# Radiation Oncology/Sarcoma/Ewing's sarcoma

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Ewing's Sarcoma

## Epidemiology

* Tumor of neuroectodermal origin, part of the Ewing Sarcoma Family of Tumors
* Usually presents in adolescents (40%), but 30% in <10 year olds
* Second most common bone tumor in children, after osteosarcoma
* Approximately 225 cases annually in U.S.
* Primarily in white children; black and Asian children rarely affected

## Clinical Presentation

* Localized pain and swelling
* Systemic symptoms (fever, low appetite, weight loss) in ~30%
* Distribution
** Lower extremity 40-45% (femur 22%, tibia 11%, fibula 9%)
** Pelvis 20-25%
** Chest wall 15-20%
** Upper extremity 10% (humerus 10%)
* Metastatic disease (20-25%)
** Primary spread is hematogenous
** Most commonly to lungs, bones, BM, soft tissue, brain, spine
** Bilateral bone marrow biopsy part of staging, regardless of tumor size

## Radiologic Findings

* Should include bone scan, CXR, CT or MRI of primary, CT of chest
* Plain films show "onion skinning" (soft tissue mass growing out from the bone, giving rise to multilamellated periosteal reaction) vs "sunburst" pattern seen in osteosarcoma.

## Staging

* Please see the bone tumors staging page

## Pathology

* Small round blue cell tumor, likely arising in the bone marrow
* Fusion between EWS gene and a partner gene which presumably dysregulates cell growth
** t(11;22) EWS-FLI1 (85%)
** t(21;22) EWS-ERF (10-15%)
** Other EWS fusions occur rarely (ETV1, E1AF, FEV)

## Prognostic factors

* Disease site: non-pelvic is favorable, with distal, ribs and other having the best prognosis. Pelvic site is unfavorable. Proximal sites are intermediate.
* Age: younger is favorable
* Size: >8cm is unfavorable
* Labs: anemia, elevated ESR, leukocytosis, and elevated LDH associated with worse prognosis
* Not prognostic: sex and time from onset of symptoms

## Treatment Overview

* Ewing's sarcoma is essentially an occult metastatic disease, and chemotherapy is the backbone of treatment
** Radiation alone had cure rate ~10%, with majority failing distally
* Chemotherapy is typically given for 12-15 weeks prior to local therapy
* Local control is imperative, either with surgery, or radiation therapy, or both
** No randomized studies comparing the two treatment approaches
** Surgery favored if complete resection is feasible without significant morbidity and functional loss
** Radiation favored for central lesions
* Radiation dose
** Doses >60 Gy result in unacceptable risk of secondary bone malignancies
** Doses <40 Gy have unacceptable local failures
** Currently, ~45 Gy are given for microscopic disease and ~55.8 Gy for gross disease (DeVita 8th ed)
** Whole lung radiation used for consolidation after chemotherapy

## Chemotherapy regimens

* Standard 5-drug U.S. regimen (VCD + IE): vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide x48 weeks
* Original IESS regimen (VAC): vincristine, actinomycin D, cyclophosphamide
* VAC + ADR - vincristine, actinomycin D, cyclophosphamide + adriamycin

## Radiation
### Localized disease

* St. Jude (1978-88) -- used chemo before surgery
** Prospective, non-randomized. 60 pts. Localized osseous Ewing's.
*** Induction chemo (ACx5) -> Resection (if possible) -> RT with concurrent chemo -> more chemo (total 57 wks).
*** RT to initial (pre-chemotherapy) osseous tumor and residual soft tissue tumor extension. 3 cm margins. No RT given if resection with negative margins. 35-41 Gy for positive margins. 35 Gy for those with CR after chemo. 50.4 Gy for those with residual tumor after chemo or a tumor >8 cm initially. 1.5-1.8 Gy/fx. Chemo consisted of VCR/DAC during RT, followed by CYC/ADR and VCR/DAC.
** PMID 1938559, 1991 — "Ewing's sarcoma: local tumor control and patterns of failure following limited-volume radiation therapy." Arai Y et al. Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1501-8.
*** 5-yr EFS 59%, similar to other studies. 64% achieved CR to induction chemo. LC 68% at 5-yrs. LC depended on tumor size, +/- 8 cm.
* POG 8346 (1983-88)
** Randomized. 178 pts. Osseous Ewing's only (excluded PNET and extraosseous).
*** Induction chemotherapy: CYC/ADR x 5.
*** Assess response:
    If PD, XRT and salvage chemo
    If CR/PR and tumor involved expendable bone (proximal fibular, distal 4/5 of clavicle, body of scapula, iliac wing, ribs), had surgery. Received post-op RT for microscopic or gross residual disease.
    If not receive surgery, received 55.8 Gy RT and randomized to whole bone RT (39.6 Gy + boost with 2 cm margin) vs a tailored, involved field (same as boost).
*** During RT, received VAC chemo followed by weekly VCR. Maintenance chemo given for a total of 50 wks.
** PMID 9747829, 1998 — "A multidisciplinary study investigating radiotherapy in Ewing's sarcoma: end results of POG #8346. Pediatric Oncology Group." Donaldson SS et al. Int J Radiat Oncol Biol Phys. 1998 Aug 1;42(1):125-35.
*** 5-yr LC for resected tumors was 88% vs 65% with RT alone. No difference in LC between those randomized to whole bone vs involved field. LF was in-field in 62% vs outside in 24%.
** Conclusion: Most failures are systemic rather than local. Thus, interpretation of local failures is difficult due to competing risks.

### Disseminated disease

* EURO-EWING 99 (1998-2006) PMID 19924786 -- "The value of local treatment in patients with primary, disseminated, multifocal Ewing sarcoma (PDMES)." (Haeusler J, Cancer. 2010 Jan 15;116(2):443-50.)
** Retrospective. 120 patients. Local treatment of the primary with surgery 22%, surgery + RT 17% or definitive RT 33%. Local treatment of mets surgery 5%, surgergy + RT 7%, definitive RT 27%. No local therapy in 27%
** Outcome: 3-year EFS 24%; by modality surgery 25% vs surgery + RT 47% vs RT 23% vs no local therapy 13% (SS). 3-year EFS if treatment of primary and met 39% vs either primary or met 17% vs no local therapy 14% (SS)
** Conclusion: Local therapy of involved sites important for patients with disseminated Ewing sarcoma and should complement systemic treatment whenever possible

## Intergroup IESS Trials

* IESS-III (1988-92)
** 518 pts. Ewings's, PNET of bone, or primitive sarcoma of bone. Allowed both localized and metastatic (23%).
*** Randomized to VAC+ADR or VAC+ADR alternating with ifosfamide and etoposide.
*** Chemotherapy was given q3weeks x 17 courses, total of 49 weeks. At week 12, radiation therapy or surgery was performed. RT was 45 Gy to initial tumor volume (with 3 cm margin) + 1080 cGy boost = 5580 cGy. For those undergoing resection, RT was to 45 Gy for microscopic residual (with 1 cm margin).
** PMID 12594313, 2003 — "Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone." Grier HE et al. N Engl J Med. 2003 Feb 20;348(8):694-701.
*** For non-metastatic pts, 5-yr EFS 69% vs 54% for VAC+ADR+IE vs VAC+ADR; RR=1.6. 5-yr OS 72% vs 61%; RR=1.6. Greater reduction in LR than in distant mets. Greater benefit for large primary tumors or pelvic tumors. For pts with mets, no difference between regimens: 5-yr EFS 22% and OS 34%.
** Conclusion: improved survival with addition of ifosfamide and etoposide (in non-metastatic pts).
* IESS-II (1978-82)
** 214 pts. Localized, non-pelvic Ewing's sarcoma of bone.
*** Randomized to VAC+ADR as high-dose intermittent regimen or as moderate-dose continuous regimen (as per IESS-I). RT given in both arms for all pts except those with resection with negative margins.
*** Chemotherapy given q3weeks (high dose intermittent) or weekly (continuous). High-dose: VA-VC x 6, then VD-VC x 7. Continuous: VC x 6, then VD-VC4-VCA x 7. RT at beginning of chemo.
** PMID 2099751, 1990 — "Multimodal therapy for the management of nonpelvic, localized Ewing's sarcoma of bone: intergroup study IESS-II." Burgert EO Jr et al. J Clin Oncol. 1990 Sep;8(9):1514-24.
*** Median f/u 5.6 yrs. 5-yr DFS, RFS, and OS 68% vs 48%, 73% vs 56%, 77% vs 63% for high-dose vs continuous. LR in only 9%.
** Conclusion: improved survival with more aggressive chemotherapy.
* Intergroup Ewing's Sarcoma Study IESS-I (1972-1978)
** 342 pts. Localized Ewing's sarcoma of bone, previously untreated. 7 pts treated with amputation were not randomized but were entered on treatment 1.
*** Initially group I institutions randomized to +/- VAC chemo. Changed protocol in 1973 because it was realized that adjuvant chemotherapy was necessary.
*** Randomized 3:2 to 1) RT to primary plus VAC + Adriamycin or 2) RT plus VAC -- group I institutions
*** Randomized 3:2 to 3) RT to primary plus VAC and bilateral pulmonary RT (BRP) or 2) RT plus VAC (same as above) -- group II institutions
*** Chemotherapy given x 6 weeks. Vincristine and cyclophosphamide given weekly and adriamycin given with the last dose. After 6 weeks rest, pts had a 7 week course of continuation therapy that consisted of dactinomycin IV x 5 days followed 9 days later by VCR and cyclophosphamide weekly x 5 weeks. For treatment 1, adriamycin given with the last course in the 7th week of each course.
*** RT treated the entire involved bone to 45-55 Gy (dose depends on age), followed by 10 Gy boost to gross radiographic tumor + soft tissue mass with margin. For pts receiving lung RT, 15-18 Gy given at 150-180 cGy/day.
** PMID 7029293, 1981 — "Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: an Intergroup Study." Nesbit ME Jr et al. Natl Cancer Inst Monogr. 1981 Apr;(56):255-62.
** PMID 2213103, 1990 — "Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study." Nesbit ME Jr et al. J Clin Oncol. 1990 Oct;8(10):1664-74.
*** Median f/u 6 yrs. 5-yr RFS treatment 1 - 60%, 2 - 24%, 3 - 44%. Similar trend for OS. Worse survival for pelvic sites. No evidence of difference among treatments for pelvic sites. 15% LR overall. DM in 30%, 72%, and 42%. BPR was not effective in preventing lung mets.
** Conclusion: improved survival with addition of Adriamycin to VAC.

## Risk of Second Malignancy

* St. Judes; 1996 PMID 8874344 -- "Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas." (Kuttesch JF, J Clin Oncol. 1996 Oct;14(10):2818-25.)
** Retrospective. 266 patients with Ewing's sarcoma. Median F/U 9.5 years (3-30)
** 16 second malignancies (10 sarcomas, 6 others). Median latency 7.6 years (3.5 - 25.7)
** 20-year cumulative incidence: 9.2% for any malignancy, 6.5% for sarcoma
** Dose-response: none in <48 Gy, 130/10,000 for >60 Gy
** Conclusion: Overall risk of 2nd malignancies similar to other pediatric tumors. RT dose-dependency justifies modification in approach to reduce radiation doses