Challenges in the Treating of Bone
and Soft Tissue Sarcomas
Margaret von Mehren, MD
Director 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
Histology
Cytogenetic
Change
Fusion Gene
Frequency
Ewing’s/PNET
t(11;22)
t(21;22)
EWS/FL1-1
EWS/ERG
90%
Embryonal
Rhabdomyosarc
+2q, +20
Alveolar
Rhabdomyosarc
t(2;13)
t(1;13)
Osteosarcoma
1p-, 6q-, 9p-,
13q-, 17p-
90%
Myxoid
Chondrosarcoma
t(9;22)
50%
80%
PAX3/FKHR
PAX7/FKHR
80%
Cytogenetic Abnormalities
Histology
Cytogenetic
Change
Fusion Gene
Frequency
Synovial
t(x;18)
SYT/SSX
95%
Liposarcoma
Myxoid/Round
t(12;16)
TLS/CHOP
75%
Leiomysarcoma
1p deletion
Dermatofibros.
Protuberans
t(17;22)
COL1A1-PGFB
> 75%
Clear Cell
Sarcoma
t(12;22)
EWS/ATF-1
> 75%
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
40
Lower Extremity
30
Retroperitoneal/Intraabdominal
Trunk
25
Upper Extremity
35
Percent of
20
cases
15
10
5
0
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
• Conservative surgery + RT had similar local progression-free and overall
survival when compared to amputation
Rosenberg et al. Annals of Surgery, 1982.
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
Overall Survival
DOX/DDP
HDMTX/DOX/DDP
Bramwell et al. JCO 1992.
European Osteosarcoma Intergroup III
• No difference in disease-free and overall survival
─ Higher rate of greater than 90% necrosis in dose intensive arm
Lewis et al. JNCI, 2007
COG Phase III Study
Meyers et al. JCO, 2005.
GPG Phase III Study
Event-free Survival
• 3-year EFS
─
─
─
─
71% Standard chemotherapy arm
68% MTP + standard chemotherapy
61% Ifosfamide + standard chemotherapy
78% Ifosfamide + MTP + standard chemotherapy
Meyers et al. JCO, 2005.
Intergroup Rhabdomyosarcoma Study-IV
• VAC remained standard even in patients with high-risk disease
─ No difference in progression-free and overall survival
Crist et al. JCO, 2001.
Ewing’s Sarcoma
• Vincristine, Adriamycin/Actinomycin-D, Cytoxan
• Ifosfamide and Etoposide
Event-free Survival Utilizing VAC Alone
or in Combination with IE in Patients
with or without Metastatic Ewing’s Sarcoma
Grier H et al. N Engl J Med, 2003.
Event-free Survival According to Study Group
and Tumor Site Among Patients without Metastases
Grier H et al. N Engl J Med, 2003.
Soft Tissue Sarcomas
• Doxorubicin
• Ifosfamide
• Dacarbazine
Meta-Analysis of the Benefit
of 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 Benefit
of Adjuvant Chemotherapy in STS
Hazard Ratio
Absolute benefit
at 10 years
Local RFS
0.73 (0.56-0.94)
P = 0.016
6%
Overall RFS
0.75 (0.64-0.87)
P = 0.0001
10%
Overall Survival
0.89 (0.76-1.03)
P = 0.12
4%
Sarcoma Meta-Analysis Group. Lancet , 1997.
Meta-Analysis of the Benefit
of 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
Adjuvant Chemotherapy
5 Cycles:
Definitive Resection
of a grade 2-3
STS
of any site
Doxorubicin 75 mg/m2
Ifosfamide 5 grams/m2
Growth factor support
Radiation
if
indicated
No Adjuvant Therapy
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)
AD
Gemcitabine + Docetaxel
28 - 47%
17%
25 - 53%
French Sarcoma Study Group Experience
with 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