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Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults
 

Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults

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Daniel Indelicato, MD, University of Florida, Jacksonville, FL

Daniel Indelicato, MD, University of Florida, Jacksonville, FL

Presented at the 2010 Texas Adolescent and Young Adult Oncology Conference, Methodist Healthcare-San Antonio

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  • In 1970’s, 30-40% extremity sarcoma’s were treated with amputation Now, its <15%
  • AP view of a knee in a teenager treated with 54.8 Gy for a synovial sarcoma Transverse pathologic fracture of the paroximal tibial metaphysis 4 years later, healed fracture but extensive radiation osteitis of the distal femur and proximal tibia 9 years later, osteosarcoma developed in the proximal tibia
  • AP view of the knee of a Ewing sarcoma patient shows growth impairment with metasphseal widening and sclerosis 14 months laters, the distal femoral metaphysis is markedly sclerotic and irregegular. The epiphyseal cartilage plate appears hypertrophied.
  • Teenager treated for Ewing sarcoma of the right humerus, photo 11 years post RT. Note difference in the muscule development when he started lifting weights.
  • Maynard

Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults Presentation Transcript

  • Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults 2008 ACC Defensive Player of the Year, and his 2009 season was expected to make him an NFL first-round draft pick
  • No conflicts of interest to disclose
  • Scope of Problem in AYAs Sarcomas 15% Leukemia 14% Germ Cell Tumors 13% Brain Tumors 10% Thyroid Carcinoma 8% Melanoma 8% Other 9% Lymphoma 23% Bone sarcoma 8% Soft tissue sarcoma 7%
  • How Radiation is Perceived Seminars in Oncology, 2009 Number of times “radiation” is mentioned relative to side effects: 11 Number of times “radiation” is mentioned as a treatment modality: 7
  • Most common sarcomas in AYA patients
    • Rhabdomyosarcoma
    • Ewing sarcoma
    • Liposarcoma
    • Synovial sarcoma
    • Undifferentiated pleomorphic sarcoma
    • Osteosarcoma
    • Leiomyosarcoma
    • Malignant peripheral nerve sheath tumor
    • Dermatofibrosarcoma protuberans
    • Chondrosarcoma
    • Neurofibrosarcoma
  • “ Pat Jones Has Prostate Cancer”
    • Pat Jones
      • is a male
      • is 50+ years old
      • has an adenocarcinoma
    • Radiotherapy will
      • provide a relatively high rate of cure
      • cause predictable GI, GU, and erectile side effects
    “ Pat Jones has breast cancer”. . . etc
    • “ Sarcomas” are defined by histopathology , rather than topography
    • Side effects of radiotherapy are spatial and depend on tumor location relative to normal tissue
    Sarcoma type = radiosensitivity, disease control outcomes Sarcoma location = treatment side effects “ Pat Jones Has Sarcoma” Spinal cord Lung Heart Femoral head Bladder Uterus Bowel
  • Value of RT for Adolescent and Young Adult Bone Sarcomas Remember: Sarcoma type determines radiosensitivity, disease control outcomes
  • “ From the most unexpected source, experimental physics, a new and powerful weapon has been brought into play.” - James Ewing, 1922
    • 50% of Ewing sarcomas occur in the AYA age range (15-29)
    • Estimated 260 AYA Ewing sarcoma cases per year in US
    Ewing sarcoma: A “radiosensitive” tumor
    • CESS 86 EICESS 92
    • (No report of age)
    • Local control with RT +/- surgery: 77-93%
    • 81% between 10-30 y/o
    • Local control with RT +/- surgery: 75-90%
  • Ewing sarcoma at the University of Florida: 1965-2007
    • Over 150 patients treated with RT +/- surgery
    Femur: 78% Leg/Foot: 80% Spine: 89% Chest wall: 60% Pelvis: 86% Local control Upper extremity: 78% Head/Neck: 87%
    • 10 patients, median age: 16 y/o (range 11-25)
    • 7/10 long term survivors with local control
    • 2/3 failures salvaged
    • 41 patients, median age: 29 y/o (range 8-70)
    • 71% local control in patients who received >55 Gy
    Osteosarcoma: A “radioresistant” tumor
  • Value of RT for Adolescent and Young Adult Soft Tissue Sarcomas
  • “ The management of this condition should be radical surgery and that no help should be expected from radiotherapy either as a pre- or postoperative procedure” - Dr. Ralston Paterson (1963) Holt Radium Institute at the Christie Cancer Hospital, founded by Ralston Patterson Soft Tissue Sarcoma: Then
  • Annals of Surgery, 1982 27 pts WLE+RT 16 pts Amputation 43 pts High grade STS Extremity
  • Level I Data: General Population
  • Retrospective Data: Children and Young Adults
    • 62 patients treated at the University of Iowa
    • Median age 14 (range:1-21)
    Radiation plays a critical role in limb salvage for all ages
  • UF Experience: Adolescent and Young Adult STS
    • 122 patients diagnosed with non-rhabdomyosarcoma STS treated with RT since 1972
    • Median age 22 years old (range 2-30)
      • 75% between 15-30 years old
      • Most common histology: Synovial sarcoma
    • 100 treated with surgery and radiotherapy
    • 80% local control
    • 55% overall survival
    • No difference in survival or local control by age
    • Rate of CTCAE Grade 3+ complication: 7%
  • Synovial Sarcoma: The Classic AYA STS
    • Hazard ratio of local recurrence 0.43 with adjuvant RT (p=0.026)
    (n=237) (n=250)
    • Hazard ratio of local recurrence 0.4 with adjuvant RT (p=0.025) if inadequate margins
  • Myxoid liposarcoma
    • Myxoid liposarcoma represents 10% of all STS but is much more commonly in young adults
    • Historical local recurrence free survival as low as 67% following surgery alone
    • Chung (2009) described 88 patients with myxoid liposarcoma treated with surgery and adjuvant radiation. The 5-year local recurrence–free survival was 97.7%
  • “ The value of adjuvant radiotherapy is in ‘extending the margin’ of limb salvage surgery that otherwise has a high risk of recurrence.” - Dr. William Enneking Soft Tissue Sarcoma: Now
    • Enrolling up to age 30
    • Radiotherapy indicated in all but lowest risk patients
  • Bone Tumors Soft Tissue Sarcoma
  • Challenges of Using Radiation for AYA Sarcoma Remember: Sarcoma location dictates treatment side effects and complications
    • 41 long term survivors from Mayo Clinic
    • 24 had a serious complication related to treatment
    • Over half of complications attributed to RT
    • 80% treated with radiation
    • Risk of second malignant neoplasms 9%, mostly breast and thyroid
    • Compared to siblings, 6X risk of severe, life threatening, or disabling chronic health conditions
    • Comprehensive report of long term Ewing survivors (1970-1986)
    Today, only 35% of Ewing patients treated with radiation
  • Local Management of Lower Extremity Ewing Tumors at the University of Florida: 1970-2006 (Indelicato 2007)
  • 1987 1969 65 Gy 60 Gy + 20 years
    • 35 patients treated from 1970-2005
    • Approximately 25% of patients had a severe complication
    - Two cases of RT-induced osteosarcoma requiring hemipelvectomy - Osteomyelitis requiring hip replacement - Hemorrhagic cystitis requiring cystectomy - Severe reflex sympathetic dystrophy and radiculopathy - Bowel perforation - Two hip fractures (Indelicato 2008) UF Experience: Pelvic Ewing Sarcoma
  • UF Experience: Chest Wall Ewing Sarcoma
    • 39 cases treated between 1966-2007
    • Approximately 20% of patients had a severe complication
    • Two fatal cases of pulmonary fibrosis/pneumonitis
    • Fatal congestive heart failure
    • Radiation pneumonitis requiring ventilator support, long term steroids
    • Esophagitis requiring hospital admission
    • Upper extremity lymphadema requiring compression pump 4 hrs/day
    • Diffuse interstitial chronic pneumonia
    (Indelicato 2010)
  • Pulmonary Complications of Radiation Treatment
    • Radiation fibrosis: more common in patients diagnosed at >15 y/o compared to patients age < 5 y/o
      • contrary to what one would expect on basis of lung and chest wall development
    • Radiation pneumonitis: seems to be constant by age
  • Musculoskeletal Complications of Radiation Treatment
  • Bone Complications of Radiation Treatment Traditional risk factors for fracture: ● radiation dose (mean dose >37 Gy) ● periosteal stripping ● female gender Pathogenesis: microvascular supply; osteoclast alteration? Rate of fracture in patients with Ewing sarcoma of weight bearing bone: 30% Slipped femoral capital epiphysis radiation injury to the proximal femoral growth apparatus + weight-bearing stress After only 12 Gy
  • Growth Complications of Radiation Treatment
    • Osteoblasts can withstand high doses of RT
    • Pathogenesis:
    • 1. RT decreases the mRNA expression of PTHrP and increases cytosolic calcium
      • Important stimulus for mitosis of chondrocytes
    • 2. RT increases vascularity of bone, particularly the metaphysis.
      • Increases bone resorption and demineralization of the immature metaphysis
    Facial asymmetry, clavicle shortening, reduced sitting height, limb length discrepancy
  • Growth Complications of Radiation Treatment
    • Risk factors for bone growth impairment:
      • age at the time of treatment
      • flat vs. long bone
      • quality of radiation (dose per fraction and total dose)
      • volume irradiated (epiphyseal plate, proximal vs distal)
      • growth potential of treated site
      • individual genetic factors
      • coexisting chemotherapy
      • As a result, estimates range anywhere from 1.3 Gy -20 Gy
      • Better models are needed
  • Interplay between bone growth and muscle atrophy
    • fibrosis of subcutaneous tissue and muscles
    • decreased range of motion
    Linear increase in T2 signal with radiation dose only in patients >12 years old Muscle Complications of Radiation Treatment
  •  
      • Surgery is now the mainstay for most patients
      • Acceptable margins difficult to achieve in the axial skeleton including skull, spine, sacrum, and pelvis
        • These are sites where radiation may be the primary means of local control
      • Radiation also may be indicated following surgery for:
        • positive margins
        • presentation with a pathologic fracture
        • close margin and poor histologic response to chemotherapy
        • Intralesional excision of or intramedullary rod placement through a radiographically benign-appearing lesion later found to be sarcoma
      • No data supports a differential tumor radiosensitivity by age
    Guidelines: AYA Bone Sarcomas
    • Conservative surgery alone with wide margins is appropriate for:
      • • Superficial low grade lesions <5 cm
      • • Selected larger low grade lesions
      • • Selected superficial intermediate and high grade lesions <5 cm
    • Most intermediate and high grade lesions > 5 cm should be considered for radiotherapy
    • Unresectable tumor: Definitive radiotherapy
    • No data supports a differential tumor radiosensitivity by age
    Guidelines: AYA Soft Tissue Sarcomas
    • Radiation avoidance or delay
      • Strong data supports a differential normal tissue radiosensitivity by age
    • Better modeling and prediction needed
      • Improve estimate of therapeutic ratio when considering role of RT
    Guidelines: Minimizing Toxicity in AYA Sarcoma
  • Guidelines: Minimizing Toxicity in AYA Sarcoma
    • 3. Improve radiation techniques
      • Sequencing: Preoperative RT decreases functional morbidity in extremity sarcoma patients (Level 1, O’Sullivan 2005)
      • Fractionation: Hyperfractioned radiation decreases the risk of bone and muscle side effects (Retrospective, Indelicato 2008 and Bolek 1996)
      • Better target definition/smaller fields:
      • Old fields were unnecessarily big (Prospective, Krasin 2009)
  • Guidelines: Minimizing Toxicity in AYA Sarcoma
    • 3. Improve radiation techniques (cont.)
      • New modalities
    Female with Ewing sarcoma of the posterior chest wall Protons Photons
  • Guidelines: Minimizing Toxicity in AYA Sarcoma Male with synovial sarcoma of the proximal medial thigh Protons Photons
  • Guidelines: Minimizing Toxicity in AYA Sarcoma
    • 4. New systemic agents to protect from RT effects
      • e.g. pentoxifylline, bisphosphonates
    • Multimodality improvements needed
    • Only 1 patient had isolated local recurrence (all the rest had component of distant disease)
    92 patients with non-metastatic synovial sarcoma treated at UF Age (y) n % receiving chemo % with relapse 1-14 6 50% 20% 15-39 48 30% 44% 40+ 38 9% 72%
  • &quot;He hasn't lost anything“ - ESPN commentator Curt Warner 9/6/2010
  • Thank you Questions?