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Radiation therapy for the entire CNS axis


Medical editor Alexander Fosså MD
Oncologist
Radiumhospitalet
Oslo University Hospital

General

Lymphomas primarily occur in the CNS or involve 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 eyes and optical nerves) or only the brain with surrounding fluid 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.

Treatment is administered together or at the end of CNS-directed chemotherapy/intrathecal chemotherapy.

Indication

  • Total CNS axis (whole brain with spinal cord and dural sac) is most often irradiated as part of protocols for acute lymphoblastic leukemia, where it is included as part of CNS prophylaxis or treatment for a manifest CNS disease.  

 

In some patients with lymphoma in the CNS, radiation to the entire neuro axis is also used.

Curative radiation therapy

Radiation treatment of of the entire CNS axis can be administered as a segment of curative treatment for:

 

  • Treatment/prophylaxis of CNS manifestations of lymphoblastic/acute lymphoblastic leukemia and Burkitt's lymphoma 
  • 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 other malignant lymphomas - In other malignant lymphomas where the CNS is involved, radiation treatment to the brain is considered individually as part of a treatment plan to cure the disease. In the case of meningeal spreading or findings in the spinal cord, it may be appropriate to combine with radiation treatment of the spinal cord.

Palliative radiation therapy

  • Radiation of the total CNS axis is resource-consuming treatment with side effects. This treatment form is therefore not suited for palliative treatment in all patients with generalized lymphoma in the CNS. For palliative radiation treatment, the method for the radiation therapy itself follows the same guidelines as for curative treatment with individual modifications.

Definitions

Target Volume

 

 

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.
OAR (Organ-at-Risk) 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).

Field Limits

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
GTV 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

CTV 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.

ITV 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

PTV Not routinely defined
Field limits 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.)

Involved node

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.

Involved field

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 extention 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.

Extended field

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.


Preparation

  • Patient is immobilized in the prone position with the help of VacFix® with head support for the prone position and mask.  
  • The patient should lie as comfortable as possible with the shoulders as far down as possible. 
  • There should be a certain hyperextension of the neck to give the smallest possible dose to the mouth.
  • The spinal column should be as straight as possible. 
  • Sedation is usually necessary to carry out fixation, simulation, and treatment in children.

Implementation

Conventional simulation

Modeling of the field to the brain and spinal cord can be done with conventional simulation, but CT-based planning is recommended.

  • The whole brain is irradiated from side to side down to the caudal border of C3 or C4 (depending on shoulder position, see other chapter). It is very important to be precise with adjustment of the field borders in relation to the base of the skull as for total brain irradiation.
  • At the caudal edge of C3 or C4, a juncture is made with the upper dorsal medulla field. The juncture must be planned with a physicist. 
  • Depending on the height of the patient, 1 or 2 medulla fields are given from behind. If there are two fields, there is also a juncture between these in the thoracic column. The juncture is calculated by a physicist and juncture movement must be planned during the simulation.
  • The lower border for the medulla fields must be below the end of the dural sac which is typically at the level of S2.
  • The lateral borders are lateral to the vertebral bodies with 1 cm margins to cover the dural sac where it follows the nerve roots out of the intevertebral foramen in addition to tuning uncertainty and penumbra.  
  • The medulla fields are dosed by depth where the depth is calculated from the dorsal skin surface to the dorsal aspect of the vertebral bodies/ventral limit of the spinal cord. Due to curvature of the vertebral column, the depth will vary according to the level of the vertebral column. It may be very difficult to identify the structures of the vertebrae on the coronal fluoroscopic simulator images. Differences in depth are compensated by filters of varying thickness.  

CT-based simulation 

Dose planning with CT is recommended for radiation to the entire CNS axis. CT uptake saves time for the patient compared to conventional simulation and is therefore considered patient-friendly. Dose planning is also more simple. 

  • A CT scan is taken after immobilization in VacFix® in the prone position with a mask. 
  • The whole brain and spinal canal limited to S2 at minimum toward the legs is modeled as CTV.
  • It is very important to include the extensions of the subarachnoid space, along the cranial nerves at the base of the skull and the dural extensions along the nerve roots in the intevertebral foramina, are well covered.
  • If the whole brain is to have more fractions than the spinal cord, the whole brain down to C3 or C4 must be modeled as a separate CTV for planning these fractions.
  • Check the field limits of the set-up cover the base of the skull well and the lateral limits for the medulla fields are 1 cm outside the vertebral bodies.
  • It may be beneficial to place the isocenter for the upper medulla field relatively high to obtain a geometric, and relatively clean juncture of the lateral fields toward the brain. Moving junctures can then be avoided between the brain and upper medulla field. 
  • Movement of junctures between the medulla fields is performed routinely.

CT dose plan    

Fractionation

Fractionation and total dose depend on multiple factors, among others, the type of lymphoma and which protocol is followed.

For a curative treatment plan, the following are indicated:

  • For lymphoblastic leukemia/ALL, treatment is administered according to study protocols, for example NOPHO in children, preferably 2 Gy x 9-12 to the whole brain and 2 gy x 6-9 to the spinal cord.
  • For other lymphomas and for palliative treatment, fractionation is determined individually.

Follow-up

Organs at risk

Brain 

There is a risk of short-term nerve toxicity such as 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 irradiation after high-dose MTX.    

Blood and bone marrow

Large amounts of bone marrow is included in the radiation field for the CNS axis. Counts with differential counts must be taken during and for a time after treatment.  

Lens of the eye

A dose of over 4-6 Gy must often be accepted to obtain sufficient coverage to structures near the lamina cribrosa. This may pose a risk for cataract development in some patients.  

Pituitary gland

The dosages used are often lower than the tolerance dose for adults, however, endocrine function should be followed long after treatment in children.

Growth inhibition

The entire spinal column is irradiated. Even if the doses are small, some growth inhibition may occur.

Gonads

Total CNS axis is irradiated as part of intensive treatment protocols, which collectively has a negative influence on fertility. The dose to the testicles should be minimized as much as possible by shielding. The ovaries in girls and women at a fertile age will be very close to the spinal cord fields and are difficult to shield.


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