Radiation therapy (RT) is the primary mode of treatment to control local disease only if surgical resection is not possible.
Surgery is considered first as a primary modality to avoid the long term risk of second malignancy associated with RT.
RT may be given:
- Alone - high dose RT to ablate tumor in situation where surgery is impossible
- Post-operatively (for gross residual disease after surgery and microscopically positive margins)
- Pre-operatively to help reduce the risk of local recurrence
Advantages and disadvantages of PREoperative radiotherapy:
Evaluation of suitability for radiation treatment involves consideration of:
- The extent of disease and whether resection is possible without unacceptable morbidity
- Patient’s age and consequent risks of late morbidity from RT (normal tissue growth will be very reduced in young children by any significant amount of RT)
- Relationship of tumor to epiphyseal plates and joints – again leading to concern about subsequent growth
- Previous pathological fracture
- Functional outcome:
- Is it possible to spare an adequate strip of limb soft tissue?
Treating a large portion of the limb circumference with high dose RT is likely to result in lymphedema and poor vascular supply to the limb.
ES is highly responsive to RT. Local control of primary tumor site and long-term survival rate with radiation and adjuvant chemotherapy is 75-90%. Distal extremity primaries have better local control outcome than large central primaries.
Most protocols call for RT to be given after two months or so after the start of the chemotherapy. This means that some chemotherapy will be given concurrently with RT.
Adriamycin and other anthracycline agents are not given during RT as these drugs enhance the toxicity of treatment.
Accurate RT planning is very important. The CESS-81 study showed that the risk of local recurrence was increased with poor RT quality. Protocol modification with central review of RT planning improved the rates of local control.
POG-8346 studied the effect of whole bone RT plus a boost versus involved field RT in ES patients and there was no difference in event free survival between these two groups.
RT planning for the treatment of ES requires:
1. Immobilization for extremity lesions – An immobilization device ensures no movement and accurate treatment set up on repeated occasions. Also reference marks can be placed on the immobilization device to ensure reproducibility.
2. Accurate outlining of entire osseous and soft tissue extension of disease at diagnosis using MRI whenever possible and CT. Treatments are generally planned using CT simulators, but some RT departments have MR simulators.
Planning attempts to treat the tumor in a 3D conformal fashion (at a minimum) – so that the disease is treated with an adequate margin homogeneously while sparing surrounding normal tissue.
In the absence of a MR simulator, it is possible to use image fusion techniques to plan therapy. In this way the pre-chemotherapy volume identified on MR can be fused to the planning CT.
General rules for treatment planning:
- It is important to spare as much normal tissue as possible.
- Uniform irradiation to the entire vertebral width in a growing child is beneficial to avoid late effects such as scoliosis.
- For extremity lesions, sparing a strip of soft tissue laterally or medially to prevent lymphatic obstruction should always be attempted. Preferably a third of the limb circumference should be spared to reduce the risk of significant lymph edema in the long term.
Multiple convergent beams are used for therapy and the prescription point is usually at the isocenter.
Historically an adequate treatment volume included a margin of 3-5 cm beyond the soft tissue tumor extension and the entire medullary cavity. Guidelines in most protocols now call for a roughly 1- 2 cm margin on the original extent of the tumor.
In general terms the following is usually true for ES radiation therapy planning. The tumor can be treated using a "cone down technique".
PTV1 (covers larger initial volume to cover pre-chemotherapy volume) receives 45 Gy in 180 cGy fractions. Then PTV2 (covers residual disease after chemotherapy) receives a further 1080 cGy in 180 cGy fractions.
GTV = Gross Tumor Volume = Extent of disease at diagnosis – pre-chemotherapy and is disease found on examination and on radiological studies (MR imaging preferable).
GTV1= Extent of disease at diagnosis – pre-chemotherapy and is disease found on examination and on radiological studies (MR imaging preferable).
Outlining the extent of GTV1 may require modification for initial tumors that have a “pushing margin” into body cavities (ie, thorax, abdomen). If the tumor has responded to chemotherapy and normal tissues have returned to their natural position, GTV1 does NOT include the pre-chemotherapy volume where that volume extends into the cavity. Examples include tumors that indent the lung, intestine or bladder and come to occupy a more normal anatomic position following chemotherapy. The modified GTV1 includes initially infiltrative tumor and bone disease. The volume of tumor that previously extended into the body cavity is excluded from the GTV to avoid excessive normal tissue toxicity.
GTV2 = Residual visible or palpable tumor as assessed by CT, MRI, PET scan or
physical exam following induction chemotherapy with or without surgery.
CTV = Clinical Target Volume = GTV + 1.0 cm. This is the area that might potentially be involved by microscopic disease.
CTV1 = GTV + 1.0 cm. When lymph nodes are clinically or pathologically involved with tumor, the entire lymph node drainage chain should be included in the CTV.
CTV2 = GTV2 + 1.0 cm
PTV = Planning Target Volume = CTV plus a margin for day to day variability in set up and is usually 0.5 cm.
PTV1 = CTV1 + 0.5 cm
PTV2 = CTV2 + 0.5 cm
The exception to this is in the case of a large soft tissue mass protruding into a body cavity at diagnosis (such as ES arising in a rib) which has responded to chemotherapy and therefore normal tissues have moved back into their usual position. The volume of tumor that previously extended into the body cavity is excluded from the GTV to avoid excessive normal tissue toxicity - but the original extent of infiltrative tumor and bone disease are included in the RT volume.
Standard RT for gross disease requires a total dose of 5580 cGy at 180 cGy per day. Doses are lower for pre-operative disease.
Typical RT Doses for ES treatment:
Post-operative gross residual disease
|5580 cGy in 31 x 180 cGy fractions|
4500 cGy in 25 x 180 cGy fractions
|On current COG protocol pre-operative dose is 3600 cGy, but this is unproven.|
|Microscopic residual tumor surgery||Microscopic residual, >90% necrosis after chemotherapy: PTV2 receives 5040 cGy|
|Microscopic residual, <90% necrosis after chemotherapy: PTV1 receives 5040 cGy|
Chest wall tumor and positive pleural cytology
Calls for ipsilateral - that is the side that is involved by disease only - whole chest cavity/lung RT of:
Then a boost to the primary tumor - doses as above depending if surgical resection is planned.
Intergroup Ewing Sarcoma Study (POG-8850) recommended RT doses:
- Gross residual disease following attempt at surgical resection: 4500 cGy to the original disease site plus a 1080 cGy boost to gross residual disease
- Microscopic residual disease after attempt at surgical resection: 4500 cGy plus a 540 cGy boost to microscopic residual disease
- No RT if no evidence of microscopic residual disease following surgical resection.
RT for metastatic disease:
The European Intergroup Cooperative Ewing Sarcoma Studies showed that whole lung RT and megatherapy improved outcome in sub-groups of ES patients with metastatic disease. It is recommended that patients with bilateral pulmonary metastases at presentation should receive 1500 cGy in 150 cGy fractions to both lungs (even if there has been complete resolution after chemotherapy).
The management of bone metastases is controversial. It is generally recommended that metastatic disease be treated - as long as the RT volume is limited to less than 50% of the total bone marrow volume.