challenges in the treating of bone and soft tissue sarcomas
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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