Whole brain radiation therapyMedical editor Alexander Fosså MD
Oslo University Hospital
Lymphomas primarily occur in the CNS or affect the CNS as part of a generalized disease.
Radiation treatment of intracerebral, intraspinal, or meningeal/cerebrospinal fluid lymphoma manifestations may be appropriate as one or more treatment alternatives. This treatment is often part of a multimodal approach in combination with systemic and intrathecal/intraventricular chemotherapy.
Radiation treatment can be given to the entire CNS axis (brain, spinal cord, and cerebrospinal fluid space down to the S1/2 level, sometimes including both eye sockets and optical nerves) or only the brain with surrounding liquor space. Due to the diffuse growth and tendency for meningeal involvement of lymphomas, whole brain radiation is almost always indicated. Radiation of only parts of the brain or a boost to parts of the brain is normally not recommended.
Radiation therapy to cure the disease
Radiation therapy to the whole brain can be given as a part of multimodal curative treatment in:
- Primary CNS lymphomas (PCNSL) - In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning , is uncertain. At the Oslo University Hospital, we use the protocol from Memorial Sloan Kettering Cancer Center. In older patients, a combination with chemotherapy often causes significant neurotoxicity, therefore radiation therapy is used with caution and preferably reserved for patients who do not achieve effect from chemotherapy, or for recurrence of the disease. For a multi-modal treatment arrangement for PCNSL, it is generally not recommended to administer radiation treatment to the spinal cord, even if lumbar puncture has shown more generalized meningeal spreading of tumor cells. If the eye ball is not known to be involved, it is not included in the radiation field. A new nordic protocol for PCNSL is under planning where radiation is not used as the primary treatment, for both older or younger patients.
- Treatment/prophylaxis of CNS manifestations for acute lymphoblastic leukemia and Burkitt's lymphoma - For treatment/prophylaxis of a CNS disease as part of treatment to cure acute lymphoblastic leukemia, radiation treatment may be included. It is often combined with CNS-directed chemotherapy/intrathecal treatment. It may be appropriate (but not obligatory) to give radiation to the spinal cord simultaneously.
- Treatment/prophylaxis of CNS manifestation from several other malignant lymphomas: In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of the treatment plan to cure the disease. If there is meningeal spreading or findings in the spinal cord, it may be appropriate to add radiation treatment to the spinal cord.
Palliative radiation therapy
- For palliative radiation therapy, the method generally follows the same guidelines as for curative treatment, with individual adjustments.
In younger patients (< 60 years), radiation to the brain is often included in treatments where CNS-directed chemotherapy is followed by radiation therapy. The role that radiation therapy plays, as well as the total dosage and fractioning, is uncertain.
The curative schedule after chemotherapy with hyperfractionated treatment may have possible advantages. At Oslo University Hospital (Radiumhospitalet), the treatment schedule from MSKCC is used. In elderly patients, a combination of chemotherapy of this kind often causes significant neurotoxicity, and radiation therapy should be used with caution, preferably reserved for patients with poor response to chemotherapy or with recurrence.
For multimodal treatment for PCNSL, radiation therapy is normally not given to the spinal cord, even if lumbar puncture has shown more generalized meningeal scattering of tumor cells. If there is no known involvement of the bulb of the eye, the eye is not included in the radiation field. A new Nordic protocol for PCNSL is planned where radiation therapy will not be used during primary treatment, either for elderly or younger patients.
For treatment/prophylaxis for CNS disease as part of the curative treatment arrangement for ALL/lymphoblastic disease, lower doses are preferably used (18–24 Gy in 1.8–2 Gy per fraction), often in combination with CNS-directed chemotherapy/intrathecal treatment. Simultaneous radiotherapy to the spinal cord is often given (but not obligatory).
For other malignant lymphomas with CNS involvement, radiotherapy to the brain is considered, either as part of a curative or palliative plan. In cases of meningeal scattering of tumor cells or findings in the spinal cord, radiation therapy of the spinal cord may also be given.
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.
For radiation therapy to the whole brain without the spinal cord, the patient lies supine and is immobilized with a mask.
There should be slight flexion of the neck.
The position of the lenses can be marked with a piece of lead at the lateral edge of the orbita.
If fields are to be joined toward the spinal cord, the patient must be immobilized as described in the procedure for the total CNS axis.
- Cranial and lateral limits are outside the patient in the air.
- For modeling of the caudal borders on the simulator, it is important to include the base of the skull with branches of the cranial nerves as these are covered by the meninges to an extent (be especially aware of the lamina cribrosa). Usually, the brain stem is included farther down than for solid tumors. At the same time, the lenses should be blocked and the eyes as much as possible. For curative treatment, it must sometimes be accepted that tolerance doses for lenses are exceeded.
- Field shaping from side to side including eye blocks will obtain a "German helmet" configuration and reaches farther down the cervical column with good margins to the spinal canal (for example to discs C2/C3 or C3/C4 level).
- Orbital cavities can be included if there is known lymphoma involvement of the eye ball or optic nerves.
- For treatment which is planned with CT, the entire brain is modeled including the outer liquor space as CTV. For practical purposes, the inside of the bone in the cranium and the spinal canal is the limit.
- Be very precise when contouring the skull. The dura sacs which follow the nerve roots in the different foramens must be included in the CTV. CTV includes also the upper cervical column such that the field limits later remain at levels with for example C3 or C4.
- The orbital cavities may be included in CTV if there is known lymphoma in the eye ball or optic nerves.
- Field shaping will be two opposing lateral fields. Field shaping should be checked with regards to skeletal structures at the base of the skull before approval just to ensure good coverage of the lamina cribrosa and other foramens in the cranial nerves.
CT dosage plan
Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and the protocol is followed. For a treatment plan intended to cure the disease the following is recommended:
For PCNSL, Oslo University Hospital follow the protocol from MSKCC, which is 1.80 Gy x 25 for patients under 60 years subsequent to 5 courses of high-dose MTX, if the patient is not in complete remission. For involvement of the eye, these are included with 1.8 Gy x 20. If the patient is in complete remission, 1.2 Gy x 30 is given with 2 fractions daily. Patients over 60 are not routinely given radiation therapy.
For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12.
For other lymphomas, fractionation is determined individually.
For palliative treatment, 3 Gy x 10 is most often used.
Organs at risk
There is a risk of short-term nerve toxicity causing dizziness, nausea, headache and long-term neuropsychiatric changes. Antiemetic treatment should be considered before starting treatment. Long-term neuropsychiatric changes may depend on multiple factors such as age and if chemotherapy is administered simultaneously (especially high-dose MTX). Those at the highest risk are patients over 60 years who receive whole brain radiation after high-dose MTX.
Lens of the eye
A dose over 4-6 Gy must often be accepted to obtain adequate coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.
The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children.