Palliation of Metastases

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Palliation of Metastases

• Iftekhar Ahmad, MD
• Wayne State University/KCI
• July 8thth, 2008

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Epidemiology

• Osseous metastases is the most common cause of
  intractable pain in cancer patients
• Third common site of spread after lung and liver
• Presentation occurs after primary diagnosis in
  majority of patients
• But in 23 of patients it is the presenting
  problem which leads to the discovery of disease

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Pathophysiology

• Tumor cells primarily gain access to the
  circulation through the capillaries
• 1). Release of tumor cells from the primary
• 2). Invasion of vascular or lymphatic channels
• 3). Dissemination to distant sites
• 4). Endothelial attachment and invasion of new
  host
• 5). Growth into a metastatic focus

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Pathophysiology

• Skeletal blood flow accounts for only 4-10 of
  total cardiac output
• Incidence of skeletal metastases appears higher
  than expected
• Microstructure of marrow renders it vulnerable to
  tumor accumulation and invasion
• Arteries tend to divide capillaries as they near
  the endosteal margin of bone
• Capillaries become continuous with venous system
  which has a 6-8 times capacity
• The circulation comes to a near standstill at
  this point potentially allowing tumor cells more
  time to invade

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Pathophysiology

• Tumor angiongenesis factor attracts vessels to a
  small tumor colony
• Otherwise it would be dependant on local tissue
  circulation and incapable of further invasion
• The production of this factor is partially
  blocked by immune responses so it may take years
  to have adequate vasculature for invasion

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Mediators

• Some tumors produce and secrete humeral mediators
  that stimulate osteoclast activity
• TGF
• PDGF
• TNF
• Prostaglandins
• Interleukins

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Distribution

• More prevalent in the axial skeleton versus the
  appendicular skeleton
• But richer blood flow in appendicular skeleton
  would predict higher rates

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Imaging

• Plain X-rays are the fastest form of imaging
• Medulla involved early and cortex late
• Role for patients with pain and positive bone
  scan to uncover pathologic fractures
• Sclerotic Prostate, Breast, GI, Bladder
• Lytic All sites
• Mixed Breast
• More than 50 cortical destruction needed to
  detect

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Imaging

• Bone scans are more sensitive and also allow
  examination of entire skeleton
• Most lesions evoke an osteoblastic response
  (increased uptake)
• Rapidly growing lesions may show decreased uptake
  because rate of destruction exceeds rate of
  formation
• Non-osteoblastic tumors include myeloma and some
  lymphomas
• Infection, fractures, and degenerative changes
  may also result in a positive result

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Imaging

• CT differentiates between metastases and
  degenerative joint disease
• DJD can manifest as positive bone scan
• Muindi and colleagues looked at patients with
  positive bone scans and negative x-rays
• 50 of patients had mets on CT, 25 had benign
  findings, and 25 had no findings
• None of the patients with no findings had
  subsequent metastases

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Imaging

• MRI is the method of choice for examining the
  spine
• More sensitive than bone scan for detecting early
  changes (medullary)
• If cord compression is suspected, thorough exam
  is warranted as 10 of patients may have
  significant disease elsewhere
• Disadvantages include
• High cost
• No metal implants
• Claustrophobia
• Still for long period

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Treatment

• Primary goal is improvement of QOL
• Decrease pain and maintain function
• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Endocrine Therapy

• Tamoxifen used for post-menopausal metastatic
  breast cancer in mainly ER patients
• But 10 of ER- patients respond
• Median tumor response of 15 months
• Aromatase inhibitors have challenged tamoxifen as
  first-line therapy for advanced or metastatic
  breast cancer

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Arimidex vs. Tamoxifen

• Milla-Santos A et al Am J Clin Oncol. 2003
  Jun26(3)317-22
• RCT comparing anastrozole with tamoxifen as
  first-line therapy in postmenopausal,
  hormone-dependent, advanced breast cancer
• Patients were randomized to daily anastrozole (n
  121) or tamoxifen daily (n 117)
• Median FU of 13.3 months, clinical benefit (CB)
  was achieved in 83 and 56 of anastrozole and
  tamoxifen patients, respectively (p lt 0.001)
• Median time to disease progression in patients
  was 18.0 months and 7.0 months (p lt 0.01)

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Femara vs. Tamoxifen

• Mouridsen H et al JCO 2003 Jun 121(11)2101-9
• 916 patients with locally advanced or metastatic
  ER or unknown tumors (30)
• Randomized to letrozole 2.5 mg (n 458) or
  tamoxifen 20 mg (n 458) daily until disease
  progression
• Time to progression (median, 9.4 v 6.0 months,
  respectively p lt.0001) and overall objective
  response rate (32 v 21, respectively p .0002)
  were higher for Femara patients
• OS at 2 years was 64 for letrozole and 58 for
  tamoxifen (p lt .01)

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Second Line

• Patients who fail on aromatase inhibitors may be
  given tamoxifen and vice-versa
• Other agents include aminoglutethimide and megace
• Pre-menopausal women may be treated with ovarian
  ablation (surgically or with LHRH agonists)

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Prostate Cancer

• Very sensitive to hormones and 80 of patients
  with metastatic disease show some response (or to
  orchiectomy)
• Flare response is noted in 10-30 of patients on
  LHRH agonist
• Can be reduced with concurrent use of
  anti-androgens
• Clinical benefit also seen with the two agent
  therapy (flutamide)

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Prostate Cancer

• Crawford ED et al N Engl J Med. 1989 Aug
  17321(7)419-24
• 603 men received leuprolide in combination with
  either placebo or flutamide
• As compared with the 300 patients receiving
  leuprolide and placebo, the 303 patients randomly
  assigned to receive leuprolide and flutamide had
  a longer progression-free survival (16.5 vs. 13.9
  months P 0.039) and an increase in the median
  length of survival (35.6 vs. 28.3 months P
  0.035).
• Differences between the treatments were
  particularly evident for men with minimal disease
  and good performance status
• Symptomatic improvement was greatest during the
  first 12 weeks of the combined androgen blockade,
  when leuprolide alone often produces a painful
  flare in the disease

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Biologic Therapy

• Her-2/neu represents the human EDGF and is
  overexpressed in 20-30 of breast cancer
• Associated with increased tumor growth rate,
  metastatic rate, and decreased OS
• Trastuzumab (Herceptin) used in these patients
• High tumor response correlated with high levels
  of overexpression

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Herceptin

• Vogel CL et al J Clin Oncol. 2002 Feb
  120(3)719-26
• 114 women with HER2-overexpressing metastatic
  breast cancer received first-line treatment with
  trastuzumab
• Objective response rate was 26 with seven
  complete and 23 partial responses
• Clinical benefit rates in assessable patients
  with 3 and 2 HER2 overexpression were 48 and
  7, respectively
• Seventeen (57) of 30 patients with an objective
  response and 22 (51) of 43 patients with
  clinical benefit had not experienced disease
  progression at follow-up at 12 months or later
• Most common treatment-related adverse events were
  chills (25 of patients), asthenia (23), fever
  (22), pain (18), and nausea (14)

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Bone Chemotherapy

• Overall response in bone is poor
• 0-30
• Only a partial response with a median duration of
  9-12 months
• Better response in Small Cell Lung and breast
• Potentially curative for lymphoma, GC tumors
  (Cytoxan)
• Myelosuppression may be problematic with
  extensive marrow involvement and XRT treatment

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Bisphosphonates

• Inhibition of osteoclast-mediated bone resorption
  (exact mechanism not clear)
• Direct biochemical effects on osteoclast
• Prevention of osteoclast attachment to matrix
• Inhibition of differentiation of osteoclast
  precursors

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Bisphosphonates

• Zoledronic Acid(Zometaâ), Risedronate(Actonelâ),
  Pamidronate(Arediaâ), Ibandronate(Bonivaâ),
  Etidronate(Didronelâ), Alendronate(Fosamaxâ)
• Four phase II trials using IV pamidronate for
  sole treatment of osteolytic bone mets from
  breast cancer
• Relieve bone pain in 50
• Radiographic evidence of bone healing in 25
• Decrease incidence of vertebral fractures

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Zoledronic Acid v Pamidronate

• Rosen LS et al Cancer 2003 Oct 1598(8)1735-44
• 1,648 patients with either stage III multiple
  myeloma or metastatic breast cancer (with at
  least one bone
• Assigned to treatment with zoledronic acid or
  pamidronate
• After 25 months of follow-up, zoledronic acid
  reduced the overall proportion of patients with
  an skeletal related event (SRE) and reduced the
  skeletal morbidity rate similar to pamidronate
• Compared with pamidronate, zoledronic acid
  reduced the overall risk of developing skeletal
  complications by an additional 16 (P 0.030)
• In patients with breast carcinoma, zoledronic
  acid was significantly more effective than
  pamidronate, reducing the risk of SREs by an
  additional 20 (P 0.025) compared with
  pamidronate and by an additional 30 in patients
  receiving hormonal therapy (P 0.009)
• Zoledronic acid and pamidronate were equally well
  tolerated the most common adverse events were
  bone pain, nausea, fatigue, and fever

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Analgesics

• WHO Analgesic Ladder
• Step I nonopioid /- adjuvant therapy
• Step II Opioid for moderate pain plus nonopioid
  /- adjuvant therapy
• Step III Opioid for moderate to severe pain /-
  nonopioid /- adjuvant therapy

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Step I

• Nonopioid Analgesics
• Acetaminophen, Aspirin, NSAIDS
• Synergistic with opioids
• Many osseous mets produce PGs involved in
  osteolysis
• Adjuvant Therapy
• Massage, Heat, Cold, Acupuncture, Vibration, TENS
• Anxiolytics, Antidepressants, Antiepileptics
• Hypnosis, Biofeedback

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Step II and Step II

• Step II Opioids
• Codeine
• Dihydrocodeine
• Hydrocodone
• Oxycodone
• Propoxyphene
• Step III Opioids
• Morphine
• Hydromorphone
• Fentanyl

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Pain Pathway
Points

• Try to cover multiple steps along the pain
  pathway to maximally treat pain.
• TCA or Neurontin when pain has neuropathic
  component
• NSAID with bone involvement
• Adding nonopioids allows a decreased dose of
  opioid and may improve QOL
• NV are not allergic reactions to
  opiates/opioids and usually resolve within a week
  when continuing med
• C-II meds cannot have refills and can only have
  one per prescription form

Pain
Central Processing
Spinal Cord
Peripheral Receptors
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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Surgery

• Should be considered for patients with pathologic
  or impending fractures
• Fixation can reduce pain and expedite healing
• Prophylactic fixation may prevent fracture
  eliminating any functional loss

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Surgery

• Both lytic and blastic lesions alter bone
  elasticity
• Lytic lesions reduce bone strength more than
  blastic lesions
• Elongated lesions reduce bone strength more

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Surgery

• Guidelines for prophylactic fixation
• Life expectancy gt3 months
• Able to tolerate surgery
• Expectation of expedited mobilization
• Adequate bone proximal and distal to lesion to
  support fixation device
• Cortical bone destruction of gt/ 50
• Pathologic avulsion fracture of lesser trochanter
• Stress pain persists after radiation

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Spinal Cord

• Most common site of skeletal metastases
• Vertebral body typically affected first
• Usually asymptomatic
• 30-50 of vertebral body needs to be destroyed to
  be detected on x-ray
• Symptoms occur when
• Enlarging mass breaks through cortex and invades
  paravertebral soft tissue
• Mass compresses the nerve roots
• Pathologic fracture occurs
• Spinal cord compression

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Spinal Cord Vertebroplasty

• Patient must be able to undergo sedation or
  anesthesia
• Indications for surgical intervention
• Progressive canal impingement or cord compression
• Bone/soft tissue extruded into canal
• Progressive spinal deformity
• Progressive kyphosis
• Previously treated with radiation

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Local Field Radiation Therapy

• Vast majority of patients managed successfully
  with external beam RT
• Optimal dose and fractionation continue to be
  debated
• Results of various studies compounded by use of
  different pain scoring systems, analgesic usage,
  and use of hormone or chemotherapy
• Treatment technique

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RTOG 7402 Tong Cancer. 50893 1982

• RCT of 1016 pts with solitary or multiple mets in
  femur, humerus, pelvis, spine.
• Pain or narcotic score at least 4
• Expected survival at least 3-months
• No previous RT
• No new CTX

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RTOG 7402 Study Design
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RTOG 7402

• Overall
• 89 experienced minimal pain relief
• 83 experienced partial pain relief
• 54 experienced complete pain relief
• No significant differences between the treatment
  arms
• Initial pain score useful predictor of treatment
  response
• Patients with breast and prostate primaries
  responded best
• Median duration of complete and partial relief
  was 12 and 20 weeks
• Median OS
• 36 weeks for solitary mets
• 24 weeks for multiple mets

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Dutch Multicenter Trial

• 1171 patients with painful bone metastases
  randomly assigned to 8 Gy in a single dose or 24
  Gy in six fractions
• Excluded melanoma, RCC, or C-spine
• Palliative benefit was similar in both groups
• Treatment-related toxicity was similar in both
  groups
• Retreatment was required by significantly more
  patients treated with a single fraction (25 vs.
  7)

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British Trial

• RCT 765 pts painful bone metastases
• 8 Gy single fraction
• 20 Gy five fractions
• 30 Gy 10 fractions
• At 12 month follow-up
• No differences in palliation of pain
• Single fraction twice as likely to require
  reirradiation
• majority successfully retreated with single
  fraction

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RTOG 97-14

• RCT 949 patients with prostate or breast cancer
  painful bone metastases
• 8 Gy in a single fraction or 30 Gy in 10
  fractions
• Patients with evidence of cauda equina syndrome
  or epidural spinal cord compression were excluded
  
• No significant differences in the rates for
  complete and partial pain relief, the use of
  narcotics, or the incidence of subsequent
  pathologic fractures
• Patients treated with a single fraction were
  twice as likely to require retreatment (18 vs 9)

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Meta-Analysis

• Wu JY et al IJROBP 2003 Mar 155(3)565-7
• 5455 patients in 16 trials
• The primary outcomes of interest were complete
  and overall pain relief
• Included complete and overall response rates from
  studies comparing single-fraction RT (median 8
  Gy, range 8-10 Gy) against multifraction RT
  (median 20 Gy in 5 fractions, range 20 Gy in 5
  fractions to 30 Gy in 10 fractions)
• Overall response rates were similar for single
  fraction and multifraction RT, at 1011 (72.7) of
  1391 and 958 (72.5) of 1321 (p 0.9)
• Exploratory analyses by biologic effective dose
  did not reveal any dose-response relationship
  among the fractionation schedules used (single 8
  Gy to 40 Gy in 15 fractions)
• Only the re-irradiation rates were consistently
  different between the treatment arms (more
  frequent re-irradiation in lower dose arms among
  trials reporting re-irradiation rates)

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Target Volumes

• Should be defined after careful review of all
  studies along with thorough patient examination
• Attention should also be paid to soft tissue
  masses which may contribute or be the cause of
  pain
• Review of any previous treatment plans
• Best assessment with CT and MRI
• Volumes should be kept to a minimum to preserve
  marrow reserves (especially for patients
  undergoing chemotherapy)

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Radiation Hemibody

• Rationale
• Most patients with bone mets have multiple sites
• Many require additional treatment within 1 year
• More rapid onset of relief than local-field
• Draw-backs
• Similar overall response
• More side effects
• Require close monitoring peri-treatment
• Largely replaced by radioisotope pharmaceuticals

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RTOG 8206

• Poulter CA et al IJROBP 1992 23(1)207-14
• RCT of 499 patients who received HBI or were
  observed following local field RT (3 Gy x 10
  followed in 8 Gy of HBI)
• Improvement was seen in time-to-disease
  progression at one year, 35 for local HBI
  versus 46 on the local-only control arm
• At one year, 50 of patients on the local HBI
  arm showed new disease compared to 68 on the
  local-only arm
• At one year, 76 of the local only group had been
  retreated versus 60 in the local HBI arm
• There were no fatalities and no radiation
  pneumonitis was seen in the local HBI arm (lung
  blocks limited dose to 7 Gy)
• The occurrence of severe hematopoetic toxicities
  were significantly different in the local HBI
  arm one life-threatening thrombocytopenia
  occurred
• But ultimate progression rates have been shown to
  not significantly different

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Treatment

• Modalities include
• Pharmacologic therapy
• Endocrine therapy
• Biologic therapy
• Chemotherapy
• Bisphosphonates
• Analgesics
• Surgery
• Radiotherapy
• External beam
• Radionuclide therapy

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Radionuclide Therapy

• Can be considered in the following situations
• Patients with widely metastatic disease as an
  adjuvant to RT
• First-line therapy in patients without a
  predominantly painful site
• When external beam RT has been used and normal
  tissue tolerance reached
• Life expectancy of less than 3 months
• No evidence of cord compression, fracture, or
  mechanical instability
• Good marrow reserve (WBC gt2400 Plt gt100,000)

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Strontium 89

• Decays by beta emission to yttrium 89 with a T1/2
  of 50.6 days
• Maximum energy of 1.46 MeV
• Quickly taken up by bone matrix
• Fraction taken up is proportional to tumor burden
  (20-80)
• Localizes to areas of osteoblastic activity
• Remains deposited for as long as 100 days
• Normal bones take up only a small amount
• Eliminated through the kidneys

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Strontium 89

• Porter AT et al IJROBP 1993 Apr 225(5)805-13
• 126 patients with metastatic hormone refractory
  prostate cancer
• Received local field radiotherapy and either
  strontium-89 as a single injection of 10.8 mCi or
  placebo
• No significant differences in survival or in
  relief of pain at the index site
• Decreased intake of analgesics in strontium 89
  arm
• Progression of pain as measured by sites of new
  pain or the requirement for radiotherapy showed
  statistically significant differences between the
  arms in favor of strontium-89
• PSA, acid phosphatase, and alkaline phosphatase
  were also reduced in patients receiving
  strontium-89
• QOL analysis demonstrated an overall superiority
  of strontium-89 with alleviation of pain and
  improvement in physical activity being
  statistically significant
• Toxicity was evaluated and demonstrated increased
  hematological toxicity in the group receiving
  strontium-89

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Strontium 89

• Quilty PM et al Radiother Oncol. 1994
  Apr31(1)33-40
• 284 patients with prostate cancer and painful
  bone metastases were treated with either
  radiotherapy or strontium-89
• After 4, 8 and 12 weeks pain sites were mapped,
  toxicity monitored, and all additional palliative
  treatments recorded
• There was no significant difference in median
  survival 33 weeks following strontium-89 and 28
  weeks following radiotherapy (p 0.1)
• All treatments provided effective pain relief
  improvement was sustained to 3 months in 61
  after local radiotherapy compared with 65.9 in
  the comparable strontium-89 group
• Fewer patients reported new pain sites after
  strontium-89 than after local or hemibody
  radiotherapy (p lt 0.05)
• Radiotherapy to a new site was required by 12
  patients in the local radiotherapy group compared
  with 2 after strontium-89 (p lt 0.01)
• Platelets and leukocytes fell by an average
  30-40 after strontium-89 but sequelae were
  uncommon, and other symptoms rare

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Samarium 153

• Man made radionuclide that emits beta particles
  and gamma photons
• T1/2 of 46.3 hours
• Maximum energy of 0.81 MeV
• Once chelated to a phosphatate it becomes a bone
  seeking complex
• About 50 of administered stays within the bone

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Samarium 153

• 118 patients w/ painful bone metastases
• All tumor types (68 prostate)
• 1.0mCi/kg 153Sm, 0.5mCi/kg 153Sm, or placebo
• If no relief in 4-weeks placebo patients
  eligible for crossover
• 72 higher dose patients had pain relief
• Significant benefit compared to placebo
• No survival difference
• Mild decrease in WBC and platelets

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Spinal Cord Compression

• Occurs in 5 of all patients with malignant
  disease and 20 of patients with vertebral
  metastases
• More than 95 due to extra-medullary malignancy
• Most commonly secondary to involvement of
  vertebral column anterior to the cord

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Signs and Symptoms

• Common symptoms pain, motor loss, autonomic
  dysfunction, and sensory loss
• Pain is initial symptom in 96
• Often radicular present for weeks-months before
  neurologic symptoms
• Weakness usually precedes sensory loss
• Incontinence, paraplegia, and paralysis are late
  effects

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Cord Compression Diagnosis

• Carefull HP (for specific symptoms as well as
  timeline of symptoms)
• MRI is study of choice
• CT myelogram (if patients cannot have MRI)
• Dianosis/treatment often delayed
• About 10 of patients will have multiple sites
  involved
• Imaging of entire spine recommended

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MRI of the same patient
L-4 comp Fx (Breast CA)
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Treatment

• Initially 10-20 mg of Decadron IV followed with 4
  mg q 6 hours
• Start on PPI and monitor blood sugar
• Careful taper of steroids necessary toward the
  end of palliative RT

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Decompression /- RT

• 101 patients with metastatic disease
• Lymphoma primary spine tumor excluded
• Treatment
• Direct circumferential surgical decompression
  followed by RT (30Gy/Gy w/in 14 days)
• RT alone (30Gy/Gy)
• Surgery RT improved
• Ambulatory rate (84 vs 57)
• Retained the ability to walk (median 122 vs 13
  days)
• Decreased doses of steroids and analgesics

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Dosing and Outcome

• 3 Gy x 10 and 4 Gy x 5 are typical
• Longer life expectancy can be treated with 2.5 Gy
  x 15
• Outcome dependent on pretreatment function
• 80 ambulatory will remain ambulatory
• 16 non-ambulatory will become ambulatory
• Worse response with greater degree of compression
  fracture at the level of compression

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Radiation Doses Rades JCO 2005
Retrospective analysis 1304pts treated from
1992-8003
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Brain Metastases

• Incidence of brain mets is 20-40 of all patients
  diagnosed with cancer
• Lung, breast, colon, and melanoma most common
• Multiple sites much more common than single
• 80 in cerebral hemispheres
• 15 in cerebellum
• 5 in brainstem
• Contrast enhanced MRI is study of choice

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Treatment

• WBRT is treatment of choice for most patients
• Goal is to limit tumor progression
• Clinical dosing varies from 20 Gy in 5 fractions
  to 40 Gy in 20 fractions
• Side Effects
• Short-term alopecia, scalp irritation, transient
  worsening of symptoms, otitis
• Long-term memory loss, decreased concentration

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Single Metastases

• Three RCTs have been done comparing WBRT to
  surgeryWBRT
• Relatively small studies
• Two showed median survival advantage (one
  significant-Patchell)

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Stereotactic Radiosurgery (SRS)

• Competing modality to surgery
• Without the disadvantage of a craniotomy
• Size limited to lesions lt3-4 cm
• RTOG 9805 randomized patients to WBRT (167) vs.
  WBRTSRS (167) All with 1-3 lesions
• Survival advantage in the WBRTSRS group for
  patients with a single metastasis (median
  survival 6.5 vs 4.9 months, p0.0393)
• SRS group more stable or improved Karnofsky
  Performance Status (KPS) score at 6 months' F/U
  (43 vs 27, respectively p0.03)
• By multivariate analysis, survival improved in
  patients with an RPA class 1 (plt0.0001)
• OS improved in patients with an RPA class 1
  (plt0.0001)