Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults


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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.
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  • Radiotherapy in the Treatment of Sarcomas in Adolescents and Young Adults

    1. 1. 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
    2. 2. No conflicts of interest to disclose
    3. 3. 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%
    4. 4. 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
    5. 5. Most common sarcomas in AYA patients <ul><li>Rhabdomyosarcoma </li></ul><ul><li>Ewing sarcoma </li></ul><ul><li>Liposarcoma </li></ul><ul><li>Synovial sarcoma </li></ul><ul><li>Undifferentiated pleomorphic sarcoma </li></ul><ul><li>Osteosarcoma </li></ul><ul><li>Leiomyosarcoma </li></ul><ul><li>Malignant peripheral nerve sheath tumor </li></ul><ul><li>Dermatofibrosarcoma protuberans </li></ul><ul><li>Chondrosarcoma </li></ul><ul><li>Neurofibrosarcoma </li></ul>
    6. 6. “ Pat Jones Has Prostate Cancer” <ul><li>Pat Jones </li></ul><ul><ul><li>is a male </li></ul></ul><ul><ul><li>is 50+ years old </li></ul></ul><ul><ul><li>has an adenocarcinoma </li></ul></ul><ul><li>Radiotherapy will </li></ul><ul><ul><li>provide a relatively high rate of cure </li></ul></ul><ul><ul><li>cause predictable GI, GU, and erectile side effects </li></ul></ul>“ Pat Jones has breast cancer”. . . etc
    7. 7. <ul><li>“ Sarcomas” are defined by histopathology , rather than topography </li></ul><ul><li>Side effects of radiotherapy are spatial and depend on tumor location relative to normal tissue </li></ul>Sarcoma type = radiosensitivity, disease control outcomes Sarcoma location = treatment side effects “ Pat Jones Has Sarcoma” Spinal cord Lung Heart Femoral head Bladder Uterus Bowel
    8. 8. Value of RT for Adolescent and Young Adult Bone Sarcomas Remember: Sarcoma type determines radiosensitivity, disease control outcomes
    9. 9. “ From the most unexpected source, experimental physics, a new and powerful weapon has been brought into play.” - James Ewing, 1922 <ul><li>50% of Ewing sarcomas occur in the AYA age range (15-29) </li></ul><ul><li>Estimated 260 AYA Ewing sarcoma cases per year in US </li></ul>Ewing sarcoma: A “radiosensitive” tumor
    10. 10. <ul><li>CESS 86 EICESS 92 </li></ul><ul><li>(No report of age) </li></ul><ul><li>Local control with RT +/- surgery: 77-93% </li></ul><ul><li>81% between 10-30 y/o </li></ul><ul><li>Local control with RT +/- surgery: 75-90% </li></ul>
    11. 11. Ewing sarcoma at the University of Florida: 1965-2007 <ul><li>Over 150 patients treated with RT +/- surgery </li></ul>Femur: 78% Leg/Foot: 80% Spine: 89% Chest wall: 60% Pelvis: 86% Local control Upper extremity: 78% Head/Neck: 87%
    12. 12. <ul><li>10 patients, median age: 16 y/o (range 11-25) </li></ul><ul><li>7/10 long term survivors with local control </li></ul><ul><li>2/3 failures salvaged </li></ul><ul><li>41 patients, median age: 29 y/o (range 8-70) </li></ul><ul><li>71% local control in patients who received >55 Gy </li></ul>Osteosarcoma: A “radioresistant” tumor
    13. 13. Value of RT for Adolescent and Young Adult Soft Tissue Sarcomas
    14. 14. “ 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
    15. 15. Annals of Surgery, 1982 27 pts WLE+RT 16 pts Amputation 43 pts High grade STS Extremity
    16. 16. Level I Data: General Population
    17. 17. Retrospective Data: Children and Young Adults <ul><li>62 patients treated at the University of Iowa </li></ul><ul><li>Median age 14 (range:1-21) </li></ul>Radiation plays a critical role in limb salvage for all ages
    18. 18. UF Experience: Adolescent and Young Adult STS <ul><li>122 patients diagnosed with non-rhabdomyosarcoma STS treated with RT since 1972 </li></ul><ul><li>Median age 22 years old (range 2-30) </li></ul><ul><ul><li>75% between 15-30 years old </li></ul></ul><ul><ul><li>Most common histology: Synovial sarcoma </li></ul></ul><ul><li>100 treated with surgery and radiotherapy </li></ul><ul><li>80% local control </li></ul><ul><li>55% overall survival </li></ul><ul><li>No difference in survival or local control by age </li></ul><ul><li>Rate of CTCAE Grade 3+ complication: 7% </li></ul>
    19. 19. Synovial Sarcoma: The Classic AYA STS <ul><li>Hazard ratio of local recurrence 0.43 with adjuvant RT (p=0.026) </li></ul>(n=237) (n=250) <ul><li>Hazard ratio of local recurrence 0.4 with adjuvant RT (p=0.025) if inadequate margins </li></ul>
    20. 20. Myxoid liposarcoma <ul><li>Myxoid liposarcoma represents 10% of all STS but is much more commonly in young adults </li></ul><ul><li>Historical local recurrence free survival as low as 67% following surgery alone </li></ul><ul><li>Chung (2009) described 88 patients with myxoid liposarcoma treated with surgery and adjuvant radiation. The 5-year local recurrence–free survival was 97.7% </li></ul>
    21. 21. “ 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 <ul><li>Enrolling up to age 30 </li></ul><ul><li>Radiotherapy indicated in all but lowest risk patients </li></ul>
    22. 22. Bone Tumors Soft Tissue Sarcoma
    23. 23. Challenges of Using Radiation for AYA Sarcoma Remember: Sarcoma location dictates treatment side effects and complications
    24. 24. <ul><li>41 long term survivors from Mayo Clinic </li></ul><ul><li>24 had a serious complication related to treatment </li></ul><ul><li>Over half of complications attributed to RT </li></ul>
    25. 25. <ul><li>80% treated with radiation </li></ul><ul><li>Risk of second malignant neoplasms 9%, mostly breast and thyroid </li></ul><ul><li>Compared to siblings, 6X risk of severe, life threatening, or disabling chronic health conditions </li></ul><ul><li>Comprehensive report of long term Ewing survivors (1970-1986) </li></ul>Today, only 35% of Ewing patients treated with radiation
    26. 26. Local Management of Lower Extremity Ewing Tumors at the University of Florida: 1970-2006 (Indelicato 2007)
    27. 27. 1987 1969 65 Gy 60 Gy + 20 years
    28. 28. <ul><li>35 patients treated from 1970-2005 </li></ul><ul><li>Approximately 25% of patients had a severe complication </li></ul>- 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
    29. 29. UF Experience: Chest Wall Ewing Sarcoma <ul><li>39 cases treated between 1966-2007 </li></ul><ul><li>Approximately 20% of patients had a severe complication </li></ul><ul><li>Two fatal cases of pulmonary fibrosis/pneumonitis </li></ul><ul><li>Fatal congestive heart failure </li></ul><ul><li>Radiation pneumonitis requiring ventilator support, long term steroids </li></ul><ul><li>Esophagitis requiring hospital admission </li></ul><ul><li>Upper extremity lymphadema requiring compression pump 4 hrs/day </li></ul><ul><li>Diffuse interstitial chronic pneumonia </li></ul>(Indelicato 2010)
    30. 30. Pulmonary Complications of Radiation Treatment <ul><li>Radiation fibrosis: more common in patients diagnosed at >15 y/o compared to patients age < 5 y/o </li></ul><ul><ul><li>contrary to what one would expect on basis of lung and chest wall development </li></ul></ul><ul><li>Radiation pneumonitis: seems to be constant by age </li></ul>
    31. 31. Musculoskeletal Complications of Radiation Treatment
    32. 32. 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
    33. 33. Growth Complications of Radiation Treatment <ul><li>Osteoblasts can withstand high doses of RT </li></ul><ul><li>Pathogenesis: </li></ul><ul><li>1. RT decreases the mRNA expression of PTHrP and increases cytosolic calcium </li></ul><ul><ul><li>Important stimulus for mitosis of chondrocytes </li></ul></ul><ul><li>2. RT increases vascularity of bone, particularly the metaphysis. </li></ul><ul><ul><li>Increases bone resorption and demineralization of the immature metaphysis </li></ul></ul>Facial asymmetry, clavicle shortening, reduced sitting height, limb length discrepancy
    34. 34. Growth Complications of Radiation Treatment <ul><li>Risk factors for bone growth impairment: </li></ul><ul><ul><li>age at the time of treatment </li></ul></ul><ul><ul><li>flat vs. long bone </li></ul></ul><ul><ul><li>quality of radiation (dose per fraction and total dose) </li></ul></ul><ul><ul><li>volume irradiated (epiphyseal plate, proximal vs distal) </li></ul></ul><ul><ul><li>growth potential of treated site </li></ul></ul><ul><ul><li>individual genetic factors </li></ul></ul><ul><ul><li>coexisting chemotherapy </li></ul></ul><ul><ul><li>As a result, estimates range anywhere from 1.3 Gy -20 Gy </li></ul></ul><ul><ul><li>Better models are needed </li></ul></ul>
    35. 35. Interplay between bone growth and muscle atrophy <ul><li>fibrosis of subcutaneous tissue and muscles </li></ul><ul><li>decreased range of motion </li></ul>Linear increase in T2 signal with radiation dose only in patients >12 years old Muscle Complications of Radiation Treatment
    36. 37. <ul><ul><li>Surgery is now the mainstay for most patients </li></ul></ul><ul><ul><li>Acceptable margins difficult to achieve in the axial skeleton including skull, spine, sacrum, and pelvis </li></ul></ul><ul><ul><ul><li>These are sites where radiation may be the primary means of local control </li></ul></ul></ul><ul><ul><li>Radiation also may be indicated following surgery for: </li></ul></ul><ul><ul><ul><li>positive margins </li></ul></ul></ul><ul><ul><ul><li>presentation with a pathologic fracture </li></ul></ul></ul><ul><ul><ul><li>close margin and poor histologic response to chemotherapy </li></ul></ul></ul><ul><ul><ul><li>Intralesional excision of or intramedullary rod placement through a radiographically benign-appearing lesion later found to be sarcoma </li></ul></ul></ul><ul><ul><li>No data supports a differential tumor radiosensitivity by age </li></ul></ul>Guidelines: AYA Bone Sarcomas
    37. 38. <ul><li>Conservative surgery alone with wide margins is appropriate for: </li></ul><ul><ul><li>• Superficial low grade lesions <5 cm </li></ul></ul><ul><ul><li>• Selected larger low grade lesions </li></ul></ul><ul><ul><li>• Selected superficial intermediate and high grade lesions <5 cm </li></ul></ul><ul><li>Most intermediate and high grade lesions > 5 cm should be considered for radiotherapy </li></ul><ul><li>Unresectable tumor: Definitive radiotherapy </li></ul><ul><li>No data supports a differential tumor radiosensitivity by age </li></ul>Guidelines: AYA Soft Tissue Sarcomas
    38. 39. <ul><li>Radiation avoidance or delay </li></ul><ul><ul><li>Strong data supports a differential normal tissue radiosensitivity by age </li></ul></ul><ul><li>Better modeling and prediction needed </li></ul><ul><ul><li>Improve estimate of therapeutic ratio when considering role of RT </li></ul></ul>Guidelines: Minimizing Toxicity in AYA Sarcoma
    39. 40. Guidelines: Minimizing Toxicity in AYA Sarcoma <ul><li>3. Improve radiation techniques </li></ul><ul><ul><li>Sequencing: Preoperative RT decreases functional morbidity in extremity sarcoma patients (Level 1, O’Sullivan 2005) </li></ul></ul><ul><ul><li>Fractionation: Hyperfractioned radiation decreases the risk of bone and muscle side effects (Retrospective, Indelicato 2008 and Bolek 1996) </li></ul></ul><ul><ul><li>Better target definition/smaller fields: </li></ul></ul><ul><ul><li>Old fields were unnecessarily big (Prospective, Krasin 2009) </li></ul></ul>
    40. 41. Guidelines: Minimizing Toxicity in AYA Sarcoma <ul><li>3. Improve radiation techniques (cont.) </li></ul><ul><ul><li>New modalities </li></ul></ul>Female with Ewing sarcoma of the posterior chest wall Protons Photons
    41. 42. Guidelines: Minimizing Toxicity in AYA Sarcoma Male with synovial sarcoma of the proximal medial thigh Protons Photons
    42. 43. Guidelines: Minimizing Toxicity in AYA Sarcoma <ul><li>4. New systemic agents to protect from RT effects </li></ul><ul><ul><li>e.g. pentoxifylline, bisphosphonates </li></ul></ul><ul><li>Multimodality improvements needed </li></ul><ul><li>Only 1 patient had isolated local recurrence (all the rest had component of distant disease) </li></ul>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%
    43. 44. &quot;He hasn't lost anything“ - ESPN commentator Curt Warner 9/6/2010
    44. 45. Thank you Questions?