# Presentation: 527986

## The ASPHO Pediatric Hematology-Oncology Review CourseSARCOMAS

- David O. Walterhouse, M.D.
- _Disclosure information_
- No financial interests, Study chair ARST0331
- No discussion of unlabeled uses

## Sarcomas: Cellular OriginMesoderm Germ Layer

**Mesoblast**
- Undifferentiated Sarcoma

- _Myoblast_
- Rhabdomyosarcoma
- Leiomyosarcoma

- _Lipoblast_
- Liposarcoma

- _Fibroblast_
- Fibrosarcoma
- Malignant peripheral nerve sheath tumor
- Hemangiopericytoma

- _Osteoblast_
- Osteosarcoma

- _Uncertain_
- Ewing sarcoma
- Synovial sarcoma
- Alveolar soft part sarcoma
- Malignant fibrous histiocytoma
- Epithelioid sarcoma

- _Chondroblast_
- Chondrosarcoma

## Average annual rate per million

**(SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)**

**Average annual rate per million**

**Age (in years) at diagnosis**

## RHABDOMYOSARCOMA

**Incidence**
- 1.  Accounts for 50% of soft tissue sarcomas in
- 	     children < 15 years
- 2.  6th most common form of childhood cancer
- 3.  250 - 350 new cases each year in US
**	****	**
**	****	**
- 		(SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)

## RHABDOMYOSARCOMA 

**Epidemiology/Biology**
**The Li-Fraumeni Familial Cancer Syndrome and RMS**
**1969:**	Increased incidence of breast cancer in mothers of children with RMS; brain tumors and adrenal cortical carcinoma were described in siblings of children with RMS (Li and Fraumeni, *Ann Intern Med* 1969; 71:747)
**1975:**	Definition of the familial cancer syndrome refined; increased susceptibility to soft tissue sarcomas, brain tumors, adrenal cortical carcinoma, breast cancer, leukemia, and osteosarcoma in families, including multiple primaries, and tumors in young individuals (Li and Fraumeni, *Ann Intern Med* 1975; 83:833)
**1990:**	Germline p53 mutations detected in families with the Li-Fraumeni familial cancer syndrome (Malkin et al., *Science* 1990; 259:1233)

**RHABDOMYOSARCOMA **

## PAX-FKHR Fusions: Alveolar RMS

**Notes:**
In ARMS, recurrent translocations result in production of tumor specific fusions of PAX and FKHR genes.

(⇓) Pax 3, on chromosome 2 OR
(⇓) Pax 7, on chromosome 1 AND
(⇓) FKHR on chromosome 13 are involved in this gene translocation (⇓)
Creating either
(⇓) a tumor specific PAX3/FKHR fusion product, OR
(⇓) the PAX7/FKHR fusion product

## Embryonal RMS (ERMS)

**Affect the imprinted gene cluster at 11p15.5 in some cases**

**Embryonal RMS (ERMS)**

**Loss of Heterozygosity:****  **Loss of an allele in tumor cells when compared with normal cells (Scrable et al., *Nature* 1987; 329:645)
- 	Classic interpretation: the allele carrying a functional tumor suppressor is lost, unmasking a remaining mutant non-functional allele at that locus
**                     ****For imprinted loci, LOH can be associated with LOI**
**Loss of Imprinting:**  Imprinted genes that are normally monoallelically expressed from either the maternal or paternal allele become biallelically expressed
- 	In RMS, biallelic expression of IGF2 at 11p15.5 (LOI) can result from loss of the maternal IGF2 imprint (LOI) (Pedone et al., *Hum Mol Genet* 1994; 3:1117) or loss of the maternally imprinted IGF2 allele (LOH) with reduplication of the expressed paternal allele (unipaternal isodisomy) (Visser et al., *Oncogene* 1997; 15:1309)
- 				(Anderson et al., *Genes Chromosomes Cancer* 1999; 26:275)

## Embryonal RMS (ERMS)

**Pathology**
-   60-70% of cases
-   Simulates immature skeletal 	muscle
-   MyoD, Myogenin expressed
**ERMS Variants:**
-   Solid (“embryonal”); favorable
-   Botryoid (polypoid grossly); 	very favorable
-   Spindle cell (leiomyomatous 	with cross striations); 	very favorable

## Alveolar RMS (ARMS)

**Pathology**
- 20% of cases
- Growth pattern reminiscent of                      pulmonary alveoli with fibrovascular septa
- MyoD, Myogenin expressed
- Associated with either a
- t(2;13)(q35;q14) or t(1;13)(p36;q14),          extremity primary, lymph node   involvement, and unfavorable   prognosis

## RHABDOMYOSARCOMA 

**Lymphatic**:  40% of paratesticular and 20% of extremity tumors
**Hematogenous:** 10-20% at diagnosis (lung, bone, bone marrow, liver)
**CNS extension:** 50% of parameningeal (cranial nerve palsies, erosion of cranial bone, direct intracranial growth)

**Clinical Presentation**
**Mass, +/- pain, +/- disturbance in function**

**RHABDOMYOSARCOMA **

## RHABDOMYOSARCOMA

- 		1.  History and physical examination
- 2.	MRI or CT of primary site
- 3.	CT of chest/CXR
- 4.	CT of retroperitoneum and liver
- 5.	Bone marrow aspirate/biopsy
- Bone scan
- PET scan (under investigation)
- 8.	Blood tests; CBC, lytes, BUN, Cr, Ca, phos, uric acid, liver function studies
- 9.	Special situations
- (a)	MRI or CT of head for cranial parameningeal tumors
- (b)	CT of retroperitoneum for GU tumors
- (c) Lymph node assessment for paratesticular/extremity
- (d) CSF cytology for parameningeal tumors

**RHABDOMYOSARCOMA**

## RHABDOMYOSARCOMA

**Group I**: Localized disease, completely resected
**Group II**: Gross total resection with evidence of regional 	     spread
- (A)	Gross resection of tumor with microscopic residual 	disease
- (B)	Complete resection of primary tumor, regional nodes 	involved
- (C)	Regional disease with involved nodes - microscopic 	residual disease and/or histologic involvement of the 	dissected regional node most distal to the primary 	tumor site
**Group III**: Incomplete resection with gross residual disease
**Group IV**: Distant metastatic disease

**RHABDOMYOSARCOMA**

## RHABDOMYOSARCOMA

- Stage	Sites			T		Size		N
**1**	Orbit, non-para-		T1 or T2     	a or b		No, N1, or Nx
- 	meningeal head
- 	and neck, non-
- 	bladder/prostate
- 	GU, biliary tract
**2**	Parameningeal,		T1 or T2     	a		N0 or Nx
- 	bladder/prostate,
- 	extremity, other
**3**	Parameningeal,		T1 or T2     	a		N1
- 	bladder/prostate,		     		b 		N0, N1, or Nx
- 	extremity, other
**4**	All with distant		T1 or T2     	a or b		N0 or N1
- 	metastases
*Definitions:  T = tumor invasiveness; T**1** = confined to anatomic site of origin; T**2** = extension and/or fixation to surrounding tissue; a = *_*<*_* 5 cm; b = > 5 cm; N = regional nodes; N**0** = regional nodes not clinically involved; N**1** = regional nodes clinically involved; N**x**=  clinical status of regional nodes unknown*

**RHABDOMYOSARCOMA**

## RHABDOMYOSARCOMA

**Prognostic Factors**
- 	**Stage/Group/Extent of disease;** important predictor of outcome
- 	**Primary site;**  affects time to diagnosis, likelihood of lymphatic 			spread, ease of excision, and potentially radiation delivery; 		represents an important prognostic factor (favorable sites; 		orbit, non-bladder prostate GU, non-parameningeal head 		and neck, biliary tract)
**Histologic type;** (most favorable) botryoid and spindle cell  		solid embryonal  alveolar (least favorable)
**Biologic factors;** t(2;13) unfavorable if stage 4 (Sorensen et al., *J **	**	**Clin Oncol* 2002; 20:2672)
**Age;** younger patients (except <1) fare better (Joshi et al., *Pediatr **	**	**Blood Cancer* 2004; 42:64)

## COG RMS Risk Group Assignment

**Low**: ~ 35% of RMS
- Embryonal histology
- Stage 1, Group I, II, III
- Stage 2, 3, Group I, II
**Intermediate**: ~ 50% of RMS
- All localized alveolar
- Stg 2, 3, Grp III ERMS
**High**: 15% of RMS
- Metastatic disease

**0.0**

**0.2**

**0.4**

**0.6**

**0.8**

**1.0**

**Years**

**0**

**2**

**4**

**6**

**Proportion FFS**

**8**

**10**

**Low**

**Intermediate**

**High**

## RHABDOMYOSARCOMA

**Treatment Philosophy**
- Optimal treatment requires a coordinated multidisciplinary management plan:
- SURGERY, RADIOTHERAPY, CHEMOTHERAPY

## RHABDOMYOSARCOMA

**Role of Surgery**
- 	Form of local control
- Excision of primary tumor upfront whenever possible without causing major functional or cosmetic deficits
- Primary re-excision for residual tumor
- Special anatomic sites requiring surgical assessment of lymph nodes:		a)  paratesticular (ISRLND)
- 			b)  extremity (node sampling)
- Second look surgery during treatment sometimes done for residual tumor

## RHABDOMYOSARCOMA

**Role of Radiation Therapy**
- 	Form of local control
- Local/regional relapse rates (IRS-IV): local (51%), regional (17%), and distant (32%) (Crist et al., *J Clin Oncol* 2001; 12:3091)
- Patients with Group I embryonal tumors do not receive RT
- Treatment usually begins during weeks 3 - 15 of therapy
- Special anatomic sites:	    a) parameningeal (early for ICE)
- 			    b) vaginal (timing depends on response)
- Treatment volume is determined by pretreatment (pre-surgical) tumor size
- Doses of 3600 - 5040 cGy generally used; dose depends on Group (microscopic vs gross disease), primary site, nodal involvement, histology, and whether second look surgery performed

## RHABDOMYOSARCOMA

**Role of Chemotherapy**
- Local and systemic tumor control
- Multi-agent/intensive/governed by risk-group
- Standard: vincristine, dactinomycin, and cyclophosphamide (VAC)
- Other active agents used in recent trials; irinotecan, topotecan, doxorubicin, etoposide, and ifosfamide

## RHABDOMYOSARCOMA

**IRS-VI/COG Protocols**
**ARST0331** **– low risk study**:  VAc (lower dose cyclophosphamide) with length of therapy (22 vs 45 weeks) assigned based on subset
**ARST0531** **– intermediate risk study**: randomization between standard VAC and VAC alternating with vincristine + irinotecan
- 	**ARST0431**** – high risk study**:  includes VAC plus the 4 	most active agents identified through IRSG window trials 	(doxorubicin, ifosfamide, etoposide, irinotecan) and 		interval compression

## Survival for RMSThree Decades of Progress

- Maurer et al., *Cancer* 1988; 61:209, Maurer et al., *Cancer* 1993; 71:1904,
- Crist et al. *J Clin Oncol* 1995; 13:610, Crist et al., *J Clin Oncol* 2001; 19:3091

## 5-yr Survival by Group

- Maurer et al., *Cancer* 1988; 61:209, Maurer et al., *Cancer* 1993; 71:1904,
- Crist et al. *J Clin Oncol* 1995; 13:610

-  IRS-I           IRS-II          IRS-III

## 3-yr FFS by Histology

**Intermediate risk patients**

- Maurer et al., *Cancer* 1993; 71:1904, Crist et al. *J Clin Oncol* 1995; 13:610,
- Crist et al., *J Clin Oncol* 2001; 19:3091

## RHABDOMYOSARCOMA

**Complications of Therapy**
**Acute toxicity**
- 	Hematologic toxicity; >85% of patients per VAC 				treatment course
- 	Infectious complications; 20% of patients per VAC 			treatment course
- 	VOD; associated with dactinomycin and 					cyclophosphamide; rate 4-5% on VAC
**Long term effects**
- 	Infertility; associated with total cumulative doses of cyclo > 7.5 		gm/m2 (Kenney et al. *Cancer* 2001; 91:613)
- 	SMNs; 3.4% at 20 years (Spunt et al., *Proc Annu Meet Am Soc **	**	**Clin Oncol* 2001; 20, 2173)
- 	Bone growth arrest/muscular atrophy

## 1.	Incidence; 40% of soft tissue sarcomas in children < 5 years of age, 	but 77% of soft tissue sarcomas among 15 - 19 year olds (SEER 		Pediatric Monograph, NIH Pub. No.99-4649, 1999).		2.	General clinical presentation;  may arise in any part of the body, 	most commonly the extremities and trunk (Spunt et al., J Clin Oncol 	2002; 20:3225).3.	Prognosis; depends on tumor type, extent of resection (Group), 		tumor size, grade, and age (Spunt et al., J Clin Oncol 2002; 20:3225).4.	Optimal treatment for NRSTS in 2006 remains undefined		(1) 	Group I; observe unless grade 3 and > 5 cm, then 			consider RT and/or chemotherapy		(2)	Group II; RT alone unless grade 3 and/or > 5 cm, 			then consider chemotherapy		(3)	Group III-IV or grade 3 and > 5 cm any group; 				RT, chemotherapy, surgery

**Non-Rhabdomyosarcoma Soft Tissue Sarcomas (NRSTS) **

**NON-RHABDOMYOSARCOMA**

## NON-RHABDOMYOSARCOMA

- 	Pratt et al., *J Clin Oncol* 1999; 17:1219-1226 (Fig. 4)
- Reprinted with permission from the American Society of Clinical Oncology

**EFS for Group I/II NRSTS:  Chemo vs Observation**

## NON-RHABDOMYOSARCOMA

- Pratt et al., *J Clin Oncol* 1999; 17:1219-1226 (Fig. 5)
- Reprinted with permission from the American Society of Clinical Oncology

**EFS for Group I/II NRSTS:  Grade 1/2 vs Grade 3**

## NON-RHABDOMYOSARCOMA

- Pappo et al., *J Clin Oncol* 2005; 23:4031- 4038 (Fig. 2)
- Reprinted with permission from the American Society of Clinical Oncology

**PFS and OS for Group III/IV NRSTS:  Vcr + Doxo + Ifos**

## NON-RHABDOMYOSARCOMA

**Tumor type****	****	****        Distinguishing characteristics**

**Synovial sarcoma**		t(X;18)(p11;q11); 80-100% express 				Bcl-2; 56% response rate to 					chemo (Pappo et al., *J Clin Oncol* 					2005; 23:4031)
**Fibrosarcoma**			Infantile form associated with
- 				t(12;15)(p13;q25) and represents 				most common STS in children < 1 yr
**MPNST****	**			20% associated with NF; 5-16% of
- 				NF patients develop; express EGFR
**Malig. fibrous histiocytoma**	Associated with prior RT
**Hemangiocytoma**		Infantile form associated with a 					more favorable outcome
**Leiomyosarcoma**		Associated with immunosuppression 				and HIV
**Alveolar soft part sarcoma**	Poor chemo responsiveness	**Liposarcoma**			Myxoid variant associated with 					t(12;16)(q13;p11)

## OSTEOSARCOMA

**Incidence**
- 1.	Accounts for 60% of malignant bone tumors 	during the first two decades of life
- 2.	Approximately 150 new cases each year in 	children under 15 and 400 new cases in 		children and adolescents under 20

- (SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)

## Bone sarcoma age-specific incidence rates by histology (SEER 1976-94 combined) 

**Bone sarcoma age-specific incidence rates by histology (SEER 1976-94 combined) **
**(SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)**

## OSTEOSARCOMA

**Epidemiology/Biology**
**Associations**
- 1.	**Ionizing radiation**; cause of 3% of osteosarcomas with at a median time of 9 - 11 years following exposure (Newton et al., *Cancer* 1991; 67:193)
- 2.	**Hereditary retinoblastoma** (germline Rb mutations); up to 50% develop a second tumor by 20 years and up to 90% develop a second tumor by 30 years about 50% of which are osteosarcomas (Abramson et al., *Ophthalmology* 1976; 81:454)
- 3.**	****Li-Fraumeni familial cancer syndrome** (germline p53 mutations) (Li and Fraumeni, *Ann Intern Med* 1975; 83:833)
- 4.	**Rothmund-Thomson syndrome** (mutations in the RECQL4 helicase gene); 32% develop osteosarcoma (Wang et al., *Am J Med Genet* 2001; 102:11)

## OSTEOSARCOMA

**Histologic Subtypes: WHO 1995**

**Central (medullary) tumors**
- 1. Conventional OS
- 	(a). Osteoblastic OS
- 	(b). Chrondroblastic OS
- (c). Fibroblastic OS
- 2. Telangiectatic OS
- 3. Small cell OS
- 4. Intraosseous well differentiated OS
- 5. Multifocal OS
**Surface tumors**
- Parosteal OS
- Periosteal OS
- High-grade surface OS

- (Schajowicz et al.,*Cancer* 1995; 75:1208)

## OSTEOSARCOMA 

**Skip lesions:**  Occur in up to 20% of cases several cm from primary
**Hematogenous:** 15-20% at diagnosis (lung [68-93%], bone [15-29%]) (Goorin et al., *J Clin Oncol* 2002; 20:426, Meyers et al., *J Clin Oncol* 1993; 11:449)

**Clinical Presentation**
**Pain, +/- mass at the primary site, typically involves metaphyses of long bones**

**OSTEOSARCOMA **

**Most common primary sites:**
- distal femur (55%) > proximal
- tibia (27%) > proximal humerus
- (11%) > other sites (Meyers et al.,
*J Clin Oncol* 2005; 23:2004)

## OSTEOSARCOMA

**Staging Workup  (localized vs metastatic)**
- 1.  History and physical examination
- 2.  Plain films of involved bone
- 3.  MRI of involved bone
- 4.  Bone scan
- 5.  CT of chest/CXR
- 6.  PET scan (under investigation)
- 7.	Blood tests; CBC, lytes, BUN, Cr, Ca, phos, Mg, uric acid, liver function studies, LDH, alk phos
- 8.  Audiogram
- Echo
- CrCl/GFR

## OSTEOSARCOMA

**Prognostic factors**
- 	**Extent of disease/stage;** metastatic disease 		unfavorable
**Response of the primary tumor to pre-surgical chemotherapy;** favorable > 90% necrosis, powerful well-documented predictor of outcome (Rosen et al., *Cancer* 1982; 6:329)
**Primary site;** axial skeletal primaries unfavorable
**Histology;** parosteal favorable

## OSTEOSARCOMA

**Treatment/Surgery**
- 	Removal of all gross tumor with margins *en bloc* and biopsy site through normal tissue planes is required
- 	Type of surgical procedure depends on tumor location, size, extramedullary extent, presence of distant metastatic disease, age, skeletal development, and life-style preference
- 	Metastatic sites must also be resected
- 	When relapse occurs, retrieval therapy must include resection

## OSTEOSARCOMA

**DFS:  Surgery vs Surgery + Chemotherapy**

-                    Link et al., *N Engl J Med* 1986; 348:694 (Fig. 1)
- Copyright © 1986 Massachusetts Medical Society.  All rights reserved.

- Surgery +
- Chemotherapy

- Surgery

## OSTEOSARCOMA

**Treatment/Chemotherapy**
- 	Primarily systemic tumor control
- 	Agents used generally depend on whether localized vs metastatic/resectable vs not
- 	Most active agents include doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide +/- etoposide
- 	Generally, chemotherapy is administered pre-surgically (neoadjuvant) and post-surgically (current trials tailoring post-op chemotherapy based on response to neoadjuvant chemotherapy)

## OSTEOSARCOMA

**Recent COG Protocols**
- 	**AOST0331**** – resectable localized OS:**
- MAP induction followed by histologic response assessment at time of resection:
- 	good responders continue with MAP and 		randomized +/- pegylated interferon alfa-2b 		maintenance
- 	poor responders randomized to continue with 		MAP or MAPIE
**AOST0121**** – metastatic OS (bone or bilateral lung):** MAP induction, followed by resection, followed by MAPIE +/- trastuzumab (depending on HER2 expression status)

## OSTEOSARCOMA

**	****Outcome**
- 		Approximately 70% of patients with localized 			osteosarcoma of the extremity will survive without 		evidence of recurrence (Meyers et al., *J Clin Oncol* 1992; 		10:5).
- 		<30% of patients presenting with metastatic disease will 	be cured of their disease; <15% if bone metastases or 	bilateral pulmonary metastases  (Meyers et al., *J Clin **	**	**Oncol* 1993; 11:449).

## OSTEOSARCOMA

**Complications/late effects of therapy**
**Surgical**
**	**Studies ongoing looking at functional outcomes for patients 	undergoing limb salvage vs amputation (Nagarajan et al., *Br **	**J Cancer* 2004; 91:1858)
**Chemotherapy**
- 	Anthracycline-induced cardiomyopathy; 7.5% incidence 		following approx 300 mg/m2; may arise > 15 years post 	therapy; role of dexrazoxane under investigation (Paulides 	et al., *Pediatr Blood Cancer* 2006; 46:489)
- 	Cisplatin-induced ototoxicity; 11% of patients (Meyers et al., *J **	**Clin Oncol* 2005; 23:2004)

## EWING SARCOMA

**Definition/Incidence**
- 	1.  	Represents a family of tumors including Ewing 			sarcoma of bone, extraosseous Ewing sarcoma, 		and peripheral neuroectodermal tumor (PNET) 			of bone or soft tissue
- 2.  	2nd most common bone tumor in children occurs 	most commonly in the second decade of life
- 	3. 	Approximately 110 new cases each year in 			children under 15 and 200 new cases in children 		and adolescents under 20
- 		           (SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)

## Ewing Sarcoma age-adjusted incidence rates by age group 

**Ewing Sarcoma age-adjusted incidence rates by age group **
**and race, both sexes, SEER 1975-95**

**Age (in years) at diagnosis**

**Average annual rate per million**

- (SEER Pediatric Monograph, NIH Pub. No.99-4649, 1999)

## Slide 45

## EWING SARCOMA

**EWING SARCOMA**

**Pathology**
- Undifferentiated small round blue cell tumor; must exclude lymphoma, NBL, RMS
- Ewing sarcoma defined as a primitive tumor without differentiation and PNET defined as a tumor possessing neural differentiation, showing rosettes and/or positivity for NSE or S-100
- CD99 antibody recognizes Ewing sarcoma/PNET but is not specific

## EWING SARCOMA

**EWING SARCOMA**

**Clinical presentation**
_**Primary Site**__	__	__	__	_
- Pain, +/- palpable mass
- May involve bone or soft tissues; diaphyses and central axis (47 -74%) involved more frequently than with osteosarcoma
- Most commonly: pelvis (23%), femur (18%), rib (13%)
- (Grier et al., *N Eng J Med* 2003; 348:694)

_**Systemic Involvement**_
- Symptoms:
- Fever; weight loss
- Pattern of spread:
- 20% metastatic at
- diagnosis (isolated lung
- [35%], bone [13%], bone
- marrow [7%])
- (Bernstein et al., *J Clin Oncol*
- 2006; 24:152)

## EWING SARCOMA

**EWING SARCOMA**

**Staging Workup (localized vs metastatic)**
- 1.  History and physical examination
- 2.	Plain films of primary
- CT/MRI of primary site
- CT of chest/CXR
- 5.	Bone scan
- 6.	Bone marrow aspirate and biopsy
- 7.	PET scan (under investigation)
- 8.	Blood tests; CBC, lytes, BUN, Cr, Ca, phos, uric 	acid, liver function studies, LDH, ESR
- 9.	Echo/EKG

## EWING SARCOMA

**EWING SARCOMA**

**Prognostic factors**
- 	**Extent of disease/stage;** metastatic disease 				unfavorable
**Primary site;** pelvis least favorable; distal bones and 		ribs most favorable
**Age;** younger patients (<10) do better
**Tumor size;** > 8 cm unfavorable
**Histology/degree of neural differentiation;** unclear
- 			(Grier et al., *N Engl J Med* 2003; 348:694)

## EWING SARCOMA

**EWING SARCOMA**

**Treatment philosophy**;
- 	a multidisciplinary approach must provide 	local control and systemic therapy
- 	Local control measures should not 		compromise systemic therapy because 		when treatment fails it is usually due to 		the development of distant metastatic 		disease

## EWING SARCOMA

**EWING SARCOMA**

**Local Control: Surgery and/or Radiation Therapy**
- 	No randomized studies comparing surgery and radiation therapy for 	Ewing sarcoma have been conducted
- Current trend favors surgery when possible; in IESS-1 21% of patients underwent surgery; in IESS-2 42% of patients underwent surgery; in IESS-3 61% underwent surgery (Nesbit et al., *J Clin Oncol* 1990; 8:1664, Burgert et al., *J Clin Oncol* 1990; 8:1514, Grier et al., 2003; *N Engl J Med*; 348:692)
- Combined surgical/radiation approach can be used if resection incomplete
- Definitive local control generally done after several weeks of chemotherapy
- Radiation doses generally 4500 – 5500 cGy

## EWING SARCOMA

**EWING SARCOMA**

**Systemic Therapy/Chemotherapy/SCT**
- All patients require chemotherapy
- Active agents include vincristine, cyclophosphamide, doxorubicin, dactinomycin, ifosfamide, etoposide, topotecan, and irinotecan
- Effective adjuvant chemotherapy has improved local control rates achieved with radiation to 85 - 90% in several studies
- PNET probably responds to the same chemotherapy agents used in the treatment of Ewing sarcoma of bone
- 	Role of SCT for high risk Ewing sarcoma still under 		investigation

## Survival on IESS-I

**Survival on IESS-I**

**    ****Trt 1 = VAC+Doxo, Trt 2 = VAC, Trt 3 = VAC +pulm RT**

- Weeks

- 	Nesbit et al., *J Clin Oncol* 1990; 8:1664-1674 (Fig 2)
- Reprinted with permission from the American Society of Clinical Oncology

## RFS on IESS-II

**RFS on IESS-II**

**Trt 1 = VAC+Doxo (high-dose intermittent schedule) **
**Trt 2 = VAC+Doxo (moderate-dose continuous schedule)**

- Weeks

- 	Burgert et al., *J Clin Oncol* 1990; 8:1514-1524 (Fig 2)
- Reprinted with permission from the American Society of Clinical Oncology

## EFS on IESS-III

**EFS on IESS-III**

**Standard therapy = VAC + Doxo**
**Experimental therapy = VAC + Doxo + Ifos/Etop **

- Years

- 	Grier et al., *N Engl J Med* 2003; 348:694-701 (Fig 1)
- Copyright © 2003 Massachusetts Medical Society.  All rights reserved.

## EWING SARCOMA

**Recent COG Protocols**
**AEWS0031**** – localized Ewing sarcoma**:  Randomization between standard 43 week VAdrC + Ifos/VP-16 arm vs 27-29 week interval compression arm
**AEWS0331 ****-  pulmonary metastases only**: Randomization between chemotherapy and HDC + SCT following induction chemotherapy
**AEWS02P1**** – metastatic Ewing sarcoma**:  Conventional therapy (VAdrC + Ifos/Etoposide) plus anti-angiogenic agents (vinblastine and celecoxib)

## EWING SARCOMA

**Complications/late effects of therapy**
**Radiation therapy**
- 	SMNs; estimated rate of 5-10% at 20 years; may be 		slightly higher than with other cancers; latent 		period of 10 yrs for carcinomas/sarcomas and 		5 yrs for leukemias (Fuchs et al., *Clin Orthop Relat **	**	**Res* 2003; 415:82)
- 	Bone growth arrest/muscular atrophy
**Chemotherapy**
- 	Anthracycline-induced cardiomyopathy; 7.5% 			incidence following approx 300 mg/m2; may 		arise > 15 years post therapy (Paulides et al., 		*Pediatr Blood Cancer* 	2006;46:489)
- 	 Ifosfamide-induced Fanconi renal tubular dysfunction

**EWING SARCOMA**

## Sarcomas: Cellular OriginMesoderm Germ Layer

**Mesoblast**
- Undifferentiated Sarcoma

- _Myoblast_
- Rhabdomyosarcoma
- Leiomyosarcoma

- _Lipoblast_
- Liposarcoma

- _Fibroblast_
- Fibrosarcoma
- Malignant peripheral nerve sheath tumor
- Hemangiopericytoma

- _Osteoblast_
- Osteosarcoma

- _Uncertain_
- Ewing sarcoma
- Synovial sarcoma
- Alveolar soft part sarcoma
- Malignant fibrous histiocytoma
- Epithelioid sarcoma

- _Chondroblast_
- Chondrosarcoma