Radiation Oncology Synopsis

PEDS: Ewings Sarcoma

Background Demographics and Natural History

Ewing's sarcoma is the second most common bone tumor following osteosarcomas. It is most common among teens with a median age of 14-15 years. There are about 200 cases per year in the United States and the disease was first described in 1921, Ewing noted the disease was most common in the metaphyseal and diaphyseal regions of the long bones or in the flat bones. Ewings is associated with pain and fever.

Histologically, Ewings is one of the little round blue cells, appearing under the microscope as sheets of cells. Ewings is exquisitely sensitive to radiation. Ewings has a slightly earlier onset in young girls, corresponding with an earlier age of puberty than boys, but both occuring more frequently during the "growth spurt."

Ewing's occurs more commonly in white males > 90% of all cases, and is rare in Asian or African descent.

Ewings originates in neuroectodermal tissue of embryonic origins.

Genetics and Associated Diseases

Ewings is associated with t(11:12) transformation in 90%. FLI1:EWS22 Other minor translocations include t(21,22) and t(7,22).

In the t(11:12) transformation of Ewings, an exon fusion of 7 of EWS and 6 of FLI1 is found in 60% of the cases and is associated with a lower proliferative rate and better prognosis.

Pathology

Ewings is also associated with PNET, malignant melanoma of the soft tissues, and desmoplastic small round cell tumors. Extra-osseous Ewings tumor of the chest wall is also known as an Askin Tumor. Askin Tumors are also considered PNETs of the chest wall or thoracic cavity. Other small round blue cell tumors include:

LEARN NMR mnemonic

Markers that differentiate Ewings from other small round blue cell tumors include:

Morphologically, Ewings appears as small round malignant cells with hyperchromatic nuclei and little cytoplasm. Cells are usually PAS positive (periodic acid Schiff stain indicating glycogen). Cells are uniformly vimentin positive, and frequently cytokeratin positive, indicating epithelia and neuronal origins. Ewings, as well as PNET have been linked to specific chromosomal abnormalities in 11 and 22 [t(11:22)] translocations. t(11:22) is detectable in 86% of Ewings, with a juxtapositioning of EWS:FLI1 genes. Ewings is NSE negative.

Prognostic Factors

A number of factors have been associated with poor prognosis:

About 25% of Ewings present with metastases at diagnosis. Metastases typically occur to the lung (40-50%) or bone (25-40%) and less commonly to the bone marrow (25%) and lymph nodes (< 10%)..

About 25% have localized disease at diagnosis, and about 40% have lung metastases.

Workup and Staging

Pain is the most frequent presenting symptom appearing in 96% of all cases. Swelling is evident in 63% of the cases. Fever appears in 21% and fractures in 16%. Radiologic imaging will frequenly show periosteal elevation (Codman's Triangle). Fever is a very poor prognostic sign.

Sites

The most common sites are:

In central tumors, the pelvis is more common (20%) than the axial skeleton at 12%.

General Workup

There is no staging system for Ewing's sarcoma. Tumors are either localized or they are metastatic. The classical presentation of the tumor is "onion skinning" on plain film radiographs. Codman's Triangle is an area of new periosteal bone as a result of periosteal lifting by underlying tumor. This is seen in both Ewings and in osteosarcomas.

The role of surgery and radiation is evolving. Initially radiation was the prime modality treatment, but concern for radiation therapy secondary malignancies and late morbidity led to increasing surgical intervention. Surgery is usually performed with smaller, more operable lesions and in "expendable" bones.

Expendable bones can be resected with minimal morbidity. The expendable bones are:


Treatment and Prognosis

The general Ewings Sarcoma treatment paradigm is:

Induction Chemotherapy : vincristine/Actinomycin D/Cytoxan (VAC) alternating with isfosfamide/etoposide (VAC/IE) → local therapy (either radiation or surgery) at week 12.→ further adjuvant chemotherapy to week 48.

In selection of local therapy, the general principle is to use surgery where possible, and post operative radiation therapy when necessary and whole lung irriadiation for lung metastases.

The German Cooperative Ewings Sarcoma Study (CESS/Sauer) reported high rates of local control and survival favoring surgical intervention. On review of the data, the high rate of local failure in the radiation group was attributed to a substantial number of cases with inadequate radiation fields. Sauer demonstrated equivalent outcomes in surgery and radiation therapy in CESS-81 in small lesions. Because of this, CESS initiated a radiation therapy quality assurance plan in 1984. CESS-86 showed a remarkable improvement in local control results with radiation compared to the previous trial.

CESS-86 studied 177 patients with localized Ewing Sarcoma treated with chemotherapy and radical surgery or surgery plus radiation (45 Gy) or radiation alone (60 Gy) with central review of radiation planning. The results were found to be comparable in terms of relapse free survival at 3 years:

If functional results are comparable, then concern for the potential for second malignancies in children treated with radiation or very young children with "expendable bone tumors would sway treatment toward surgery. High risk lesions might benefit from combined surgery and radiation.

Surgery

The role of surgery was expanded by MSKCC with overall disease free survival approaching 80% at 3.5 years. Locat treatment failure was reported in 21% with definitive radiation therapy and aggressive multi-agent chemotherapy. Mayo Clinic (Wilkins) reported 74% overall survival at 5 years with surgical cases compared with 27% in patients treated without surgery. Other reports have described improvement in local control with the addition of surgery. Unfortunately, these studies contained significant bias. Wilkins included in the "non-surgical" series, patients who did not receive chemotherapy with radiation and were compared with surgical cohort who did receive chemotherapy in R0 resections, clearly biasing results in favor of surgical cohorts. More balanced comparisons describe improvements in local control with surgery in extremity lesions, and Brown pointed out the role of selective use of surgery with distal and smaller lesions.

Chemotherapy

Early studies established multi-agent chemotherapy as useful in Ewings Sarcoma. VACA (vincristine, actinomycin D, cyclophosphamide and adriamycin) resulted in overall survival rates of 50 - 75% in localized Ewings. IESS-1 (1973-78) demonstrated the importance of combining alkylating agents and anthracyclines. IESS-2 (1978-82) showed that early and intensive chemotherapy combined with local treatment of the primary tumor was beneficial.

CESS-81 (German Cooperative Ewings Sarcoma Study/ Sauer -- 81 -85) used VACA chemotherapy for two cycles followed by local therapy followed by chemotherapy.. CESS-81 was not randomized, but its results demonstrated better local control with adjuvant therapy. Surgery alone showed an RFS5 of 43%, while adding post-operative radiation increased RFS5 to 68%. With its known problems of inadequate irradiation fields radiotherapy alone was high due to volume deviations. After central review of proposed radiation fields was instituted, local control improved with the radiation arm.

The response of the primary tumor to chemotherapy is an important prognostic factor. Tumor necrosis at resection after inductionchemotherapy

Radiation Doses and Techniques

Radiation doses are based on the nature of the radiation treatment: definitive (non-operable), post-operative for microscopic residual disease and lower doses for vertebral body involvement:

Radiation therapy doses:

  • Definitive: 55.8 Gy
  • Postoperative (microscopic/spill) 50.4 Gy
  • 45 Gy for vertebral body involvement
  • 55.8 Gy for gross residual disease.
  • 50.4 Gy to resected positive node beds

Volumes

Proper radiotherapy volumes are essential. Local control with radiation improved after general acceptance of a target volume encompassing the medullary cavity to moderately high doses. Herman Suit recommended dose to the entire bone with a boost to the GTV. He noted few instances of marginal or intramedullary recurrence with large fields and boost. Subsequently, reduced fields to exclude the opposite epiphysis have not demonstrated marginal recurrences not withstanding variable rates of local tumor control. The importance of adequate treatment volume and radiation quality cannot be over-emphasized. CESS-81 indicated excess rates of local recurrence due to poor quality radiation therapy.

Marcus reports adequate local control and few marginal misses with margins of 3 to 5 cm rather than the whole long bone. He noted the ability to spare bone in tumors > 8 cm was limited as a 4 cm margin would often amount to full bone irradiation.

POG 8346, included a study of appropriate radiation field size in 179 eligible children with localized Ewings Sarcoma. This study used induction chemotherapy followed by local treatment (surgery or radiation therapy) followed by additional chemotherapy. In the radiation arm, the local site was treated:

Current Recommendations for treatment volume determination mandate the use of MRI whenever possible to identify the extent of tumor. The entire bony abnormality and soft tissue mass are included as identified at diagnosis, before any treatment as the GTV.


Radiation Therapy Recommended Treatment Volumes:

  • GTV: all pre-treatment bone and soft tissue abnormalities
  • MRI imaging mandatory whenever possible for identification of bone and soft tissue extent of disease
  • CTV: GTV + ≥ 1.5 cm - 2 cm margin to cover potential occult tumor.
  • PTV: CTV + institution dependent planning target volume for setup, movement and dosimetry.
  • Exception: large soft tissue mass protruding into a body cavity at diagnosis with good response to chemotherapy allowing previously displaced normal tissues to return to their normal anatomic positions. The original bony abnormality is always treated.

  1. Bone Only Disease (definitive): treat pre-chemotherapy GTV + 2 cm margin (1.0 cm CTV + 0.5 cm PTV) to 55.8 Gy
  2. Bone with Soft Tissue Extension: treat pre-chemotherapy GTV + 2 cm to 45 Gy then pre-chemo bone GTV and post-chemo soft tissue extent+ 2 cm to 55.8 Gy.
  3. Post-operative setting: Treat preop, prechemotherapy volume (except pushing borders of lung, bowel + 2 cm to 45 Gy and then boost pos-op residual + 2 cm to 55.8 Gy. Data appears to support treatment encompassing the surgical incision and drains.
  4. Treatment is 3D conformal and IMRT with skin strip sparing in extremity treatment to avoid circumferential irradiation and late fibrosis and edema.

Indications for Radiation

Indications for post-operative radiation therapy include positive margins, tumor spill, and > 10% viable tumor after induction chemotherapy (i.e. a poor response to chemotherapy). Adequate margins per the COG/AEWS0031 Protocol are

The local failure rate for Ewings after definitive radiation, overall is around 5-25%. This is worse in pelvic disease, with local failures in the pelvis of 15-70%, worse with large (> 8 cm) tumors with local failure of 20%. In general for localized Ewings Sarcoma, the OS5 is between 60% and 80%.

Analysis of pre-operative radiation, post-operative radiation and definitive radiation treatment has been performed. Schuck performed a secondary analysis of CESS-81 and CESS-86 and EICESS 92, reviewing over 1000 patients. He found no difference between pre-operative radiation therapy with local failure at 5.3% and post-operative radiation therapy with local failure at 7.3%. He did find that definitive radiation therapy alone had significantly worse local control. This study is critiqued by noting a strong negativeselection bias against the definitive radiation therapy cohort There was no difference in local failure between radiation therapy alone and surgery plus post-operative radiation therapy in those cases where only partial resection could be achieved. Preoperative RT may improve local control if sub-total resection is deemed likely. (IJROBP 2003).

Surgery is preferred when there is a pathologic fracture, when expendible bones are involved, and when there is lower extremity in a child less than 10 years old.

POG 8346 studied Radiation field sizes (IJROBP 1998) in osseous Ewings patients receiving definitive radiation therapy after induction chemotherapy:

CESS-86 examined hyperfractionation The CESS-86 study randomized local osseous Ewings being treated with definitive radiation therapy to conventinal fractaion during a chemotherapy break or split-course hyperfractionated radiation concurrently with chemotherapy. Local control was somewhat higher in thehyperfractionated arm at 86% from 76% but the differences were not statistically significant and could be explained by the treatment break.

Lung Metastasis

The IESS-1 study documented the efficacy of radiation therapy in low doses for controlling pulmonary metastases. The frequency of pulmonary relpase was lower and survival rates higher with prophylactic pulmonary irradiation when compared to triple agent chemotherapy alone.

For patients with metastatic Ewings Sarcoma to the lungs, local irradiaiton to the lungs and primary site are valuable in overall disease control.

A review of the CESS (German/Sauer) data from 1981 - 1992 examined 42 patients who presented with pulmonary metastases. One died of disease progression prior to treatment and the remaining experienced complete radiologic remission after chemotherapy (25) or had surgical resection of lung metastases (4). 22 patients received bilateral lung irradiation to a dose of 12 - 12 Gy, 6 had no further treatment after chemotherapy. Of the 10 patients with complete remission, 9 received lung irradiation and one had complete resection.

These data suggest that either whole lung irradiation or surgical resection(if < 5 metastatic sites) are treatment options in Ewings metastatic to the lungs.

The EICESS Secondary Analysis reviewed the outcomes of Ewings with either isolated lung metastases or combined lung/bone/bone marrow metastases who were treated ± whole lung irradiation. Whole lung irradiation was associated with improved survival in both cases. (Paulussen 1998 Ann. Oncol.)

A St. Jude retrospective study examined outcomes with isolated lung recurrences. This study found that patients with isolated lung recurrence who received whole lung irradiation had improved post-recurrence 5 year survival at 30% over 17% without whole lung irradiation. (2002 Cancer)

Whole lung irradiation doses are dependent on age:

Outcomes

There is a difference in patients with metastatic Ewings. Those with isolated pulmonary metastases or skeletal metastases have similar event free survival, but those who have both do worse.

Askin Tumors -- Special Considerations

Askin tumors are Ewings/PNET sarcomas of the rib/thorax. They are generally large tumors with extension to the pleural surfaces. Surgical resection must not be attempted prior to chemotherapy other than biopsy for tissue diagnosis. Chemotherapy should be given for large lesions to induce tumor shrinkage. In thoracic rib and soft tissue primaries, the post chemotherapy volume appears adequate to define the radiation volume. If surgery is done prior to chemotherapy, there may be positive margins, requiring a much larger volume of irradiated tissue with consequent increased morbidity.

Resection after chemotherapy may be adequate if the margins are clearly negative and there is a complete or nearly complete response to chemotherapy. If margins are positive or the tumor is not completely resected, local radiation is indicated to increase the likelihood of local control. Askin included the pleura in a significant number of cases in positive effusions because of a pattern of failure in the pleural cavity.

Toxicity

The 20 year risk of secondary malignancies in Ewings patients (St Jude data) demonstrated a 9.2% risk for any malignancy and 6.5% for sarcomas. There appeared to be a radiation dose response relationship for second malignancy with a relative risk of 40 if the radiation dose was > 60 Gy.

Radiation cystitis is known to be of concern in patients treated with ifosfamide and cyclophosphamide.

Radiation doses of > 20 Gy causes premature closure of the epiphysis.

Lymphedema is of high concern. Sparing a 1 - 2 cm skin stripe in the extremity or minimizing circumferential radiation to 20 - 30 Gy will help reduce this risk.

Fracture risk is associated with the degree of cortical disruption from disease, younger age and development of a second malignancy within the treated radiation field.