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Radiation therapy for the liver for malignant lymphoma


Medical editor Alexander Fosså MD
Oncologist
Oslo University Hospital

General

Indications

The liver is often involved with lymphoma as part of advanced disease and usually with multiple lesions or diffuse spreading in the liver. This applies to both Hodgkin's lymphoma and all forms of non-Hodgkins lymphoma. In most cases, patients will be candidates for chemotherapy primarily for advanced disease and only isolated residual lesions are suitable for radiation therapy. Primary extranodal involvement in the liver with only localized focal lymphoma spreading to the liver is very rare, and even then should it be considered whether to treat as advanced disease. 

Since the tolerance for ionizing radiation for the entire liver is likely slightly under 30 Gy (TD5/5 for liver failure), irradiation of the entire organ is difficult if it is desired to give doses the same as for malignant lymphomas. Irradiation of up to 1/3 of the liver is, however, possible with doses up to 50 Gy.

Curative radiation therapy

  • Isolated residual lesions after chemotherapy for the respective lymphoma may be appropriate for consolidative radiation therapy. 
  • Primary extranodal involvement in the liver with focal lymphoma spreading (stage PeI) is very rare. In such a case, treatment for advanced disease with chemotherapy and radiation therapy should still be considered only for possible residual lesions. 

Palliative radiation therapy

  • For palliative radiation therapy, the method usually follows the same guidelines as for curative therapy with individual modifications.
  • Smaller doses to the entire liver are considered for local symptoms such as liver involvemet and capsule pain. 

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

  • Liver function should be evaluated before treatment based on the planned treatment and irradiated volume.
  • One or both kidneys will usually be partly or completely involved during treatment, and evaluation of kidney function for total and each side separately with GFR and renography may be done before treatment. 

Implementation

Conventional simulation

Direct contouring on the simulator may be appropriate for a palliative situation to initiate treatment quickly. 

  • X-ray, palpation findings, or ultrasound with margining of liver borders in the abdominal cavity may be advantageous to determine field borders.

  • Since the liver moves during respiration, a good margin in all phases of respiration is necessary.

CT-based simulation

Treatment is done using CT dose planning for curative treatment of residual lesions. 

  • The residual lesion after chemotherapy is GTV and CTV is generated with 1 cm margin.

  • Since the liver moves during respiration, a minimum of 1-2 cm margin to ITV is favorable in the craniocaudal direction while 1 cm is sufficient in the transversal plane. 

Fractionation

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

  • For HL: 1.75 Gy x 17
  • For indolent NHL: 2 Gy x 15
  • For aggressive NHL: 2 Gy x 20
  • For palliative treatment, fractionation and total dose must be adapted for each patient. Caution should be used if there is suspicion of extramedullary hematopoiesis in the liver.  


Follow-up

Risk organs

Liver

Liver testing should be evaluated during and in the first weeks after treatment.

Stomach and intestines

If parts of the stomach or intestines are included in the fields, nausea can be expected and prophylaxis should be given before the first fraction. Dyspepsia, diarrhea, and pain may be signs of mucositis in the stomach and intestines. Ulcerations and peforation may occur.

Bone marrow 

With extramedullary hematopoiesis in the liver, radiation therapy is considered to cause significant decline in counts during and in the weeks after treatment. Regular examination is necessary during this time. Caution should be used with fraction size, number of fractions per week, and total dose in such cases.  Kidneys

Depending on the dose, renal function may be reduced. Renal hypertonia may occur later on. 


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