3 Mr. SV ID: 65 year old male with PMHx of CAD and emphysema EC: present to clinic with one week history of increasing SOBHPI: 3 month history of weight loss, decreased appetite, a change in his chronic cough, and intermittent hemoptysis
13 EtiologyCaused by either invasion or external compression of the SVC by contiguous pathologic processRight lung pathology, lymph nodes, other mediastinal structures, or thrombosis
14 EtiologyBefore antibiotics the most common causes were from complications of untreated infectionSyphilitic thoracic aneurysmsfibrosing mediastinitisMalignancy is presently the most common cause
15 Symptoms and SignsAs the obstruction develops venous collaterals are formedSymptom onset depends on speed of SVC obstruction onsetMalignant disease can arise in weeks to monthsNot enough time to develop collateralsFibrosing mediastinitis can take years to have symptoms
16 Symptoms and SignsCentral venous pressures remain high even in collateralsHigh pressures cause the characteristic clinical pictureShortness of breath is the most common symptom11. Parish, JM, Marschke, RF Jr, Dines, DE, Lee, RE. Etiologic considerations in superior vena cava syndrome. Mayo Clin Proc 1981; 56:407.
17 Signs and Symptoms Facial swelling or head fullness Cough Arm edema exacerbated by bending forward or lying downCoughArm edemaCyanosis
18 Facial swelling associated with SVC Syndrome in a patient with malignancy
20 Patient who presented with progressively enlarging veins over the anterior chest wall. A diagnosis of a right-sided superior sulcus (Pancoast) tumor compressing the SVC was made.
21 Etiology: Malignancy Lung cancer is the most common2 Lymphoma is second most commontogether represent 94% of cases2. Escalante, CP. Causes and management of superior vena cava syndrome. Oncology (Huntingt) 1993; 7:61.
22 NSCLC 2-4% of bronchogenic cancer patients develop SVC syndrome3 extrinsic compression or direct invasionprimary tumor or by enlarging mediastinal nodes3. Armstrong, BA, Perez, CA, Simpson, JR, Hederman, MA. Role of irradiation in the management of superior vena cava syndrome. Int J Radiat Oncol Biol Phys 1987; 13:531.
23 Small Cell Lung Cancer Greatest risk 20% will develop SVC obstruction3 more common because SCLC tends to occur centrally in contrast to other types
24 Lymphoma 2-4% of patients predominantly non-Hodgkin’s lymphoma4 Hodgkin’s rarely causes SVC syndrome4. Perez-Soler, R, McLaughlin, P, Velasquez, WS, et al. Clinical features and results of management of superior vena cava syndrome secondary to lymphoma. J Clin Oncol 1984; 2:260.
25 Lymphoma Extrinsic compression caused by enlarging lymph nodes subtypes of large B cell can be intravascular and cause occlusion (angiotropic)diffuse large cell and lymphoblastic are most commonly associated with SVC syndrome
26 Other cancers Thymoma primary mediastinal germ cell neoplasm solid tumors with mediastinal nodal metastasesbreast cancer most common type
27 Other causesPost radiation local vascular fibrosis can also be considered in oncology patientsThoracic radiation treatment may predate syndrome by many years
28 Other causes Thrombosis Indwelling central venous catheters Subcutaneous tunneled catheters have fewer thrombotic and infectious complicationsCan also cause pulmonary embolism55. Sivaram, CA, Craven, P, Chandrasekaran, K. Transesophageal echocardiography during removal of central venous catheter associated with thrombus in superior vena cava. Am J Card Imaging 1996; 10:266.
29 Diagnosis Timely identification of the cause is essential Radiographic studies are usefulUp to 60% of patients with SVC syndrome related to neoplasm do not have a known diagnosis of cancer6Need a tissue biopsy for histologic studies6. Schraufnagel, DE, Hill, R, Leech, JA, Pare, JA. Superior vena caval obstruction. Is it a medical emergency?. Am J Med 1981; 70:1169.
30 Radiographic StudiesMost patients have an abnormal chest x-ray at presentationMost common findings areMediastinal wideningPleural effusion
31 CT Chest Preferred choice IV contrast defines the level of obstruction Maps out collateral pathwaysCan identify underlying cause of obstruction
32 Venography Bilateral upper arm venograpy superior to CT to define site of obstructionDoes not define cause unless thrombosis is solely responsible
33 Helical CT With bilateral upper arm IV contrast injection Best visualization of level of obstruction and cause
34 MRICan be useful in patients with IV contrast allergies
35 T1-weighted axial MRI demonstrating the primary tumor and the paratracheal soft tissue mass that invades into the SVC
36 Same patient’s MRI with different technique to further define the intramural mass
37 Histologic Diagnosis Essential Guides treatment Aids in defining prognosis
38 Histologic DiagnosisSputum cytology, pleural fluid cytology, biopsy of enlarged peripheral nodesBone marrow biopsy for NHLBronchoscopy, mediastinoscopy, or thoracotomy are more invasive but sometimes necessary
40 Treatment Aimed at underlying cause Evolution of thought has occurred in recent years
41 Historically SVC syndrome was considered a potentially life-threatening emergency Standard of care was immediate radiotherapyZap nowAsk questions laterThe emergent approach is not appropriate for most patients
43 Emergent to UrgentSymptomatic obstruction is usually a prolonged processMost patients are not in immediate danger at presentationMost have time for a full diagnostic work up
44 Emergent to Urgent Prebiopsy radiation can obscure the diagnosis Current strategies aim at accurate diagnosis of underlying etiology before therapy
45 Exception to new rule Stridor True medical emergency Central airway obstruction or laryngeal edemaTrue medical emergencyImmediate action neededPossible intubation and ICU admissionImmediate therapy to target obstruction needed
46 Linked to tumor histology and stage at presentation Prognosis…Linked to tumor histology and stage at presentation
47 Treatment Sensitive Tumors NHLs, germ cells, and limited-stage small cell lung cancers usually respond to chemotherapy and or radiationCan achieve long term remission with tumor specific directed therapySymptomatic improvement usually takes 1-2 weeks after start of therapy
48 Note: Corticosteroids Controversial issue with regards to treatment benefit at presentation
49 Non-small cell lung cancer SVC obstruction is a strong predictor of poor prognosisMedian survival around 5 months7Choice of therapy considers likelihood of response to each modality7. Martins, SJ, Pereira, JR. Clinical factors and prognosis in non-small cell lung cancer. Am J Clin Oncol 1999; 22:453.
50 Non-small cell lung cancer Goal usually directed to palliation rather than long term remissionPalliative radiation and chemotherapy can be used
51 Intraluminal Stents Endovascular placement under fluoroscopy Patients who have recurrent disease in previously irradiated fieldsTumors refractory chemotherapyPatient too ill to tolerate radiation or chemotherapy
52 Intraluminal StentsSome data suggests benefit from immediate stent placement in NSCLC at presentation8Tends to provide more rapid relief of symptomsIssue of anticoagulation after is not resolved8. Rowell, NP, Gleeson, FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 2002; 14:338.
54 Mr. EC ID: 56 year old man with history of HTN and osteoarthrtis EC: presents to family doctor with one month history of back pain that is not responding to TylenolPain beginning to wake him at nightMore pain with recumbancySome shooting pains down right legROS: negative
55 On examination vitals stable, no fever CVS, Respiratory, GI, GU exams reported as normalBack examInspection: normalPalpation: some pain in L1ROM: normalSome pain in right leg with straight leg raising
56 Investigation in Clinic Lumbar Spine X-raySome age related degeneration
57 Diagnosis Sciatica vs. Back strain Treatment: NSAIDS Few days of bed rest
58 The story continues… Mr. EC’s pain does not resolve More trials of various forms of pain control failOne month later Mr. EC awakens in the morning and has difficulty supporting his weightSubjective leg muscle weaknessGoes to HSC Emergency room
59 In ER Patient has objective leg weakness on physical exam A very keen medical student does a rectal exam and discovers a large nodular prostatePSA: 45.0MRI Spine…..
62 Malignant Epidural Spinal Cord Compression (ESCC) Neoplastic invasion of the space between vertebrae and spinal cord (epidural invasion)Usually from bone metastasesCompresses thecal sac of spinal cordFrequent complication of malignancyCan cause painCan cause irreversible loss of neurologic function
65 Definition Any radiological indentation of the thecal sac Tip of the spinal cord lies at the L1 vertebral levelLumbosacral nerve roots form the cauda equina
66 Epidemiology Many cases of unrecognized ESCC Difficult to define incidenceAutopsy review studies suggest around 5% of cancer patients die with ESCC99. Barron, KD, Hirano, A, Araki, S, Terry, RD. Experiences with metastatic neoplasms involving the spinal cord. Neurology 1959; 9:91.
67 Causes Metastatic tumor from any primary site Tumors with predilection to metastasize to spinal columnProstate, breast, and lung carcinoma15-20% of casesRenal cell, non-Hodgkin’s lymphoma, or myeloma5-10% of cases
68 Vertebral metastases are more common than ESCC Prostate cancer: 90% Breast Cancer: 74%Lung Cancer: 45%Lymphoma: 29%Renal cell: 29%GI: 25%10. Posner, JB. Neurologic Complications of Cancer. FA Davis, Philadelphia, 1995
69 ESCC can be initial presentation of a malignancy Around 20% of casesIn many cases diagnosis is made by biopsy of the spinal lesion
70 Spinal Location10 Thoracic spine: 60% Lumbosacral spine: 30% Cervical spine: 10%Specific tumor predilection is difficult to define
72 Important to recognize Early recognition leads to better outcomes Efficacy of treatment depends most on patient’s neurological function at presentationMedian time from symptoms to diagnosis is around 2 months11More than half of patients who present to hospital are non-ambulatory11. Husband, DJ. Malignant spinal cord compression: Prospective study of delays in referral and treatment. BMJ 1998; 317:18.
74 First Red Flag: Pain Usually first symptom12 80-90% of the timeUsually precedes other neurologic symptoms by seven weeksIncreases in intensitySevere local back painAggravated by recumbencyDistension of venous plexusMay become radicular12. Bach, F, Larsen, BH, Rohde, K, et al. Metastatic spinal cord compression. Occurrence, symptoms, clinical presentations and prognosis in 398 patients with spinal cord compression. Acta Neurochir (Wien) 1990; 107:37.
75 Second Red Flag: Motor Weakness: 60-85%13 At or above conus medularis Extensors of the upper extremitiesAbove the thoracic spineWeakness from corticospinal dysfunctionAffects flexors in the lower extremitiesPatients may be hyperreflexic below the lesion and have extensor plantars13. Greenberg, HS, Kim, JH, Posner, JB. Epidural spinal cord compression from metastatic tumor: Results with a new treatment protocol. Ann Neurol 1980; 8:361.
76 Weakness tends to be symmetrical Progressive weakness is followed by lost of gait function then paralysisThe severity of weakness is greatest with thoracic metastases
77 Third Red Flag: Sensory Less common than motor findingsStill present in majority of casesAscending numbness and parathesias
78 Fourth Red Flag: Bladder and Bowel Function Loss is late findingAutonomic neuropathy presents usually as urinary retensionRarely sole finding
80 Diagnosis depends on ability to demonstrate a mass compressing the thecal sac Plain radiographs are not enoughHistorically this involved invasive proceduresAdvent of MRI has allowed non-invasive diagnosisClinical examination is not reliable in determining level of lesion
81 Entire imaging of spine is ideal Focused CT imaging can miss clinically unapparent lesionsMyelography and MRI are better than plain X-Rays, bone scans and CT for diagnosis
82 Plain Spine Radiographs Easiest and cheapestNeed large bony destruction or vertebral collapse to be diagnosticHigh false negative rateNot recommended to confirm diagnosis
84 Both image thecal sac and display indentation and encircling CT myelography involves a lumbar punctureContraindicated in brain metastases, thrombocytopenia, or coagulopathyCan diagnose leptomeningeal metastasesAvailable in Winnipeg in middle of the night
85 MRI Images whole spine High detail Spares lumbar puncture Patients in pain must lie still
86 Roughly equivalent in terms of sensitivity and specificity Presently no large comparative studies b/c MRI in the US has become so readily availableMRI standard of care in centers that have access
87 Bone Scan More sensitive than plain radiograph Visualizes entire skeletonCan miss neoplasms that do not have increased blood flow
88 CT Scan aloneDoes not visualize spinal cord and epidural space clearly
89 Intramedullary Metastases Less commonOften present with hemicord symptomsUnilateral weakness below lesionContralateral diminution of pain and temperature sensationCan progress to bilateral dysfunction
90 Radiation MyelopathyCan mimic ESCCMR imaging can make distinction
91 MRI of epidural spinal cord compression in a women with past history of breast cancer.
98 Anticoagulation Cancer is a hypercoaguable state High burden of tumor in metastatic diseasePossible value in prophylaxis against venous thromboembolismIf patient not mobile subcutaneous heparin or compression devices is indicated
99 Prevention of Constipation FactorsAutonomic dysfunctionLimited mobilityOpiate analgesicRisk of perforationMasked by corticosteroidsBowel regimen needed
104 Definitive choicePortal 8 cm wideCentered on spineExtends one to two vertebral bodies above and below the epidural metastasis
105 Relieves pain in most cases Post-neurological function usually determines responseResponse most associated with tumor type and radiosensitivity; eg. lymphomaDosing 20 to 40 Gy in 5 to 20 fractionsPopular30 Gy in 10 fractions
106 SurgeryChanging roleHistorically posterior vertebral decompression was doneNo survival benefit with or without radiation1515. Findlay, GF. Adverse effects of the management of malignant spinal cord compression. J Neurol Neurosurg Psychiatry 1984; 47:761.
107 Better techniques today allow aggressive approach Gross spinal tumor resection with vertebral reconstruction now possibleExperienced surgeon required
108 Improvement in surgery+rads Recent controlled trial comparing aggressive surgery followed by radiation vs. radiation alone16Improvement in surgery+radsDays remained ambulatory (126 vs. 35)Percent that regained ambulation after therapy (56% vs. 19%)Days remained continent (142 vs. 12)Less steroid dose, less narcoticsTrend to increase survival16. Patchell, R, Tibbs, PA, Regine, WF, et al. A randomized trial of direct decompressive surgical resection in the treatment of spinal cord compression caused by metastasis (abstract). proc Am Soc Clin Oncol 2003; 22:1.
109 Chemotherapy Can be successful in chemosensitive tumors Hodgkin’s lymphomaNon-Hodgkin’s lymphomaNeuroblastomaGerm cellBreast cancer (hormonal manipulation)Prostate cancer (hormonal manipulation)
110 Bisphosphonates Recommended Decrease pathologic fractures in bony diseaseMultiple myelomaBreast cancer
111 Prognosis Median survival with ESCC is 6 months14 Ambulatory patients with radiosensitive tumors have the best prognosis14. Sorensen, PS, Borgesen, SE, Rohde, K, et al. Metastatic epidural spinal cord compression. Results of treatment and survival. Cancer 1990; 65:1502.
113 Case 3: Mrs. HCID: 75 year old female living alone with no significant past medical historyEC: brought to ER by paramedics after neighbor called b/c she was found in her apartment unresponsiveNo collateral history
114 Examination Fluctuating level of consciousness Vitals normal, no fever DehydratedCoarse upper airway soundsNo other pertinent findings
115 Investigations CBC normal Mildly elevated BUN and Cr Normal LFTs Standard electrolytes normal
120 Symptoms Usually nonspecific Many times patients present with very high calcium levelMost research done in hyperparathyroidism
121 Gastrointestinal Constipation is most common15 Anorexia Exacerbated or confused with narcotic effectsRelated to autonomic dysfunctionAnorexiaVague abdominal painRarely can lead to pancreatitis15. Heath, H 3d. Clinical spectrum of primary hyperparathyroidism: Evolution with changes in medical practice and technology. J Bone Miner Res 1991; 6(Suppl 2):S63.
122 Renal Dysfunction Nephrolithiasis Nephrogenic diabetes insipidus More common in hyperparathyroidismNephrogenic diabetes insipidusDefect in concentrating abilityPolyuria and polydipsiaChronic renal failureLongstanding high calciumCalcifcation, degeneration, and necrosis of tubules
130 Non-small cell lung cancer Cytokines released Breast cancerNon-small cell lung cancerCytokines releasedTumor necrosis factorInterleukin-1Stimulate osteoclast precursor differentiation into mature osteoclastsLeading to more bone breakdown and release of calcium
131 PTH-Related Protein Most common in patients with non-metastatic tumors Called humoral hypercalcemia of malignancySecretion of PTH itself is a rare eventPTHrP binds to same receptor as PTH and stimulates adeynylate cyclase activityIncreased bone resorptionIncreases kidney calcium reabsorption and phosphate excretion
132 Calcitriol Hodgkin’s disease (mechanism in majority) Non-Hodgkin’s (mechanism in 1/3)Usually responds to glucocorticoid therapy
134 Clinical symptomology with History of cancerRisk factors for cancerSuppressed PTHSome centers can test for PTHrP to confirm Dx of humoral hypercalcemiaHigh PTHrP may predict response to pamidronate16Less of a response16. Gurney, H, Grill, V, Martin, TJ. Parathyroid hormonerelated protein and response to pamidronate in tumourinduced hypercalcemia. Lancet 1993; 341:1611.
135 Malignancy must be ruled out in patients that present with a very high calcium and no other obvious cause
138 Volume Large volume of normal Saline administration Expands intravascular volumeIncreases calcium excretionInhibition of proximal tubule and loop reabosrptionReduces passive reabsorption of calicumFollow fluid status b/c of danger of fluid overload
139 Inhibition of Bone Resorption Three therapiesCalcitoninBisphosphonatesGallium nitrateHistorical therapyAntitumor antibiotic plicamycin (mithramycin)Multiple serious side effectsNo longer manufactured
140 Calcitonin Salmon calcitonin Increases renal excretion of calcium Decreases bone reabsorption by interfering with osteoclast maturationWeak agentWorks the fastest
141 Bisphosphonates Adsorb to the surface of bone hyroxyapatite Interfere with osteoclast activityCytotoxic to osteoclastsInhibit calcium release from boneThree commonly usedPamidronateZoledronic acidEtidronate (1st generation, weaker)
142 Bisphosphonates More potent than calcitonin Maxium effect occurs in 2 to 4 daysTrend to use of IV zoledronic acid in the acute situationBoth are can be renal toxicMore potent than pamidronateAdministered over a shorter period of time (15 minutes vs. 2 hours)
143 Prophylactic Bisphosphonates Pamidronate use in patients with known lytic lesions17Less episodes of hypercalcemiaLess pathologic fracturesLess painLess spinal cord compressionLess need for radiation or surgery17. Hortobagyi, GN, Theriault, RL, Porter, L, et al for the Protocol 19 Aredia Breast Cancer Study Group. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996; 335:1785.
144 Newly discovered side effect… Osteonecrosis of the jawRecent case reports of jaw bone necrosis in patients on pamidronateEDUCATION needed
145 Gallium Nitrate Effective More potential for nephrotoxicity Rarely used
146 DialysisLast resortDialysis fluid with little or no calcium is effectiveUseful when patients can’t tolerate large volume resuscitationIf calcium needs to be correct emergently
147 Recommendations in symptomatic situation Volume expansionSalmon calcitoninIV zoledronic acid or pamidronateClose follow up of calcium level and symptoms
149 Chemotherapy Two roles Direct treatment of cancer Palliation of symptoms
150 Palliative Chemotherapy Goal is not cureGoalsControl of tumorPreservation of functionHelp tumor symptomsPainDsypneaPruritisPoor appetiteWeight loss
151 Fine Balance Chemotherapy can be very toxic Ratio: benefit vs. toxicityHost factors and tumor factorsDelicate balance in palliative situationWant medications that affect tumor but do not heavily affect host
152 Psychology of Cancer Psychological evolution during cancer treatment Many people have fought very hard with their diseaseChemotherapy for “relief” not “cure” can be difficult concept for patientsART of medicine
153 Evolution Chemotherapeutic protocols that have less side effects molecular targeted therapiesAttack tumor specificallyLess effect on host
154 Breast cancerColon CancerProstate cancerLung cancer
155 Breast Cancer Aromatase inhibitors for ER positive tumors Anastrozole, Letrozole, ExemestaneTrastuzumab (Herceptin)Humanized monoclonal antibody targeting Her-2/neu protein on breast cancer cellsInhibits growth factor signal transductionTolerated quite well
156 Colon Cancer Capecitabine (Xeloda) Oral drug that is transformed into 5-FU with three enzymatic reactionsFinal enzyme is at higher levels in tumor cellsContributes to drug’s less toxic side effect profileLess stomatitis, less myelosupression
157 Targeted GI Therapies Bevacizumab Cetuximab Monoclonal antibody to vascular endotheial growth factor receptorSome cardiac toxicityCetuximabMonoclonal antibody to human epidermal growth factor receptorSkin toxicity
158 Prostate Cancer LHRH analogues Leuprolide (Lupron) Goserelin (Zoladex) Stop testosterone production with limited side effects
159 Lung CancerIn stage IV disease patients who receive Cisplatin based doublet chemotherapy live longer and feel better than best supportive careHard to balance side effects
160 Gefitinib (Iressa)Targets epidermal growth factor receptor (tyrosine kinase small molecule inhibitor)May have a role in the palliation of advanced non small cell lung cancer patients
161 Palliative Care Debate Do not accept any patient on “active” therapyThis needs to be further elucidatedPatients being palliated with chemotherapy or targeted therapies still have other palliative care issues and needsShould a patient still on Xeloda for breast or colon cancer not be admitted to St. Boniface 8A?