Total Body IrradiationMedical editor Alexander Fosså MD
Oslo University Hospital
Total Body Irradiation (TBI) is variation of radiation therapy where the entire body is the target volume. The treatment is a challenge geometrically, dosimetrically, and logistically.
Malignant diseases originating from myeloid and lymphoid cells may be appropriate for TBI for two reasons. The neoplastic cells are usually relatively sensitive to radiation and must generally be considered a systemic disease.
The doses administered for TBI are very limited mainly due to acute toxicity of bone marrow and lungs, but this is usually surmounted by subsequent transplantation of hematopoietic stem cells. This limits the use of TBI considerably.
The treatment arrangement requires a high degree of cooperation from the patient. TBI in children requiring general anesthesia consitutes a special problem.
- TBI is used today mainly as a step in conditioning of hematopoietic stem cell tranplantation for myeloid and lymphoid neoplasias and related conditions. For autologous or syngeneic stem cell transplantation, the antitumor effect of radiation therapy is the intended effect, usually together with chemotherapy. Irradiation given in adequate doses for an allogeneic stem cell transplantation will also suppress the patients immune system such that the danger of rejection (host versus graft reaction, graft rejection) of the allogeneic stem cells is reduced. For a traditional stem cell transplant, doses higher that 9 Gy are given. Considering the danger of radiation pneumonitis, traditionally the most serious side effect of acute toxicity from TBI, it has been shown that fractionated treatment with 1.2-2 Gy per fraction given 1-2 times daily is preferred over single fractions above 9 Gy, and the total dose for fractionated treatment can be increased. The dose rate varies between 0.05–0.1 Gy/min (low dose rate) to 0.5–0.7 Gy/min (high dose rate) and also plays an important radiobiological role. The most common conditioning regimen utilizing TBI at Oslo University Hospital consists of 13 Gy with fractionation in 1.3 Gy x 10 with two fractions daily at a low dose rate followed by cyclophosphamide 3 g/m2 daily for two subsequent days (total 6 g/m2).
- TBI has a possible place in conditioning of allogenic stem cell transplantation with reduced conditioning (mini-allo transplantation). Here, TBI is given in lower doses, usually in one fraction but doses far under 8 Gy. The purpose of TBI for a mini-allo is mainly to suppress the patient's remaining healthy immune system to prevent rejection of the allogeneic stem cells. The most commonly used regimen containing TBI at Oslo University Hospital is the Seattle regimen where TBI is given in one fraction of 2 Gy together with fludarabine.
- Use of TBI as part of conditioning before a stem cell transplantation must be a considered individually. The most common indications for TBI today are part of conditioning for allogeneic stem cell transplantation for certain patients with acute leukemias, myelodysplastic syndrome and anaplastic anemia. TBI is used rarely today for autologous stem cell transplantations where conditioning regimens consisting of chemotherapy alone are mostly used.
- Low-dose TBI (less than 2 Gy) given as a single fraction or in fractions of 0.05–0.15 Gy/fraction given in 2–5 fractions per week have previously been used without hematopoietic stem cell support, especially for chronic lymphatic leukemia and indolent lymphomas. Bone marrow suppression, especially thrombocytopenia, is considerable. This from of treatment is not used in Norway today.
The following definition is partly based on StrålevernRapport 2003:13, which is referring to ICRU50 and 62 as well as NACP.
Definitions of target volumes in accordance with the ICRU (International Commission on Radiation Units and Measurements)
|GTV (Gross tumor volume)
Gross palpable or visible/identifiable area of malignant growth.
|CTV (Clinical target volume)
Macroscopic tumor volume including any remaining tumor tissue.
|ITV (Internal Target Volume)
Volume containing CTV and internal margin to allow for internal movements and changes to CTV.
|PTV (Planning Target Volume)
||Geometric volume containing ITV with set-up margin taking into accound patient movements, variations in patient positioning, and field settings.
||Normal tissue senstive to radiation that may significantly affect planning and/or dose.
PRV (Planning organ-at-risk volume)
|Geometric volume containing risk volume with set-up margin.
|TV (Treated Volume)
||Volume within an isodose surface considered sufficient based on the treatment intention.
|IV (Irradiated Volume)
||Volume-to-receive dose that is of significance with regard to normal tissue tolerance.
|CI (Conformity Index)
||Relationship between the planning target volume and treated volume (PTV/TV).
The field limit is defined as the required course for the 50% isodose curve outside the target volume to give a therapeutic isodose (90% isodose) to the target volume which is intended to be treated. The distance from 90-50% of the isodose (penumbra) depends on multiple conditions and is typically 5-7 mm.
Definition of margins
For radiation therapy of malignant lymphomas, a table is formulated which summarizes standards used for GTV, margins for CTV and ITV, as well as shaping of field limits.
|Target volume for radiation therapy
||Current tumor for indolent NHL stage I/II1, original tumor(before chemotherapy minus balloon effect) for aggressive NHL stage I/II1 and HL stage I/IIA
Residual tumor for aggressive NHL stage II2/IV and HL stage IIB/IV
||GTV + 2 cm craniocaudal for limited disease/short chemotherapy
GTV + 1 cm craniocaudal for residual tumor from extensive disease after full chemotherapy
GTV + 1cm in transverse plane
CTV should always contain the entire lymph node region in the levels to be radiated (limited for lungs and bone, if there is no suspicion of infiltration).
CTV may for indolent NHL stage I/II1 contain the nearest unaffected lymph node region or parts of it.
||CTV if internal movement can be ignored (CNS, ENT)
CTV + 1 cm craniocaudal and + 0.5 cm transverse in the mediastinum
CTV + 2–3 cm in mesentery
CTV + 0-0.5 cm transverse retroperitoneally
Not routinely defined
||ITV + Setup margin and penumbra (1.2 cm)
The field limits should be such that later junctions are simple (on one side of the spine, in vertebral discs etc.)
The radiation field which surrounds the macroscopically involved lymph node only with margin. Thus far, this definition is rarely used in Norway, but increasingly in international studies.
Radiation field which includes the involved macroscopic lymph node region or organ with margin. After limited chemotherapy for localized lymphomas, the originally affected macroscopic area is used as a basis for field shaping (with the exception of the balloon effect). For residual changes after full chemotherapy in advanced stages, the residual tumor is usually used as a basis (multiple exceptions). What are adequate margins from the macroscopic tumor to the field limit depend on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3-6 CHOP-based treatments, 2-4 ABVD or equivalent), the margins from the initial extension to the field limit should be 3-4 cm in the vertical direction, from the initial extent and 2 cm in the transversal plane (with the exception of the balloon effect). For residual changes after full chemotherapy for advanced NHL and HL and relatively little internal mobility, then 2 cm from the residual tumor to the field limit is used. Wider margins must be considered in areas of large internal mobility (abdomen, structures near the diaphragm). Regularly, for nodal involvement, the target volume includes the entire lymph node region in the transversal plane for those levels included in the field.
Traditionally, the entire involved lymph node region has been included completely in the craniocaudal direction (direction for lymph drainage). This provides a recognizable geometric field (parts of mantle field or inverted Y-field) which has advantages for standardizing, reproducibility, later junctioning etc. The lymph node regions, as they are defined in the Ann-Arbor classification, represent no functional biological unit and are not intended as a basis for radiation therapy. In this way, it is natural to see the regions as coherent in the vertical direction of the lymph drainage and to use margins to the involved lymph nodes to avoid radiation of entire regions (for example neck/supraclavicular region, mediastinum, and retroperitoneum). Parts of the neighboring regions may be included to compensate for the minimum margins given above. Field shaping should still follow the geometric forms as much as possible, making later field junctioning easier and to avoid border recurrences in areas which are difficult to re-irradiate.
For extranodal lymphomas/organ manifestations, the entire organ is sometimes included (thyroid gland, stomach, brain, spinal cord). Internal mobility must also be taken into consideration here, for example stomach movement, movement of lungs etc. For several organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidney), and the fields/doses must be adapted accordingly.
This concept is utilized for fields which include macroscopically involved regions/organs and lymph node regions where it is assumed there is microscopic disease. This may be the nearest macroscopic normal region or multiple, more distant areas. The concept was developed for Hodgkin's lymphoma at a time when radiation therapy was the only modality used and was given to large areas with assumed microscopic disease on one or both sides of the diaphragm (mantle field, paraaortal field, inverted Y-field). For today's purposes, the concept is not of much benefit. For localized stages of low-grade NHL, where radiation therapy is given alone with the intention of curing the disease, we have chosen to include the nearest unaffected region in the radiation field, that is, a "minimally extended field." However, this is not practiced at all radiation therapy centers.
Before treatment, planning around the stem cell transplantation must be finalized.
- The indication for hematopoietic stem cell transplant must be determined by a team with experience in this treatment. The general health status of the team and complicating comborbidity must also be evaluated by the team.
- Stem cells must be available and ready for use by harvesting from the patient or a donor.
- Days before radiation therapy starts, plans must be made for admission, transport to and from treatment, days for chemotherapy, and planned stem cell reinfusion, as well as necessary follow-up during the aplasia period.
- Due to the complexity of the procedure, morbidity and mortality, adequate information for the patient and loved ones from the oncologist responsible for treatment is very important.
- A close dialog between the hematologist and oncologist is also very important.
TBI is complicated in both theory and practice. This is a very simplified summary of the how it is implemented.
In order to to have room for the entire body in one radiation field, the distance from the source to the skin must be increased, which can be achieved by setting the source to irradiate horizontally such that it is as far as possible from the wall in the bunker. The patient can be positioned 3-4 m away in the other end of the bunker in the desired position. The patiet can lie, stand, or sit in the fetal position depending on the distance allowed by the source whether irradiating with opposing anteroposterior field, lateral field, or a combination.
At Oslo University Hospital, the patient lies down sometimes with slightly angled legs in a bed. Half-way through each fraction, the bed is turned 180 degrees. The patient is also changed for every other fraction between laying supine and laterally. The arms are positioned such that they compensate for 'missing' soft tissue in the lungs in the fractions where the lungs are not shielded. The lungs are shielded for fractions 3, 7, of 10 and the patient keeps their arms away from the anterior planes of the lungs during these fractions. Oslo University Hospital uses a moulded mat of VacFix® to give the best possible reproducible lateral position. To achieve full coverage of the skin, a device must be used that functions as a bolus (blanket of tissue-equivalent bolus) or, as at Oslo University Hospital, a shield of plexiglass in a suitable position between the patient and the source generating scatter electrons.
Simulation of TBI is done 1-2 weeks before treatment in a procedure known as a test shot or test fraction. The entire procedure can take up to 1.5 hours.
A VacFix® is made to stabilize the patient in the lateral position and is used for the fractions where the lungs are to be blocked out (fraction 3 and 7 of 10).
The patient will then complete a simulated treatment with a low dose (<0.1 Gy) with a series of dosimeters placed at relevant measuring points on the body.
X-ray images are taken of the patient in the lateral position in the VacFix® for contouring of lung blocks.
The treating doctor will draw the lung blocks on the X-ray image. These are drawn analogous to the lung blocks for a mantle field. Blocks follow the lower border of the fourth rib cranially, laterally 0.5–1 cm into the lung tissue, caudally turning 0.5–1 cm above the diaphragm, and medially 1–1.5 cm from the mediastinum/hilum into the lung tissue. The hilar contours are most visible on the right side. On the left side, the contours are drawn equivalent so that part of the lung in front of the heart and parts of the stomach are under the block.
- During treatment, the patient is admitted to the hospital at the latest the day before treatment. The patient should begin with antiemetic treatment (ondansetron 8 mg x 2 or equivalent) and fluids before the first fraction the evening before starting treatment. A serotonin antagonist is supplemented during treatment with other treatment, if necessary.
- Fluids and nausea treatment is constant during TBI treatment. Standard treatment for adults is 2 L NaCl 0.9 % and 2 L glucose 5 %, alternating with 40 mmol KCl per 1000 ml fluid.
- During this treatment, the patient will start serious bone marrow aplasia and should be handled both at the ward and treatment unit as extra susceptible to infection.
- The radiation bunker is washed before each afternoon fraction, and the device the patient is in contact with is washed with alcohol before treatment. The patient will be the last patient of the afternoon and the first patient the following morning.
- Additional protection for infection may be necessary such as isolation for neutropenia and the danger of infection upon contact.
- For fractions 3 and 7, the treating doctor will check and approve the positioning of the lung blocks.
Side effects of TBI must be considered in accompany with other elements of conditioning (chemotherapy) and the type of stem cell donor. For an allogeneic stem cell transplant and a mini-allo transplant, toxicity is more significant and more complex, especially due to graft versus host complications.
The most significant acute side effects:
Nausea and vomiting
Affect most patients, also after the first fraction. Antiemetic prophylaxis before the first fraction, preferably the evening before, is recommended.
Affects most patients and can be serious. Opiates may be necessary for pain treatment. Diarrhea may be a consequence of radiation-induced intestinal mucosa changes.
Hair and nail growth
Radiation therapy together with chemotherapy will cause reversible alopecia. Nail growth will stop and new nails may grow in replacement.
Fall of white blood cells will increase the risk of infections necessitating isolation of the patient during the aplasia period. Together with chemotherapy and immunosuppressive treatment, TBI may cause serious infections. Fall in platelets may lead to bleeding and require transfusions. Fall in red blood cells will cause anemia-related symptoms and require transfusions.
The most significant long-term side effects:
For certain regimens of TBI at Oslo University Hospital, dosing to the lungs is relatively low, but together with chemotherapy, injections and GVH, lung toxicity may occur.
Both women/girls and men/boys, the risk for sterility is considered very high with TBI with a total dose of 13 Gy, but this is not obligate for all patients. The risk depends most likely on multiple circumstances such as age, sex, total dose, and collective amount of chemotherapy.
Despite low doses, endocrine function should be monitored after TBI especially in children and adolescents.
Doses to the bone are low, but together with endocrine disturbances, growth disturbances may occur in children and adolescents.
The risk for a new malignant disease increases partly due to chemotherapy and radiation therapy, and partly due to necessary immunosuppressive treatment for allogeneic transplantations.