 34 patients with NSCLC. Treated with immediate RT + cisplatin vs. cisplatin/epirubicin/vinblastine. Info from PMID 12555872
  • Outcome: no difference in relief or survival, but larger number of treatment-related deaths in chemo-only arm

• Washington University, 1987 PMID 3558044 -- "Role of irradiation in the management of superior vena cava syndrome." (Armstrong BA, Int J Radiat Oncol Biol Phys. 1987 Apr;13(4):531-9.)
  • Retrospective. 125 patients with SVC syndrome.
  • Outcome: 80% good to excellent symptomatic relief. 2-week relief initial high dose (3-4 Gy/fx x3) 70% vs. low dose (2 Gy/fx) 56% (p=0.09). 1-year OS lymphoma 41%, SCLC 24%, NSCLC 17%. Combined chemo-RT didn't improve response, symptom relief or survival. Recurrence of SVC syndrome in 13%
  • Toxicity: Minimal, dysphagia most common 26%

• London (UK)(no dates given) -- SCLC: chemo +/- RT
  • Randomized. 37/366 patients with SCLC enrolled in trial of chemotherapy +/- RT presented with SVC obstruction. 9 relapsed during chemo and were not randomized. Induction chemotherapy (adriamycin + vincristine + cyclophosphamide alternating with cyclophosphamide + MTX) x4 cycles then randomized Arm 1) RT 40/20 AP/PA vs. Arm 2) continued chemotherapy. Both consolidated with 8 cycles of chemotherapy
  • 1983 PMID 6310812 -- "Treatment of obstruction of the superior vena cava by combination chemotherapy with and without irradiation in small-cell carcinoma of the bronchus. (Spiro SG, Thorax. 1983 Jul;38(7):501-5.)
    • Outcomes: After induction chemo, 21/37 (57%) CR, 10/37 (27%) PR of SVC symptoms. Median OS identical.
    • Conclusion: Chemo alone effective for SVC; no benefit for consolidative RT induction chemo x4 cycles

• Oklahoma/Virginia -- high dose RT vs. nitrogen mustard + RT
  • Randomized. 28 patients with SVC syndrome, 22 completed treatment. Arm 1) nitrogen mustard 0.4 mg/kg, then in 3-8 days RT 40-50 Gy in 1.5-2.0 Gy/fx vs. Arm 2) RT only (4 Gy/fx until drop in venous pressure at least 30 mm H2O or 20 Gy, then 2 Gy/fx for total 40-50 Gy), diuretics as necessary. Tumor + 1cm margin. Delivered by 2 MeV Van de Graaff unit.
  • 1969 PMID 4898825 -- "Treatment of malignant superior vena caval obstruction. A randomized study." (Levitt SH, Cancer. 1969 Sep;24(3):447-51.)
    • Outcome: Time to venous pressure drop (NS), relief of symptoms (NS), duration of relief (NS), recurrence (NS), OS (NS)
    • Toxicity: Combined arm more severe complications
    • Conclusion: No difference between groups, suggest initially high daily dose

Review

• 2007 PMID 17476012 -- "Clinical practice. Superior vena cava syndrome with malignant causes." (Wilson LD, N Engl J Med. 2007 May 3;356(18):1862-9.)