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Palliation brain, spinal and bone mets

Palliation of brain, spinal cord compression and bone metastasis. A review of Guidelines

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Palliation brain, spinal and bone mets

  1. 1. Palliation of Brain, Spinal Cord and Bone Metastases By Dr. Ayush Garg Senior Resident
  2. 2. Palliation of Brain Metastases
  3. 3. Introduction • Most common intracranial lesion in adults, occurring at a median time of 8.5 to 12 months from primary diagnosis. • The heterogeneity of patients with brain metastases and evolving treatment approaches, their management is complex, evolving, and controversial. • As a result, a number of clinical trials are ongoing to determine the optimal treatment strategy for these patients.
  4. 4. Epidemiology It develops in nearly 30% of cancer patients 20%–50% 5%–20% 7%–10%2%–5%4%–6%
  5. 5. Clinical Presentation
  6. 6. Pathophysiology Arterial Circulation Arrest in the capillar y bed Crosses BBB Crosses BBB A B C D E F G Peritumoral edema
  7. 7. Diagnosis Imaging modality of choice is an MRI Cerebral hemispheres (80%) Cerebellum (15%) Brain stem (<5%)
  8. 8. • Typically they are solid or ring-enhancing lesions and pseudospherical in shape at the junction of gray-white matter. • Generally they are T1 iso- or hypointense, T2 hyperintense and enhance with contrast administration
  9. 9. Role of Whole Brain Radiation Therapy Question Should whole brain radiation therapy (WBRT) be used as the sole therapy in patients with newly- diagnosed, surgically accessible, single brain metastases, compared with WBRT plus surgical resection, and in what clinical settings?
  10. 10. Recommendation Surgical resection plus WBRT versus WBRT alone • Level 1 Class I evidence supports surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with: – Good performance status – Limited extracranial disease. • Patients with poor performance scores, advanced systemic disease, or multiple brain metastases- Limited data
  11. 11. If WBRT is used, is there an optimal dosing/ fractionation schedule? Recommendation • Level 1 Class I evidence- altered dose/ fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. • 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy
  12. 12. If WBRT is used, what impact does tumor histopathology have on treatment outcomes? Recommendation • Insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology.
  13. 13. Question Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone? Recommendation Surgical resection plus WBRT versus surgical resection alone • Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site
  14. 14. Role of Surgical Resection Question Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings?
  15. 15. Surgical resection plus WBRT versus SRS ± WBRT • Level 2 Sx plus WBRT, versus SRS plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates • SRS is unsuitable for larger lesions (>3 cm) or for those causing >1 cm midline shift • Level 3 Class I suggests SRS alone may provide equivalent functional and survival outcomes compared with Sx + WBRT for patients with single brain metastases
  16. 16. Question • Does surgical resection in addition to WBRT improve outcomes when compared with WBRT alone? • Target population • This recommendation applies to adults with a newly diagnosed single brain metastasis amenable to surgical resection • The recommedation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma).
  17. 17. Recommendation Surgical resection plus WBRT versus WBRT alone • Level 1 Class I evidence supports surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with: – Good performance status – Limited extracranial disease. • Patients with poor performance scores, advanced systemic disease, or multiple brain metastases- Limited data
  18. 18. Role of Radiosurgery Question • Should patients with newly-diagnosed metastatic brain tumors undergo stereotactic radiosurgery (SRS) compared with other treatment modalities? • Target population • These recommendations apply to adults with newly diagnosed solid brain metastases amenable to SRS; • Lesions measuring less than 3 cm in maximum diameter • Less than 1 cm of midline shift
  19. 19. Recommendations SRS plus WBRT vs. WBRT alone • Level 1 Single-dose SRS + WBRT  significant longer survival compared with WBRT alone for patients with single metastatic brain tumors who have a KPS ≥ 70. • Level 2 Single-dose SRS + WBRT is superior in terms of local tumor control and maintaining functional status when compared to WBRT alone for patients with 1–4 metastatic brain tumors who have a KPS ≥ 70.
  20. 20. • Level 3 Single-dose SRS + WBRT may lead to significantly longer patient survival than WBRT alone for patients with 2–3 metastatic brain tumors. • Level 4 There is class III evidence that single- dose SRS + WBRT is superior to WBRT alone for improving patient survival for patients with single or multiple brain metastases and a KPS < 70.
  21. 21. SRS plus WBRT vs. SRS alone • Level 2 Single-dose SRS alone may provide an equivalent survival advantage for patients with brain metastases compared with WBRT + single-dose SRS. SRS alone vs. WBRT alone • Level 3 Single-dose SRS alone appears to be superior to WBRT alone for patients with up to three metastatic brain tumors in terms of patient survival advantage.
  22. 22. Question • What is the role of SRS alone in the management of patients with 1 to 4 brain metastases? • Level 3: For patients with solitary brain metastasis, SRS should be given to decrease the risk of local progression. • Level 3: For patients with 2 to 4 brain metastases, SRS is recommended for local tumor control, instead of whole brain radiotherapy, when their cumulative volume is < 7 mL.
  23. 23. Question • What is the role of SRS alone in the management of patients with more than 4 brain metastases? • Level 3: The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume <7 mL
  24. 24. Role of Chemotherapy Question • Should patients with brain metastases receive chemotherapy in addition to whole brain radiotherapy (WBRT)? • Target population • This recommendation applies to adults with newly diagnosed brain metastases; • However, the recommendation below does not apply to the exquisitely chemosensitive tumors, such as germinomas metastatic to the brain.
  25. 25. Recommendation • Level 1 Routine use of chemotherapy following WBRT for brain metastases has not been shown to increase survival and is not recommended. • Four class I studies examined the role of carboplatin, chloroethyl nitrosoureas, tegafur and temozolomide, and all resulted in no survival benefit.
  26. 26. Recurrent/Progressive Brain Metastases Question • What evidence is available regarding the use of whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or chemotherapy for the treatment of recurrent/progressive brain metastases? • Target population • This recommendation applies to adults with recurrent/progressive brain metastases who have previously been treated with WBRT, surgical resection and/or radiosurgery.
  27. 27. Recommendation • Level 3 There is insufficient evidence to make definitive treatment recommendations • Treatment should be individualized based on – Patient’s functional status – Extent of disease – Volume/number of metastases – Recurrence or progression at original versus non- original site – Previous treatment and type of primary cancer
  28. 28. • In this context, the following can be recommended depending on a patient’s specific condition: – No further treatment (supportive care), – Re-irradiation (either WBRT and/or SRS), – Surgical excision – Chemotherapy
  29. 29. Question If WBRT is used in the setting of recurrent/progressive brain metastases, what impact does tumor histopathology have on treatment outcomes? • No studies were identified that met the eligibility criteria for this question.
  30. 30. The Role of Anticonvulsants Question • Do prophylactic anticonvulsants decrease the risk of seizure in patients with metastatic brain tumors compared with no treatment? • Target population • These recommendations apply to adults with solid brain metastases who have not experienced a seizure due to their metastatic brain disease.
  31. 31. Recommendation • Routine prophylactic use of anticonvulsants is not recommended
  32. 32. The Role of Steroids Question • Do steroids improve neurologic symptoms in patients with metastatic brain tumors compared to no treatment? If steroids are given, what dose should be used? • Comparisons include: – Steroid therapy versus none – Comparison of different doses of steroid therapy. • Target population • These recommendations apply to adults diagnosed with brain metastases.
  33. 33. Recommendations Steroid therapy versus no steroid therapy • Asymptomatic brain metastases patients without mass effect Insufficient evidence exists to make a treatment recommendation for this clinical scenario.
  34. 34. Brain metastases patients with mild symptoms related to mass effect • Level 3 Corticosteroids are recommended to provide temporary symptomatic relief of symptoms related to increased intracranial pressure and edema secondary to brain metastases. • It is recommended for patients who are symptomatic from metastatic disease to the brain that a starting dose of 4–8 mg/day of dexamethasone be considered.
  35. 35. Brain metastases patients with moderate to severe symptoms related to mass effect • If patients exhibit severe symptoms consistent with increased intracranial pressure, it is recommended that higher doses such as 16 mg/day or more be considered.
  36. 36. Choice of Steroid • Level 3 If corticosteroids are given, dexamethasone is the best drug choice given the available evidence. Duration of Corticosteroid Administration • Level 3 Corticosteroids, if given, should be tapered slowly over a 2 week time period
  37. 37. New and Emerging Therapies Question • What evidence is available regarding the emerging and investigational therapies for the treatment of metastatic brain tumors? • Target population • These recommendations apply to adults with brain metastases.
  38. 38. Recommendations New radiation sensitizers • Level 2 A RCT suggested a prolongation of time to neurological progression with the early use of motexafin-gadolinium (MGd). Interstitial modalities • There is no evidence to support the routine use of new or existing interstitial radiation or chemotherapy
  39. 39. New chemotherapeutic agents • Level 2 Treatment of melanoma brain metastases with concurrent temozolomide (Class II) • Level 3 Fotemustine is used in certain studies Molecular targeted agents • Level 3 The use of EGFR inhibitors may be of use in the management of brain metastases from NSCLC
  40. 40. • RPA (Recursive Partition Analysis) • GPA (Graded Prognostic Assessment) Prognosis
  41. 41. Disease Specific GPA
  42. 42. Symptom Management • Corticosteroids- – To decrease peritumoral edema – Dexamethasone 16mg no advantage over 4-8mg/day – More side effects with high dose – Should be tapered within 1-2 weeks – Concurrent with PPIs (Pantoprazole/ Rabiprazole) • Anticonvulsants- – No benefit of prophylactic use of AEDs in patients without a previous history of seizures – Preferable agents that do not interact with hepatic cytochrome P450 (e.g., levetiracetam) • Venous Thromboembolism- Anticoagulants • Inferior Vena Cava filters can be used
  43. 43. Whole Brain RT • Whole Brain Radiotherapy is gold standard • Extended or hypofractionated WBRT has shown no survival benefit • RTOG 0933 and 0614 is evaluating the role of hippocampal avoidance WBRT (HA-WBRT) and use of WBRT + memantine • Role of PCI only in SCLC FACT
  44. 44. VARIOUS FRACTIONATION SCHEDULES FOR BRAIN METASTASIS
  45. 45. RT Fields • Parallel opposed lateral portals used • The inferior field border should be inferior to the cribriform plate, the middle cranial fossa, and the foramen magnum • The safety margin depends on penumbra width, head fixation, and anatomic factors but should be at least 1 cm, even under optimal conditions.
  46. 46. Surgery • Surgery provides immediate and effective relief from symptomatic mass effect and can confirm or establish the diagnosis • Three trials by Patchell et al, Noordijk et al and Mintz et al concluded that suggest that surgical resection should be reserved for lesions: – Causing life-threatening complications, – Requiring pathologic confirmation or – In patients with KPS ≥ 70 – Controlled extracranial disease burden
  47. 47. Stereotactic Surgery • No randomized trials compare surgery with SRS, SRS boost appears to provide comparable local control rates (80% to 90% when combined with WBRT) • Ideal candidate for SRS: – Patients with controlled or absence of extracranial metastases – Excellent KPS – Lesion less than 4 cm size • Historically, the number (one to four) of brain metastases was considered a general contraindication, although recent publications refute this.
  48. 48. • RTOG 9005 Dose Prescription: ≤2cm- 24Gy >2 to 3cm- 18Gy >3 to 4cm- 15Gy • In conclusion, although SRS boost is indicated in patients with a single metastasis • It is difficult to justify its routine use in patients with multiple metastases sue to equivocal phase III trials.
  49. 49. Comparison of the Advantages of Surgery and Stereotactic Radiosurgery Surgery Stereotactic Surgery • Treatment of larger lesion(s) (>4 cm diameter) • Immediate removal of mass effect and edema • Histologic confirmation • Rapid taper of steroids for symptomatic lesions • Removal of cancer • Minimal risk for radiation necrosis • Less intensive follow-up • Less long-term dependency on steroids • Treatment of small deep lesion(s) or eloquent areas • Minimally invasive • No general anesthesia use • Outpatient procedure • Treatment of multiple lesions at same session • Short recovery time (<1 wk) • Potentially avoid whole-brain radiation therapy • Rapid initiation of systemic therapies • Fewer immediate complications
  50. 50. Chemotherapy & Targeted Therapy
  51. 51. Concurrent Radiosensitizers No trial has demonstrated a survival advantage
  52. 52. Re-Irradiation • Wong et al and Son et al did a study to check for adequate doses for Re Irradiation. • A minimum of 20Gy in 1.8-2Gy per fraction should be given.
  53. 53. Palliation of Spinal Cord Metastases
  54. 54. Continued growth & expansion of vertebral bone mets into the epidural space Neural foramina extension by a paraspinal mass Destruction of vertebral cortical bone Vetebral body collapse Displacement of bony fragments into epidural space Continued growth and expansion of vertebral bony mets into the epidural space Epidural venous plexus compression
  55. 55. Spinal cord edema Increased pressure on small arteries White matter ischemia White matter infarctionPermanent cord damage
  56. 56. • Most common primary sites include: – Breast Cancer – Lung Cancer – Prostate Cancer • Most commonly involved vertebrae: – Thoracic (60-80%) – Lumbar (15-30%) – Cervical (<10%)
  57. 57. • Clinical Features: – Back pain (70-94%) – Weakness (61-91%) – Sensory Deficits (46-90%) – Autonomic Dysfunction (40-57%) • MRI is gold standard • CT Myelogram can be performed for patients who are contraindicated to MRI
  58. 58. Lancet Oncol 2017; 18: e720–30
  59. 59. Initial assessment algorithm for patients with spinal metastases
  60. 60. MNOP algorithm for spinal metastasis management
  61. 61. Confusion? When not to Treat? • KPS ≤ 40 • Life Expectancy ≤ 2 months • Extensive, Uncontrolled, Progressive Primary • No effective systemic therapies available When to Treat? • KPS > 40 • Life Expectancy > 2 months • Controlled or stable disease
  62. 62. TREATMENT • Surgery • Radiation for non-radiosensitive tumors typically takes several days to have an effect and does not stabilize the spine, whereas surgery allows for immediate cord decompression • If operable, patients should undergo surgical decompression and stabilization followed by radiotherapy. • Even for radiosensitive tumors, surgery can often stabilize the spine. • Therefore, all patients with MSCC should be evaluated by a surgeon.
  63. 63. Kyphoplasty or vertebroplasty and EBRT • The updated literature review demonstrates no prospective data suggesting either kyphoplasty or vertebroplasty obviate the need for EBRT for painful bone metastases. • A new prospective study of 11 patients treated with vertebroplasty and samarium-153 is under study. • However, these limited data do not allow definitive statements regarding combined regimens and highlight the importance of future prospective trials
  64. 64. Radiotherapy • A single fraction of 8Gy should be used in MSCC patients with limited survival expectations and that 30Gy in 10 fractions should be used for all other patients. • Hypofractionated schedules (8Gy × 1 to 2 or 4Gy × 5) should be routinely avoided.
  65. 65. Target volume definition • The GTV includes vertebral and soft tissue tumor as seen on CT planning scan and diagnostic MRI. • The CTV includes the spinal canal, the width of the vertebra and one vertebra above and below the SCC if the planning is based on MRI, or • two vertebrae above and below if based on X-ray or CT to allow for uncertainty about extent of microscopic disease. • The CTV to PTV margin is 1 cm.
  66. 66. Bisphosphonates and EBRT • Literature suggests benefit from bisphosphonates and similar medications (ie, denosumab) in reducing skeletal-related events. • Several prospective trials of Denosumabhave suggested improved efficacy compared with bisphosphonates. • Further studies may further elucidate circumstances where EBRT may be omitted.
  67. 67. Palliation of Bone Metastases
  68. 68. Introduction • The axial skeleton is the most common site for bone metastasis. • Most frequest sites are spine, pelvis & rubs. • Most frequent primary are breast, prostate followed by lung, melanoma, kidney, gastrointestinal sites & sometimes myeloma and lymphoma. • Certain sites give specific types of bone mets: – Scapula  Renal – Skull  Breast – Tibia, Fibula/ Hands  Lungs – Toes Genitourinary sites
  69. 69. Pathophysiology • There are 3 types of cells within mature bone: Osteocytes, Osteoblasts and Osteoclasts. • Metastases to the bone most often occur in the red marrow, which is found in highest concentration in the skull, irregular bones of the axial skeleton, and the medullary portion of the appendicular skeleton. • Most often occur by hematogenous spread but may occur by direct extension as well
  70. 70. • Breast and lung cancers more commonly cause osteolytic-appearing lesions. • Prostate and thyroid cancers more often have osteoblastic-appearing lesions. • Only myeloma is associated with purely osteolytic lesions. • Most other tumors have a combination of osteolytic and osteoblastic components.
  71. 71. Diagnosis • Osteoblastic bone mets can be detected by Bone Scan. • Bone scan is the best method for screening patients at risk for bone metastasis who may not present with bone pain. • It is also useful to evaluate the extent of metastatic disease in the bone.
  72. 72. Treatment • Optimal management requires a multi- disciplinary team. • Medical treatment, radiation therapy, surgery, and bone targeted treatment with the bisphosphonates and denosumab are combined depending on the: – Biology of the disease, – Extent of the skeletal involvement, – Life expectancy of the patient
  73. 73. Radiopharmaceuticals and EBRT • Samarium-153 (46.3 hours) • Strontium-89 (50.6 days) • Rhenium-186 (3.71 days) • Radium-223 (11.4 days) • In patients with bone-only or bone-dominant disease, these agents may provide benefits beyond pain relief, including prevention of skeletal-related events and improved survival
  74. 74. • These radionuclides emit beta particles with a mean range between 0.2 and 3 mm, thereby minimizing toxicity to surrounding tissue. • Retention in the areas of bone metastases is greater than in the normal bone marrow, with a tumor-to-marrow ratio of 10:1. • The average time to clinical response is 7 to 14 days. • Re-treatment time: – 10 to 12 weeks  Sr 89 – 6 to 10 weeks  Sm 153
  75. 75. • A phase 3 RCT of Sm-153 ± EBRT (8 Gy in 1#) in metastatic prostate cancer with painful bony metastases demonstrated a significant improvement in pain relief with addition of EBRT and no extra toxicity.
  76. 76. Received 4 May 2016; revised 15 July 2016; accepted 3 August 2016
  77. 77. KQ 1. What fractionation schemes have been shown to be effective for the treatment of painful and/or prevention of morbidity from peripheral bone metastases? • Studies show pain relief equivalency following a single 8 Gy fraction, 20 Gy in 5 fractions, 24 Gy in 6 fractions, and 30 Gy in 10 fractions for patients with previously unirradiated painful bone metastases. Agreement:100%, Strength: High
  78. 78. KQ 2. When is SF RT appropriate for the treatment of pain and/or prevention of morbidity from uncomplicated bone metastasis involving the spine or other critical structures? • A single 8 Gy fraction provides noninferior pain relief. Agreement:100%, Strength: High
  79. 79. KQ 3. Are there long-term side-effect risks that should limit the use of SF therapy? • There continues to be no suggestion from data that SF therapy produces unacceptable rates of long-term side effects that might limit its use for patients with painful bone metastases. Agreement:100%, Strength: High
  80. 80. KQ 4. When should patients receive retreatment with radiation to peripheral bone metastases? • Patients with persistent or recurrent pain more than 1 month following EBRT for symptomatic, peripheral bone metastases should be considered for retreatment while adhering to normal tissue dosing constraints. Agreement:100%, Strength: High
  81. 81. KQ 5. When should patients receive retreatment with radiation to spine lesions causing recurrent pain? • Patients with recurrent spine pain more than 1 month after initial treatment should be considered for EBRT retreatment while adhering to normal tissue dosing constraints Agreement:100%, Strength: High
  82. 82. KQ 6. What promise does highly conformal RT hold for the primary treatment of painful bone metastasis? • Advanced RT techniques such as SBRT as the primary treatment for painful spine bone lesions or for spinal compression should be considered in the setting of a clinical trial due to insufficient data Agreement:100%, Strength: Moderate
  83. 83. KQ 7. When should highly conformal RT be considered for retreatment of spine lesions causing recurrent pain? • Advanced radiation techniques such as SBRT retreatment for recurrent pain in spine bone lesions may be feasible, effective, and safe. • But the panel recommends that this approach should be limited to clinical trial. Agreement:100%, Strength: Moderate
  84. 84. KQ8. Does the use of surgery, radionuclides, bisphosphonates, or kyphoplasty/vertebroplasty obviate the need for palliative RT for painful bone metastasis? • The panel reiterates that the use of surgery, radionuclides, bisphosphonates, or kyphoplasty/ vertebroplasty does not obviate the need for EBRT for patients with painful bone metastases. Agreement:100%, Strength: Moderate
  85. 85. Take Home Message • Sx + WBRT vs WBRT alone • Sx + WBRT vs Sx alone • Sx + WBRT vs SRS ± WBRT • SRS + WBRT vs SRS alone • SRS alone vs WBRT alone • Effective multidisciplinary teamwork is critical to the rapid evaluation and management of patients with MSCC

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