Download Challenges in the treating of Bone and Soft Tissue Sarcomas

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