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