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Radiation therapy for bone with malignant lymphoma


Medical editor Alexander Fosså MD
Oncologist
Oslo University Hospital

General

Indications

Malignant lymphomas originating in the bone are rare, except for solitary plasmacytoma. If localized malignant lymphomas in the bone are present, there is often uncertainty whether they should be staged as PeI and treated accordingly or be considered cases of primary generalized disease. Bone involvement occurs most often as part of generalized disease of all histological subgroups of Hodgkin's and Non-Hodgkin lymphoma. Bone involvement can also occur as a local extension of lymphoma in the legs, for example from extranodal lymphomas in the nose/sinuses and from retroperitoneal nodal tumors with spinal invasion.

Myeloma is usually associated with bone involvement, and most patients are candidates for radiotherapy during the course of the disease.

Curative radiation therapy

  • Histology and stage determine whether treatment can be curative. 
  • For isolated unifocal bone involvement of indolent lymphomas or solitary plasmacytoma, radiotherapy alone can be given with a curative intention. 
  • For isolated bone involvement, bone involvement as part of generalized disease, or extension to legs from surrounding structures of Hodgkin's or aggressive non-Hodgkin lymphoma, it is indicated to irradiate after curative chemotherapy, but only if there is one or maximum two areas of bone involvement. If radiation therapy is given, it is to be given to the entire area with initial bone involvment even if the tumor has responded well to chemotherapy. With more than two areas of bone involvement, spreading to the bone is considered generalized and radiotherapy to all lesions is not sensible.

Palliative radiation therapy

  • According to regular palliative guidelines, it is appropriate to irradiate bone involvement in danger of fracture, pain, or compression of the spinal cord and other neurogenic tissue.

Definitions

Target Volume

 

Target volume definitions from ICRU
(International Commission on Radiation Units and Measurements)

GTV (= Gross Tumor Volume)

Tumor volume

Palpable or visible/identifiable area of malignant growth.

CTV (= Clinical Target Volume)

Clinical target volume

Tissue volume containing GTV and subclinical microscopic malignant disease.

ITV (= Internal Target Volume)

Target volume

Volume containing CTV and an internal margin taking into account internal movements and changes in CTV. This is the volume that should receive an optimal dose.

PTV (= Planning Target Volume)

Planning volume

Geometric volume containing ITV and one Setup margin taking into account assumed variation in patient movements, patient positioning, and field alignment.

Planning contour: Beams-Eye-View projection of PTV.

IM (= Inner margin) and SM (= Setup margin)

IM and SM cannot be summed linearly. Total margin must be given specifically for different tumor localizations.

Field limit

The field limit is defined as the area that 50% of the isodose curve outside the target volume must have to give a therapeutic isodose (90% isodose) which encircles the target volume 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

The table below summarizes standards for use of the term GTV, for margins to CTV and ITV, as well as formulation of field limits for radiation therapy of malignant lymphomas.

Target volume for radiotherapy

GTV Tumor in indolent NHL stage I/II1, original tumor (before chemotherapy minus balloon effect) in aggressive NHL stage I/II1 and HL stage I/IIA

Residual tumor in aggressive NHL stage II2/IV and HL stage IIB/IV

CTV GTV + 2 cm craniocaudal to confined disease/short chemotherapy

GTV + 1 cm craniocaudal to residual tumor from advanced disease after full chemotherapy

GTV + 1 cm in the transversal plane

CTV should always include the entire lymph node region in the levels to be irradiated (limited in the lungs and bone, unless there is suspicion of infiltration).

CTV may for indolent NHL stage I/II1 include the nearest non-infiltrated lymph node region or parts of it.

ITV CTV if internal movement is negligent (CNS, ENH and others)

CTV + up to 1 cm craniocaudal and up to 0.5 cm transversal in the mediastinum

CTV + 2–3 cm in mesentary and stomach

CTV + up to 0.5 cm transversal retroperitoneally

PTV

Not routinely defined

Field limits

Are set to 1 cm outside ITV for set-up margin and penumbra

Field limits should be arranged so that later junctions are as simple as possible (for example on one side of the spine, in invertebral discs)

Involved node

The field of radiation surrounding macroscopically involved lymph nodes alone with margin. This definition is currently not widely used in Norway, but is emerging in international studies.

Involved field

The involved field is the field of radiation surrounding the macroscopically involved lymph node region or organ with margin. After limited chemotherapy of localized lymphomas, the original macroscopically involved area is used as the foundation for field contouring (with the exception of the balloon effect). For residual lesions after full chemotherapy for advanced stages, the residual tumor is usually used as the foundation (with some exceptions). What determines an adequatemargin from the macrotumor to the field limit depends on multiple factors. For early stages of NHL and HL without previous chemotherapy or after chemotherapy (3–6 CHOP-based cycles, 2–4 ABVD or equivalent), the margins from the initial tumor to the field limit should be 3-4 cmin the direction of lymph drainage lengthwise from initial extent and 2 cm in the transversal plan (exception for balloon effect). With residual lesion have full chemotherapy for advanced NHL and HL and relatively little internal movement, then 2 cm from residualtumor to the field limit is used. Larger margins may be considered in areas for greater internal movement (abdomen, structures near diaphragm). As a general rule with nodal involvement, the target volume includes the entire lymph node region in the transversal plane for the levels included in the field.

Traditionally, the entire inolved lymph node area has been included completely in the craniocaudal direction (direction of lymph drainage). This provides a recognizeable geometric field (parts of mantle or inverted Y field) which is advantageous for standardization, reproduciblity, later junctioning etc. The lymph node regions as defined in the Ann Arbor classification then do not represent any biologically functional entitites and are not considered a base for radiation therapy. Thus, it is natural to see the regions coherently length-wise inthe direction of lymph drainage and use margins to involved lymph nodes to avoid irradiation of entire regions (for example in the neck, supreclavicular region, mediastinum, and retroperitoneum). Parts of neighboring organs are included to satisfy the minimum margins given above. Field modeling should still be geometric shapes as much as possible to make later joining of fields easier and to avoid border recurrences in areas difficult to irradiate again.

For extranodal lymfomas/organ manifestations, it is sometimes natural to include the entire organ (thyroid gland, stomach, brain, spinal cord). In such cases, it is also necessary to take internal movement into consideration, for example, stomach movement and movement of lung borders etc.. With multiple organ localizations, it is not possible to give full doses to the entire organ due to the tolerance for ionizing radiation (lungs, liver, kidneys) and the fields and doses must be adapted accordingly.

Extended field

This type of field includes macroscopically involved regions/organs and lymph node regions that are assumed to have diseased cells. This may be the nearest macroscopically normal region or multiple, more distant areas. This technique was developed for Hodgkin's lymphoma when radiation therapy was used as the only treatment modality 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). In today's practice, the term 'extended field' is not widely used. For localized stages of low-grade NHL, where radiotherapy is given alone to cure the disease, we have chosen to include the nearest uninvolved regions in the field of radiation, a type of "minimally extended field". This is not, however, practiced by all radiation therapy centers in Norway.


Preparation

Preparation for radiotherapy and immobilization depends on the area to be treated with radiation.


Implementation

Conventional simulation

  • Modeling the field on the simulator should give a minimum 2 cm margin from visible tumor to the field border. The original tumor before chemotherapy determines the shape of the field regardless.

  • The fields should follow regular geometric guidelines so that later joinings and retreatment is as easy as possible.

    For example, the field limits are always placed in the intervertebral spaces and the entire body of vertebra with transverse processes and spinous processes are included.

    Likewise, the long bones are irradiated in full width with good margin lengthwise in the marrow cavity and in soft tissue outside the bones.

  • When irradiating extremities, it is important to be aware of the degree of uncertainty in modeling from one fraction to the next. Also, when treating the extremities, a border of healthy soft tissue should be excluded to prevent development of lymphedema.

CT-based simulation

  • For modeling on CT, visible tumor (the original tumor in legs for consolidative treatment after chemotherapy) is GTV.

  • CTV is generated with a 1 cm margin to GTV.

  • Bone structures usually have little internal movement except for the ribs and sternum which move during respiration. For the sternum, margins should be 1–1.5 craniocaudally and 0.5–1 cm transversally evaluated from CTV to ITV.

  • The finished fields should follow the geometric guidelines given above such that later joinings and retreatment is as easy as possible.

    For example, the field limits are always placed in the intervertebral spaces and the entire body of vertebra with transverse processes and spinous processes are included.

    Likewise, the long bones are irradiated in full width with good margin lengthwise in the marrow cavity and in soft tissue outside the bones.

  • A possible solution to this is to first define the desired field borders in the coronal slice on the CT dose plan program according to the guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin for the set-up variation and penumbra (1–1.2 cm). This ITV can if necessary be modified for individual situations.

CT dose plan, bone

Fractionation

Standard fractionation and total dose for curative treatment is given below.

  • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
  • Otherwise for Hodgkin's lymphoma: 1.75 Gy x 17.
  • For localized indolent lymphomas: 2 Gy x 15
  • For solitary plasmacytomas: 2 Gy x 20
  • For aggressive non-Hodgkin lymphomas: 2 Gy x 20.

For a palliative indication, doses of 3 Gy x 10 (fracture danger, weight-bearing bone structures, compression of neurogenic tissue), 4 Gy x 5 or 8 Gy x 1 (pain as indication) are considered.


Follow-up

Organs at risk depend on the area with bone pathology. Remember to consider use of gonadal shielding when treating near testicles or ovaries. 

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