Article Tools
DIAGNOSIS IN ONCOLOGY
Article Tools
BRAF-Targeted Therapy to Treat Superior Vena Cava Syndrome in a Patient With Metastatic Cancer
The superior vena cava (SVC) is a large-diameter thoracic vein that returns blood from the upper half of the body into the heart's right atrium. When the SVC is compressed or internally obstructed, the result is often clinical presentation of superior vena cava syndrome (SVCS). The SVC becomes a bottleneck for incoming blood flow, eventually forcing the blood through alternative routes and increasing the pressure in preceding vessels.1 Nearly 70% to 80% of new cases of SVCS arise as a result of thoracic malignancies.2 The most common malignancies associated with SVCS include non–small-cell lung cancer (> 50%), small-cell lung cancer (22%), and lymphoma (12%).3 SVCS is rarely seen with metastatic melanoma.
Virtually all patients with SVCS present with clinical symptoms resulting from impaired return of blood to the heart.3 These include facial or cervical edema (82%), upper extremity swelling (68%), dyspnea (66%), cough (50%), and dilated collateral circulation in the chest (38%).2 More severe complications include syncope and stroke.1,3 The severity and incidence of the symptoms are increased with faster and more extensive narrowing of the SVC.4
Because SVCS does not typically present as an emergency situation, it is classically treated only when the symptoms are severe or there is an underlying malignancy. Common approaches include chemotherapy, radiation, stenting, or combination treatment with corticosteroids and/or anticoagulants.4,5
Melanoma is one of the deadliest forms of metastatic cancer and has been previously observed in patients with SVCS.6 Like other tumors, melanoma cells harbor numerous oncogenic mutations that are responsible for increased cell growth, proliferation, and metastatic potential. Approximately 60% of melanomas express a mutated version of a surface protein known as BRAF.7,8 When mutated, this BRAF protein effectively bypasses a tightly regulated cell-signaling pathway of cell growth and differentiation, giving the cells a higher potential to invade and spread.9 Extensive research is underway to target mutant BRAF and the downstream pathway it initiates. Recently approved by the US Federal Drug Administration is PLX4032 (vemurafenib), an oral molecular therapy that preferentially binds to and inhibits mutant BRAF, arresting cell proliferation and survival in tumor cells.10 In patients with a mutant BRAF tumor that is responsible for SVCS, such a therapy could provide efficient palliative relief.
A 67-year-old white man with metastatic cutaneous melanoma presented to a clinic with shortness of breath, tachycardia, and facial and cervical plethora. Further assessment revealed sublingual venous engorgement and extensive collateral circulation in the chest. SVCS was immediately recognized by the patient's physician, and a treatment discussion ensued. Initially diagnosed with stage II disease 12 years before, he had been treated with biochemotherapy, targeted therapy, and a CTLA-4 antibody. This patient was originally diagnosed with metastatic melanoma in the mediastinal lymph nodes 10 years earlier and had previously progressed on multiple systemic therapies. Imaging studies revealed progressive thoracic disease compressing and partially obstructing his SVC. Work-up also revealed that his tumor tissue expressed mutation in the BRAF protein, making him eligible for molecular targeted therapy with BRAF inhibitors.
After careful assessment, the patient enrolled onto a clinical trial with a BRAF inhibitor at a dose of 960 mg twice per day. Within 48 to 72 hours of the start of treatment, all clinical symptoms of SVCS (ie, shortness of breath, facial and cervical plethora, and so on) had resolved, with minimal adverse effects reported (eg, rash, pruritus, and photosensitivity), requiring a dose reduction to 720 mg twice per day. Computed tomography imaging 2 months into the treatment demonstrated a marked decrease in thoracic tumor size as well as visible adjustment of SVC compression compared with baseline (Figs 1A through 1C, arrows). The lymphadenopathy throughout the thoracic cavity was also drastically reduced (Fig 1B). A subsequent computed tomography scan 5 months after the start of treatment showed durability in the tumor response (Fig 1C). The patient continued to receive PLX4032 (vemurafenib) for more than 6 months, with complete relief of SVCS-related clinical symptoms and reduced tumor size.
Fig 1.The combination of complete symptomatic relief, reduction of tumor size, and increased SVC blood flow provides compelling evidence for the effectiveness of the BRAF inhibitor in addressing SVCS. This therapy has several key advantages compared with current options (Table 1), most notably its noninvasive nature, fast action, and treatment of the underlying malignancy. In our patient, SVCS resolution was a result of the rapid reduction of the tumor mass by vemurafenib. Numerous other studies have also shown a quick reduction in BRAF-mutant–type tumors, although there are no previously documented cases of SVCS resolution.8,11
|
| Pros and Cons | BRAF Inhibitor | Chemotherapy | Radiotherapy | Stenting/Surgery |
|---|---|---|---|---|
| Pros | Treats tumor source | Treats tumor source | Treats tumor source | Fast acting (24-72 hours) |
| Noninvasive | Noninvasive | Noninvasive | ||
| Fast acting (24-72 hours) | ||||
| Cons | Potential adverse effects | Most severe side effects | Slow response (> 1 week) | Invasive/higher risk |
| Durability of response | Slow response (> 1 week) | Durability of response | Does not treat malignancy | |
| Durability of response | Radiation necrosis |
Up to 89% patients with SVCS caused by malignancy receive chemotherapy and/or radiation.4 These options are noninvasive and can directly treat the tumor; however, symptomatic relief takes 7 to 15 days, and there are considerable toxicities with both treatments.4 Stenting combined with angioplasty is currently the most rapidly acting treatment, with resolution in 24 to 72 hours.5 However, this therapeutic option does not address the underlying malignancy. Stenting also carries substantially higher risk than any of the other options because of its invasive nature.5 Vemurafenib combines the advantages of both of these treatments while reducing the risk of complications.
Beyond highlighting the utility of vemurafenib in SVCS, this case suggests a much wider spectrum of potential therapeutic applications for this drug. Over 60% of melanomas harbor the BRAF mutation, and it is expressed in 7% to 8% of all tumor types, including lung cancers, which account for the majority of cases of SVCS.11 For patients with BRAF-mutated tumors, targeted inhibiting therapies have many key advantages, with minimal toxicities that include cutaneous growths, fatigue, arthralgias, and photosensitivity.7,12 The future holds promise for further research to explore targeted therapies and the role they play in cancer treatments and oncologic emergencies.
Although all authors completed the disclosure declaration, the following author(s) and/or an author's immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Katherine J. Rosenthal, Zelboraf (C); Omid Hamid, Genentech (C), Merck (C), Bristol-Myers Squibb (C) Stock Ownership: None Honoraria: Peter D. Boasberg, Bristol-Myers Squibb; Omid Hamid, Genentech, Bristol-Myers Squibb Research Funding: Peter D. Boasberg, Genentech, Bristol-Myers Squibb, Merck; Omid Hamid, Genentech, Merck, GlaxoSmithKline, Bristol-Myers Squibb Expert Testimony: None Patents: None Other Remuneration: None
| 1. | LD Wilson, FC Detterbeck, J Yahalom , etal: Clinical practice: Superior vena cava syndrome with malignant causes N Engl J Med 356: 1862– 1869,2007 Crossref, Medline, Google Scholar |
| 2. | S Eren, A Karaman, A Okur : The superior vena cava syndrome caused by malignant disease. Imaging with multi-detector row CT Eur J Radiol 59: 93– 103,2006 Crossref, Medline, Google Scholar |
| 3. | TW Rice, RM Rodrguez, RW Light : The superior vena cava syndrome: Clinical characteristics and evolving etiology Medicine 85: 37– 42,2006 Crossref, Medline, Google Scholar |
| 4. | NP Rowell, FV Gleeson : Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: A systematic review Clin Oncol (R Coll Radiol) 14: 338– 351,2002 Crossref, Medline, Google Scholar |
| 5. | PY Marcy, N Magné, F Bentolila , etal: Superior vena cava syndrome: Is stenting necessary? Support Care Cancer 9: 103– 107,2001 Crossref, Medline, Google Scholar |
| 6. | CL Lau, RC Bentley, JP Gockerman , etal: Malignant melanoma presenting as a mediastinal mass Ann Thoracic Surg 67: 851– 852,1999 Crossref, Medline, Google Scholar |
| 7. | A Ribas, KB Kim, LM Schuchter , etal: BRIM-2: An open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma J Clin Oncol 29: 528s,2011 suppl abstr 8509 Link, Google Scholar |
| 8. | H Davies, GR Bignell, C Cox , etal: Mutations of the BRAF gene in human cancer Nature 417: 949– 954,2002 Crossref, Medline, Google Scholar |
| 9. | R Kumar, S Angelini, K Czene , etal: BRAF mutations in metastatic melanoma: A possible association with clinical outcome Clin Cancer Res 9: 3362– 3368,2003 Medline, Google Scholar |
| 10. | PB Chapman, A Hauschild, C Robert , etal: Improved survival with vemurafenib in melanoma with BRAF V600E mutation N Engl J Med 364: 2507– 2516,2011 Crossref, Medline, Google Scholar |
| 11. | K Flaherty, I Puzanov, J Sosman , etal: Phase I study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer J ClinOncol 27: 461s,2009 suppl abstr 9000 Link, Google Scholar |
| 12. | PB Chapman, A Hauschild, C Robert , etal: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine in patients with V600E BRAF-mutated melanoma 29: 6s,2011 suppl abstr LBA4 Google Scholar |
