Challenges in the Treating of Bone and Soft Tissue Sarcomas

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