Challenges in the Treating of Bone and Soft Tissue Sarcomas
Margaret von Mehren, MDDirector Sarcoma Oncology
Fox Chase Cancer Center
Philadelphia, PA
Definition of Sarcomas
“Sarcoma is a malignant tumor composed cells of connective-tissue type. This definition is based on the morphology of the tumor cells and on their histogenesis.”
James Ewing, MD
Pathologist
Sarcoma Histologies
• Over 70 different histologies
• No agreement on the cell of origin
• Most are sporadic with unknown causes
Sarcoma Etiologies
1. Ionizing Radiation:
• 2000-7800 cGy
• Osteosarcoma, MFH, angio- and fibrosarcoma
2. Chemical Exposure:
• Dioxin, phenoxyacetic acids, agent orange
• Hepatic angiosarcoma: vinyl chloride, arsenic
Sarcoma Etiologies
3. Immunosuppression:
• Kaposi’s Sarcoma
4. Viral:
• HSV-8, KSHV- Kaposi’s Sarcoma
• EBV- smooth muscle tumors
5. Trauma/Scars:
• Fibro- and osteosarcoma
Sarcoma Etiologies
6. Bone Abnormalities: • Paget’s disease, bone infarcts – osteosarcoma
• Osteochondroma/fibrous displasia of bone:
– Osteosarcoma
– Chondrosarcoma
7. Lymphedema:
• Stuart-Treves Syndrome: angiosarcoma
Genetic Syndromes
1. Hereditary Retinoblastoma: 13q deletion
• 1000x more likely to get osteosarcoma
• Risk increased with exposure to XRT or alkylating agents
2. Neurofibromatosis: 17q deletion
• 7-15% risk of developing a malignant schwanoma
3. Gardner’s Syndrome: 5q deletion
• Associated with intra-abdominal desmoid tumors
Genetic Syndromes-p53 related
1. Li-Fraumeni Syndrome:
• 17p deletion resulting in abnormal p53
• Phenotype: multiple tumors at an early age
– Including breast, leukemia, glioma, and sarcomas
2. MDM2 mutations:
• Amplification of 12q cluster resulting in abnormal p53 function
Cytogenetic Abnormalities
HistologyCytogenetic
ChangeFusion Gene Frequency
Ewing’s/PNETt(11;22)
t(21;22)
EWS/FL1-1
EWS/ERG90%
Embryonal Rhabdomyosarc
+2q, +20 80%
Alveolar
Rhabdomyosarc
t(2;13)
t(1;13)
PAX3/FKHR
PAX7/FKHR80%
Osteosarcoma1p-, 6q-, 9p-,
13q-, 17p-90%
Myxoid Chondrosarcoma t(9;22) 50%
Cytogenetic Abnormalities
HistologyCytogenetic
ChangeFusion Gene Frequency
Synovial t(x;18) SYT/SSX 95%
Liposarcoma
Myxoid/Roundt(12;16) TLS/CHOP 75%
Leiomysarcoma 1p deletion 75%
Dermatofibros.
Protuberanst(17;22) COL1A1-PGFB > 75%
Clear Cell Sarcoma
t(12;22) EWS/ATF-1 > 75%
Sarcoma Annual Statistics 2008
New Cancer Diagnoses Estimated Cancer Deaths
Sarcoma Male Female Male Female
Soft Tissue 5,720 4,670 1,880 1,800
Bone/Joints 1,270 1,110 820 650
Jemal et al. CA: A Cancer J for Clinicians 58:71-96, 2008.
Body Distribution of Cases
0
5
10
15
20
25
30
35
40
Percent of cases
Lower Extremity
Retroperitoneal/Intra-abdominalTrunk
Upper Extremity
Genitourinary
Visceral
Head and Neck
Other
Commonest Histology by Age
• Children: Rhabdomyosarcoma
• Adolescents: Synovial sarcoma
• Adults: MFH > liposarcoma > leimyosarcoma
Treatment for Localized Disease
• Surgery: main stay of treatment for majority of tumors
– Extremity tumors: in the past required often required amputations
– Most undergo limb salvage surgeries today
• Consider role of radiation
• Consider role of chemotherapy
The Benefit of Adjuvant Radiation Therapy
Local Progression-free Survival Overall Survival
Rosenberg et al. Annals of Surgery, 1982.
• Conservative surgery + RT had similar local progression-free and overall survival when compared to amputation
Neoadjuvant or Adjuvant Chemotherapy
• Neoadjuvant or adjuvant chemotherapy indicated for:
– Osteosarcoma
– Rhabdomyosarcoma
– Ewing’s Sarcoma/PNET
Osteogenic Sarcoma
• Surgery with adjuvant chemotherapy increased long term survival from 20% to 80%
• Effective agents:
– Cisplatin and doxorubicin
– Addition of high dose methotrexate is controversial
– Ifosfamide is also active
European Osteosarcoma Intergroup Study I
Bramwell et al. JCO 1992.
DOX/DDP
HDMTX/DOX/DDP
Overall Survival
European Osteosarcoma Intergroup III
Lewis et al. JNCI, 2007
• No difference in disease-free and overall survival─ Higher rate of greater than 90% necrosis in dose intensive arm
COG Phase III Study
Meyers et al. JCO, 2005.
GPG Phase III Study
Meyers et al. JCO, 2005.
Event-free Survival
• 3-year EFS─ 71% Standard chemotherapy arm─ 68% MTP + standard chemotherapy─ 61% Ifosfamide + standard chemotherapy─ 78% Ifosfamide + MTP + standard chemotherapy
Intergroup Rhabdomyosarcoma Study-IV
Crist et al. JCO, 2001.
• VAC remained standard even in patients with high-risk disease─ No difference in progression-free and overall survival
Ewing’s Sarcoma
• Vincristine, Adriamycin/Actinomycin-D, Cytoxan
• Ifosfamide and Etoposide
Event-free Survival Utilizing VAC Aloneor in Combination with IE in Patients
with or without Metastatic Ewing’s Sarcoma
Grier H et al. N Engl J Med, 2003.
Grier H et al. N Engl J Med, 2003.
Event-free Survival According to Study Groupand Tumor Site Among Patients without Metastases
Soft Tissue Sarcomas
• Doxorubicin
• Ifosfamide
• Dacarbazine
Meta-Analysis of the Benefitof Adjuvant Chemotherapy in STS
• 14 clinical trials of adjuvant therapy
– 1568 patients with STS
• Doxorubicin containing regimens
• Some trials also included radiation therapy
Sarcoma Meta-Analysis Group. Lancet , 1997.
Meta-Analysis of the Benefitof Adjuvant Chemotherapy in STS
Hazard RatioAbsolute benefit
at 10 years
Local RFS0.73 (0.56-0.94)
P = 0.0166%
Overall RFS0.75 (0.64-0.87)
P = 0.000110%
Overall Survival0.89 (0.76-1.03)
P = 0.124%
Sarcoma Meta-Analysis Group. Lancet , 1997.
Meta-Analysis of the Benefitof Adjuvant Chemotherapy in STS
Confounding Factors
• Studies with mixed patient populations
– Extremity sarcomas
– Uterine sarcomas
– Retroperitoneal sarcomas
• Doses and regimens non-uniform
• Some trials utilized local radiation therapy as well as adjuvant chemotherapy
Sarcoma Meta-Analysis Group. Lancet , 1997.
EORTC 62931: Study Design
Definitive Resectionof a grade 2-3
STSof any site
Adjuvant Chemotherapy5 Cycles:
Doxorubicin 75 mg/m2
Ifosfamide 5 grams/m2
Growth factor support
No Adjuvant Therapy
Radiation if
indicated
Woll et al. ASCO 2007, Abs 10008.
EORTC 62931: Key Eligibility Criteria
• Grade 2-3 soft tissue sarcoma
• Gross resection of a primary of locally recurrent sarcoma
• No metastatic disease
• Radiation therapy after chemotherapy for:
– Microscopic residual disease
– Local recurrence
– Inadequate surgical margins
Woll et al. ASCO 2007, Abs 10008.
EORTC 62931: Adjuvant Chemotherapy Administration
• N = 173
– 73% received all 5 cycles
– 37% required a dose reduction or cycle delay
• Reasons all planned therapy was not given included:
– Progressive disease
– Toxicity
– Patient refusal
Woll et al. ASCO 2007, Abs 10008
EORTC 62931: Relapse-free Survival
EORTC 62931: Overall Survival
Therapy for Metastatic STS
• Surgical Resection
• Palliative Radiation Therapy
• Palliative Chemotherapy
2nd Line Chemotherapy for STS
Single agent RR in pretreated STS
Ifosfamide 18 - 35%
Doxorubicin 17%
DTIC 27%
Paclitaxel 7%
Docetaxel 0 - 17%
Gemcitabine 18%
Combination Chemotherapy
MAI(D) 28 - 47%
AD 17%
Gemcitabine + Docetaxel 25 - 53%
French Sarcoma Study Group Experiencewith Gemcitabine with Docetaxel
Bay et al. Int J Cancer, 2006.
Conclusions
• Childhood sarcomas are more responsive to chemotherapy
– Improves overall survival
• Chemotherapy in adult sarcomas does not improve overall survival
• Chemotherapy can palliate patients with metastatic disease
• Median survival for metastatic disease in adults is 12-24 months
• We need new therapeutic options for treatment of sarcomas