Ewings Sarcoma

Ewing’s SarcomaEwing’s SarcomaA Radiation Oncologist’s A Radiation Oncologist’s

PerspectivePerspective

Professor Of Radiation OncologyMadras Medical College & Govt. General HospitalChennai

Prof. Mohan Ram RProf. Mohan Ram R

aroi - tn & pondicherrystate conference-2006

Chennai08 Jul’2006

Ewing’s Sarcoma - RTEwing’s Sarcoma - RT [email protected]@yahoo.com 2

Tributes – Dr. James Ewing

• Clinical and Surgical Pathologist

• Experimental Oncologist• Professor at the age of 33

at Cornell University Medical School

• Founding Member of - American Cancer Society

& - Memorial Sloan-Kettering

Cancer Centre, New York. (Director)1866 - 1943


What Prof. Ewing said…

“ the first indication is for treatment by radiation in full doses, and over considerable periods. This recommendation is based on the reported cure of certain cases….by radiation alone, and on the clinical disappearance of the disease by variable periods in many more cases. The response to radiation also confirms the diagnosis….”

James Ewing, 1940

Textbook – “ Neoplastic Diseases”, 4th Edn


Objectives of this talk

• Management Guidelines

• Local treatments in Ewing’s Sarcoma

• Indications for Radiation therapy

• Radiation therapy Planning

• Radiation therapy in Metastatic Disease

• Complications of Radiation therapy

• Future Directions


Ewing’s Sarcoma - Sites

• More common in the Extremities

Incidence

• Extremities – 50%

• Pelvis – 26%

• Chest Wall – 16% (Data from 1,426 pts in EI-CESS trials)


Management of Ewing’s Sarcoma

• Multi-disciplinary Team Approach consisting of Surgical / Orthopaedic Oncologist, Radiation Oncologist, Medical Oncologist, Surgical Pathologist

• All local Imaging Studies (with a high degree of suspicion) to be done prior to biopsy

• Radiation Oncologist & Pathologist consultation prior to Biopsy procedure is essential

- To avoid compromise on Radiation Portals - Multiple types of tissue samples




Ewing’s Sarcoma is Radiosensitive

• Possible Explanation is now available

• In 75 – 90 % of Ewing’s sarcoma tumors the p53 dependant DNA damage apoptotic response pathway is largely intact.

• Radio-responsiveness is possibly a contribution of the wild type p53, which is intact.

Kovar et al. Characterization of distinct consecutive phases in non-genotoxic p53-induced apoptosis of Ewing’s tumor cells and the rate limiting role of Caspase-8.Oncogene 2000; 19:4096-4107Kovar et al. Response of Ewing’s tumor cells to forced and activated p53 expression. Oncogene 2003; 22: 3193-3204


LOCAL TREATMENT• Radiation Therapy

(Historically, the treatment of choice)

• Surgery( Emerging Standard)

• Surgery + Radiation therapy(Complimentary)


Emerging Role of Surgery

• Development of Innovative Surgical Techniques: Limb preservation & Structural bone function preservation

• Chemo - cytoreduction makes resection possible• Local failure rates with RT in historical series :

9 - 25% *• Concern over second malignancies

* Horonitz et al, Pediatr Clin Nor Am, 1991Horonitz et al, Pediatr Clin Nor Am, 1991


Is there a Surgical Bias in Literature ?

YES


Evidence for the Surgical bias

• Recurrence rate after RT is strongly correlated with the primary site

Extremities – 5 to 10%

Pelvis – 15 to 70%• Tumor size is strongly related to Recurrence rates

< 8cms = ≤ 80%

> 8cms = 90 %

Larger lesions are generally treated by RT• Combined modality trials are designed to evaluate

[RT Vs Surgery + RT] not [Surgery Vs Surgery + RT]


• Quality of the RT delivered in some negative trials is doubtful

e.g. Review of CESS-81 trial showed that there were major shortcomings in Volume delineation which accounted for high recurrence rates with RT, which when corrected subsequently improved results on par with Surgery in later CESS trials (e.g. CESS-86)

• Surgical series always select patients at low-risk (e.g. Extremity lesions with low volume disease)

• Second malignancies are related not to RT alone but to chemotherapy as well (Anthracyclines & alkylating agents)

Evidence for the Surgical bias


Interpretations for the Radiation Oncologist in decision making

• Not all Studies are Strictly comparable, in fact no randomized study compares Surgery alone and RT directly.

• Importance in practice should be attached to - Relative functional deficits with RT Vs Surgery Vs Surgery + RT - Patient’s rehabilitation capacity - Psychological adjustment of the patient• Surgery and RT are not competing modalities

but are COMPLIMENTARY


INDICATIONS FOR RTDEFINITIVE RADIATION THERAPY

• Tumors where Resection is Impossible or where only an intra-lesional resection is achievable

Surgery is the preferred arm where wide or marginal resection is possible

• Patient with poor Surgical risk

• Patient refusing surgery


POST-OPERATIVE RADIATION THERAPY

• Intra-Lesional Resection

• Marginal Resection

• Wide-resection with Poor Histological response to Neo-adjuvant Chemotherapy (>10% viable tumor cells in the specimen)

Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003Based on CESS-81, CESS-86, EICESS-92 Studies : Schuck et al,IJROBP-1998 & 2003

INDICATIONS FOR RT


INDICATIONS FOR RTPRE-OPERATIVE RADIATION THERAPY

• When Narrow resection margins are expected

Principle : To sterilize the tumor compartment before surgery & to potentially reduce the risk of dissemination during surgery

Local recurrence with pre-op RT : <5%

EI-CESS-92 : Schuck et al – IJROBP-1998 & 2003


DOSE & FRACTIONATION


TREATMENT PLANNING

Technique


RT in METASTATIC DISEASE


SIDE EFFECTS• Functional results : Of all the patient’s treated

with RT (NCI data), 60 % have good functional activity 20 % have mild morbidities 20 % have significant morbidities• Risk for Post treatment Fractures Are caused not by RT alone but also - Cortical disruption by tumor - Younger age - Large tumor size


SIDE EFFECTS

• Second malignancy after RT

- Cumulative risk @ 15yrs = 6 – 6.7% ( CESS-81 & CESS-86; IJROBP:1997; 39)

- No secondary sarcomas seen at doses <48 Gy

( Kutterch et al; JCO:1996, 14 )

- Risk increased by anthracycline and alkylating agent chemotherapy


IN THE NEAR FUTURE

• Use of 3D-CRT / IMRT as a standard protocol in Ewing’s sarcoma

• Evaluation of the role of Prophylactic B/L Lung Irradiation in patient’s with localized disease with documented complete response to decrease the systemic failures

• Incorporation of functional imaging modalities e.g. PET-CT / PET-MRI for Target Volume delineation, Boost treatment and IMRT

• Combination of Molecular agents like Apoptosis directed targeted therapies e.g. TRAIL therapy (TNF Related Apoptosis Inducing Ligand) with RT to improve results with RT


MANY THANKS

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Ewings Sarcoma