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IS THERE STILL A ROLE FOR RADIOTHERAPY IN
       METASTATIC BREAST CANCER?

                       ALAN RODGER
    SPECIALTY EDITOR (RADIATION ONCOLOGY), THE BREAST.
               RETIRED CLINICAL ONCOLOGIST.

               ABC1, Lisbon, November 2011.
ALTERNATIVE QUESTIONS?

• HAVE BISPHOSPHONATES, CYTOTOXICS, TARGETED
  THERAPIES AND AROMATASE INHIBITORS CURED
  METASTATIC BREAST CANCER (MBC)?




• CAN THEY PALLIATE EVERY SYMPTOM AND PREVENT
  EVERY COMPLICATION OF MBC?
SO IS THERE STILL A ROLE FOR
  RADIOTHERAPY IN MBC?
         UNDOUBTEDLY!
   AND, WHAT’S MORE, THERE’S
    EVIDENCE TO SUPPORT IT
• KEY MESSAGES.
RADIOTHERAPY HAS AN IMPORTANT ROLE IN MBC IN THE
PALLIATION AND TREATMENT OF:



•   BONE PAIN
•   SPINAL CORD COMPRESSION
•   PATHOLOGICAL FRACTURES
•   INTRACRANIAL METASTASES
•   CRANIAL METASTASES – BASE OF SKULL AND ORBITAL
•   SOFT TISSUE DISEASE
•   SOLID VISCERAL METASTASES
PALLIATION OF BONE PAIN WITH RADIOTHERAPY

• COMPLETE PAIN RELIEF IN 25% @ 1 MONTH
  (395/1580)

• > 50% PAIN RELIEF IN 41% AT SOME TIME (788/1933)

• WHEN COMPLETE PAIN RELIEF, 52% ACHIEVE THIS IN
  4 WEEKS WITH MEDIAN DURATION 12 WEEKS

• LEVEL OF EVIDENCE I - Cochrane Review, McQuay et
  al, 1999.
RADIATION MODALITY


• LOCALISED BONE PAIN – EXTERNAL BEAM
 RADIOTHERAPY (EBRT)



• GENERALISED BONE PAIN ► RADIO-ISOTOPES
                         ► HEMIBODY RT
RADIATION FRACTIONATION for EBRT



• SINGLE FRACTION IS EQUIVALENT TO
  MULTIPLE FRACTIONS

• LEVEL OF EVIDENCE I – Cochrane
  Review, ASTRO 2011 Guidelines, other
  guidelines, numerous RCTs.
SINGLE FRACTION EBRT for PAIN
               RELIEF
• PAIN CONTROL EQUIVALENT
• TOXICITY SIMILAR (though poor assessment)
• RETREATMENT RATES HIGHER – 20% v. 8% (Kachnic
  et al, 2011)
• MORE COST-EFFECTIVE – it costs less (ASTRO, 2011)
• BISPHOSPHONATES DO NOT ELIMINATE THE NEED
  FOR RADIOTHERAPY
• LEVEL OF EVIDENCE I
NON-COMPRESSIVE SPINAL
             METASTASES
• INTERVENTIONAL RADIOLOGY –
  vertebroplasty, kyphoplasty (see Gerszten et al in
  Neurosurg. Focus, 2005) with Stereotactic Body
  Radiosurgery (SBRS)
• EXTERNAL BEAM RT
• STEREOTACTIC RADIOSURGERY (SBRS) – single
  fraction
• STEREOTACTIC RADIOTHERAPY (SBRT) - multiple
  fractions (often a few)
• LEVEL OF EVIDENCE III/IV
SPINAL SBRS/SBRT

• NO RCTs
• SMALL SERIES
• RETREATMENTS/SOLE TREATMENT/POST-
  INTERVENTIONAL PROCEDURE – mixes in studies
• EQUIPMENT CAN BE EXPENSIVE – so cost per
  treatment high
• COMPLEX, TIME CONSUMING RADIOTHERAPY
  PLANNING
• NEED FOR MORE HIGH QUALITY STUDIES AND RCTs
• LEVEL OF EVIDENCE – need for more research (III/IV)
COMPRESSIVE SPINAL METASTASES

•   SURGERY – decompression and stabilisation
•   RADIOTHERAPY – sole treatment
•   RADIOTHERAPY - postoperative
•   RADIOTHERAPY - EBRT
•   RADIOTHERAPY – SBRT/SBRS
•   LEVEL OF EVIDENCE III/IV
COMPRESSIVE SPINAL CORD METASTASES

• EBRT and PROGNOSIS on MULTIVARIATE
  ANALYSIS - Rades et al JCO 2006 (n = 1852) LoE
  III
• BETTER LOCAL CONTROL – histology
  (breast, prostate, lymphoma); no visceral mets;
  no/few other bone mets; good ambulatory
  status; longer interval from first diagnosis; slow
  loss of motor function
• RADIOTHERAPY COURSE – longer course (10, 15
  or 20 fractions) better than shorter (1 or 5
  fractions) – only a trend on univariate analysis
COMPRESSIVE SPINAL METASTASES

• EMERGENCY
• MRI – of not just area of neurological interest
  but also adjacent areas superior and inferior
• MUTLIDISCIPLINARY OPINIONS – surgery and
  radiation oncology
• CONSIDER FAST-TRACKING SYSTEM
• MORE RESEARCH REQUIRED – radiation
  dose/fractionation; indications for SBRS/SBRT
IMPENDING LONG BONE FRACTURES
• PROPHYLACTIC SURGERY and POST-
  OPERATIVE EBRT – when compared with
  fracture followed by surgery and EBRT: more
  likely to maintain or improve pre-diagnosis
  level of mobility and self-care
                 Hardman et al Clin. Oncol.1992
 LEVEL OF EVIDENCE IV
PATHOLOGICAL LONG BONE FRACTURES

• POST-OPERATIVE EBRT – more likely to regain
  normal use of the extremity
• POST-OP EBRT – fewer re-operations
• MEDIAN SURVIVAL – 12-14 months after EBRT
  v.3.3 months when no RT - ns ?? selection bias
• LEVEL OF EVIDENCE III – Townsend et al
  JCO, 1994
CRANIAL METASTASES
            BASE of SKULL
• BONE METASTASES
• COMPRESSIVE NEUROLOGICAL SYMPTOMS
  and SIGNS
• RESPOND TO CONVENTIONAL PALLIATIVE
  EBRT – five fractions/20 Gray
• RESPONSE MAY BE SEEN AFTER PROLONGED
  SIGNS/SYMPTOMS (unlike cord compression)
• LEVEL OF EVIDENCE IV
CRANIAL METASTASES
              ORBITAL
• SOFT TISSUE MASS MAY BE PRESENT
• COMPRESSIVE SYMPTOMS
• CHOROIDAL METASTASES – special case and
  rare
• CONVENTIONAL PALLIATIVE EBRT
  (dose/fractionation/technique) – can be
  beneficial
• SBRS/SBRT may be considered
• LEVEL OF EVIDENCE III/IV
INTRACRANIAL (BRAIN) METASTASES
• PROGNOSIS – depends on age, PS and extent
  of disease (LoE II – RTOG trials)
• PROGNOSIS in MBC – influenced also by ER
  status, availability of therapy for extra-cranial
  disease ( LoE III/IV)

• SINGLE/FEW BRAIN METS – generally respond
  better. (LoE III/IV)
INTRACRANIAL (BRAIN) METASTASES
        Treatment Options
• MULTIPLE METASTASES – EBRT 20 Gray/5
  fractions as no other fractionation is superior
  in terms of overall survival, symptom
  control, neurological function, toxicity

• LEVEL OF EVIDENCE I – Cochrane Review 2007
SOLITARY OR FEW (1-3?) BRAIN
             METASTASES
          Treatment options
• SURGERY – with post-op whole brain EBRT
• SURGERY – alone
• EBRT – alone to whole brain
• EBRT (whole brain) – with SBRS/SBRT “boost”
• COMBINATION SBRS/SBRT and EBRT seems
  ‘equivalent’ to surgery and EBRT
• LEVEL OF EVIDENCE III/IV
BRAIN METASTASES
         QUESTIONS FOR FURTHER RESEARCH


• SURGERY v. SBRS/SBRT

• PLACE of whole brain EBRT – in combination
  or alone

• DOSE/FRACTIONATION of SBRT
SOFT TISSUE and SOLID VISCERAL
            METASTASES
• LOCAL SYMPTOM CONTROL – from skin
  lesions, nodal masses, uncontrolled local
  recurrence
• RADIOTHERAPY
  DOSE/FRACTIONATION/TECHNIQUE – will
  depend on site, lesion, previous
  EBRT, PS, symptoms
• LEVEL OF EVIDENCE IV
AREA for URGENT RESEARCH
   SBRS and SBRT IN OLIGO-METASTATIC DISEASE
• NATURAL HISTORY of OLIGO-METASTATIC DISEASE in
  MBC - what is it?
• The EFFICACY (RESPONSE and IMPACT ON SURVIVAL)
  of IMRT and SBRS and SBRT against solid visceral
  metastases
• OPTIMAL TECHNIQUES, DOSES and FRACTIONATION
  – if any
• COST-EFFECTIVENESS
• TOXICITY
RADIOTHERAPY IN MBC
              LET US NOT FORGET

• IT IS PALLIATIVE – reduce symptoms that are
  there; cause no distress; do not treat the
  asymptomatic (Ralston Patterson)
• TO BE EFFECTIVE IT MUST BE PART OF GOOD
  MULTI-DISCIPLINARY CARE
• TODAY IT MUST BE COST-EFFECTIVE
• IT MUST CONSIDER THE PATIENT FOREMOST –
  as sadly MBC is still incurable

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ABC1 - A. Rodger - Is there still a role for radiotherapy in advanced breast cancer?

  • 1. IS THERE STILL A ROLE FOR RADIOTHERAPY IN METASTATIC BREAST CANCER? ALAN RODGER SPECIALTY EDITOR (RADIATION ONCOLOGY), THE BREAST. RETIRED CLINICAL ONCOLOGIST. ABC1, Lisbon, November 2011.
  • 2. ALTERNATIVE QUESTIONS? • HAVE BISPHOSPHONATES, CYTOTOXICS, TARGETED THERAPIES AND AROMATASE INHIBITORS CURED METASTATIC BREAST CANCER (MBC)? • CAN THEY PALLIATE EVERY SYMPTOM AND PREVENT EVERY COMPLICATION OF MBC?
  • 3. SO IS THERE STILL A ROLE FOR RADIOTHERAPY IN MBC? UNDOUBTEDLY! AND, WHAT’S MORE, THERE’S EVIDENCE TO SUPPORT IT
  • 4. • KEY MESSAGES. RADIOTHERAPY HAS AN IMPORTANT ROLE IN MBC IN THE PALLIATION AND TREATMENT OF: • BONE PAIN • SPINAL CORD COMPRESSION • PATHOLOGICAL FRACTURES • INTRACRANIAL METASTASES • CRANIAL METASTASES – BASE OF SKULL AND ORBITAL • SOFT TISSUE DISEASE • SOLID VISCERAL METASTASES
  • 5. PALLIATION OF BONE PAIN WITH RADIOTHERAPY • COMPLETE PAIN RELIEF IN 25% @ 1 MONTH (395/1580) • > 50% PAIN RELIEF IN 41% AT SOME TIME (788/1933) • WHEN COMPLETE PAIN RELIEF, 52% ACHIEVE THIS IN 4 WEEKS WITH MEDIAN DURATION 12 WEEKS • LEVEL OF EVIDENCE I - Cochrane Review, McQuay et al, 1999.
  • 6. RADIATION MODALITY • LOCALISED BONE PAIN – EXTERNAL BEAM RADIOTHERAPY (EBRT) • GENERALISED BONE PAIN ► RADIO-ISOTOPES ► HEMIBODY RT
  • 7. RADIATION FRACTIONATION for EBRT • SINGLE FRACTION IS EQUIVALENT TO MULTIPLE FRACTIONS • LEVEL OF EVIDENCE I – Cochrane Review, ASTRO 2011 Guidelines, other guidelines, numerous RCTs.
  • 8. SINGLE FRACTION EBRT for PAIN RELIEF • PAIN CONTROL EQUIVALENT • TOXICITY SIMILAR (though poor assessment) • RETREATMENT RATES HIGHER – 20% v. 8% (Kachnic et al, 2011) • MORE COST-EFFECTIVE – it costs less (ASTRO, 2011) • BISPHOSPHONATES DO NOT ELIMINATE THE NEED FOR RADIOTHERAPY • LEVEL OF EVIDENCE I
  • 9. NON-COMPRESSIVE SPINAL METASTASES • INTERVENTIONAL RADIOLOGY – vertebroplasty, kyphoplasty (see Gerszten et al in Neurosurg. Focus, 2005) with Stereotactic Body Radiosurgery (SBRS) • EXTERNAL BEAM RT • STEREOTACTIC RADIOSURGERY (SBRS) – single fraction • STEREOTACTIC RADIOTHERAPY (SBRT) - multiple fractions (often a few) • LEVEL OF EVIDENCE III/IV
  • 10. SPINAL SBRS/SBRT • NO RCTs • SMALL SERIES • RETREATMENTS/SOLE TREATMENT/POST- INTERVENTIONAL PROCEDURE – mixes in studies • EQUIPMENT CAN BE EXPENSIVE – so cost per treatment high • COMPLEX, TIME CONSUMING RADIOTHERAPY PLANNING • NEED FOR MORE HIGH QUALITY STUDIES AND RCTs • LEVEL OF EVIDENCE – need for more research (III/IV)
  • 11. COMPRESSIVE SPINAL METASTASES • SURGERY – decompression and stabilisation • RADIOTHERAPY – sole treatment • RADIOTHERAPY - postoperative • RADIOTHERAPY - EBRT • RADIOTHERAPY – SBRT/SBRS • LEVEL OF EVIDENCE III/IV
  • 12. COMPRESSIVE SPINAL CORD METASTASES • EBRT and PROGNOSIS on MULTIVARIATE ANALYSIS - Rades et al JCO 2006 (n = 1852) LoE III • BETTER LOCAL CONTROL – histology (breast, prostate, lymphoma); no visceral mets; no/few other bone mets; good ambulatory status; longer interval from first diagnosis; slow loss of motor function • RADIOTHERAPY COURSE – longer course (10, 15 or 20 fractions) better than shorter (1 or 5 fractions) – only a trend on univariate analysis
  • 13. COMPRESSIVE SPINAL METASTASES • EMERGENCY • MRI – of not just area of neurological interest but also adjacent areas superior and inferior • MUTLIDISCIPLINARY OPINIONS – surgery and radiation oncology • CONSIDER FAST-TRACKING SYSTEM • MORE RESEARCH REQUIRED – radiation dose/fractionation; indications for SBRS/SBRT
  • 14. IMPENDING LONG BONE FRACTURES • PROPHYLACTIC SURGERY and POST- OPERATIVE EBRT – when compared with fracture followed by surgery and EBRT: more likely to maintain or improve pre-diagnosis level of mobility and self-care Hardman et al Clin. Oncol.1992 LEVEL OF EVIDENCE IV
  • 15. PATHOLOGICAL LONG BONE FRACTURES • POST-OPERATIVE EBRT – more likely to regain normal use of the extremity • POST-OP EBRT – fewer re-operations • MEDIAN SURVIVAL – 12-14 months after EBRT v.3.3 months when no RT - ns ?? selection bias • LEVEL OF EVIDENCE III – Townsend et al JCO, 1994
  • 16. CRANIAL METASTASES BASE of SKULL • BONE METASTASES • COMPRESSIVE NEUROLOGICAL SYMPTOMS and SIGNS • RESPOND TO CONVENTIONAL PALLIATIVE EBRT – five fractions/20 Gray • RESPONSE MAY BE SEEN AFTER PROLONGED SIGNS/SYMPTOMS (unlike cord compression) • LEVEL OF EVIDENCE IV
  • 17. CRANIAL METASTASES ORBITAL • SOFT TISSUE MASS MAY BE PRESENT • COMPRESSIVE SYMPTOMS • CHOROIDAL METASTASES – special case and rare • CONVENTIONAL PALLIATIVE EBRT (dose/fractionation/technique) – can be beneficial • SBRS/SBRT may be considered • LEVEL OF EVIDENCE III/IV
  • 18. INTRACRANIAL (BRAIN) METASTASES • PROGNOSIS – depends on age, PS and extent of disease (LoE II – RTOG trials) • PROGNOSIS in MBC – influenced also by ER status, availability of therapy for extra-cranial disease ( LoE III/IV) • SINGLE/FEW BRAIN METS – generally respond better. (LoE III/IV)
  • 19. INTRACRANIAL (BRAIN) METASTASES Treatment Options • MULTIPLE METASTASES – EBRT 20 Gray/5 fractions as no other fractionation is superior in terms of overall survival, symptom control, neurological function, toxicity • LEVEL OF EVIDENCE I – Cochrane Review 2007
  • 20. SOLITARY OR FEW (1-3?) BRAIN METASTASES Treatment options • SURGERY – with post-op whole brain EBRT • SURGERY – alone • EBRT – alone to whole brain • EBRT (whole brain) – with SBRS/SBRT “boost” • COMBINATION SBRS/SBRT and EBRT seems ‘equivalent’ to surgery and EBRT • LEVEL OF EVIDENCE III/IV
  • 21. BRAIN METASTASES QUESTIONS FOR FURTHER RESEARCH • SURGERY v. SBRS/SBRT • PLACE of whole brain EBRT – in combination or alone • DOSE/FRACTIONATION of SBRT
  • 22. SOFT TISSUE and SOLID VISCERAL METASTASES • LOCAL SYMPTOM CONTROL – from skin lesions, nodal masses, uncontrolled local recurrence • RADIOTHERAPY DOSE/FRACTIONATION/TECHNIQUE – will depend on site, lesion, previous EBRT, PS, symptoms • LEVEL OF EVIDENCE IV
  • 23. AREA for URGENT RESEARCH SBRS and SBRT IN OLIGO-METASTATIC DISEASE • NATURAL HISTORY of OLIGO-METASTATIC DISEASE in MBC - what is it? • The EFFICACY (RESPONSE and IMPACT ON SURVIVAL) of IMRT and SBRS and SBRT against solid visceral metastases • OPTIMAL TECHNIQUES, DOSES and FRACTIONATION – if any • COST-EFFECTIVENESS • TOXICITY
  • 24. RADIOTHERAPY IN MBC LET US NOT FORGET • IT IS PALLIATIVE – reduce symptoms that are there; cause no distress; do not treat the asymptomatic (Ralston Patterson) • TO BE EFFECTIVE IT MUST BE PART OF GOOD MULTI-DISCIPLINARY CARE • TODAY IT MUST BE COST-EFFECTIVE • IT MUST CONSIDER THE PATIENT FOREMOST – as sadly MBC is still incurable