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Cutaneous radiotherapy for malignant lymphoma


Medical editor Alexander Fosså MD
Oncologist
Oslo University Hospital

General

Primary cutaneous lymphomas (PCL) and skin involvement occur as part of generalized lymphomas originating from other parts than the skin. PCL is defined as lymphomas assumed to arise in skin and which primarily manifest only in skin. 

Of PCL arising from T cells (ca. 70 % off PCL), mycosis fungoides dominates followed by cutaneous large cell anaplastic CD30+ T-cell lymphoma, lymphomatoid papulous and peripheral T cell lymphomas. Treatment of PCL arising from T cells is summarized elsewhere. Of PCL arising from B cells (ca. 30 % of PCL), marginal zone lymphomas and DLBCL are the most common. The histological profile correlates poorer with the clinical profile than for other lymphomas. Large cell anaplastic T cell lymphoma and subgroups of DLBCL isolated in skin have relatively good prognosis. The skin area of the primary localization is significant for the prognosis since DLBCL, leg type, has a poorer prognosis tham PCL of type DLBCL.  

Indications

  • For MF, radiation therapy is often part of multiple local measures. Depending on the size of the area and danger of delayed cosmetic disfiguring in the skin, fractionation in 2 Gy x 15 or 3 Gy x 8 is often chosen. Internationally, fractionation down to 2 Gy x 4 is also recommended for single lesions. For generalized disease in the skin that is not treatable by other local measures, total skin electron irradiation is an option.
  • CD30+ ALCL is often localized to one or more areas in the skin, and is often suitable for local radiation therapy as 30–40 Gy in fractions of 2 Gy, as recommended in the literature. With more extensive skin involvement, the disease is considered generalized (stage IV) and treated with chemotherapy. Radiation therapy is given to any residual lesions as 2 Gy x 20. 
  • CD30- ALCL and PTL have -even with primary involvement in skin- a poorer prognosis and are treated with chemotherapy such as aggressive T cell lymphomas, followed sometimes by radiation therapy. For localized involvement (stage PeI), 3 CHOP-based cycles are given followed by radiation therapy as 2 Gy x 20, or only radiation therapy alone. With more advanced skin involvement, the disease is considered generalized (stage IV), and is treated with 6–8 courses and radiation therapy is given to any residual lesions as 2 Gy x 20. 
  • Indolent PCL of B celle origin (marginal zone lymphoma, folicular lymphoma) with localized disease (stage PeI) or few areas of involvement in skin is treated radiation therapy alone as 2 Gy x 15. For advanced disease in skin (stage IV), treatment can be postponed or possibly given to symptomatic or cosmetically disfigured areas. Systemic treatment is used only if local treatment does not provide adequate control of symptoms.  
  • For aggressive PCL of B cell origin (DLBCL), radiation therapy is given at the end of chemotherapy according to the stage-adapted arrangement. With local involvement (stage PeI), 3 CHOP-based cycles are given along with radiation therapy as 2 Gy x 20. For extensive skin involvement (stage IV) 6-8 cycles is given, possibly followed by radiation therapy to remaining residual lesions. 

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 and examinations prior to treatment will depend on which area and size of the skin to be irradiated and depth of the chosen treatment. The need for immobilization depends also on individual circumstances.


Implementation

Conventional simulation

Local skin areas are usually treated with electrons where energy and use of bolus is customized for each patient. The field border on the skin should be 2 cm from visible tumor. X-rays (photons with 50–150 keV) are considered for very superficial lesions up to 2-3 mm, but compared to electrons, have a longer tail on the depth dose curve, and therefore give larger doses to deeper structures. For curved surfaces, electrons may be difficult to use, and irradiation with photons and use of bolus may be more simple, for example, on parts of an extremity.  

With extensive involvment of the skin on a foot or leg, irradiation in a water bath is an option. This treatment provides good dose coverage in the skin around the entire foot and leg. This treatment causes significant dermatitis with desquamation and edema in large areas in most patients after a short time.

Fractionation

Fractionation and total dose for indolent lymphomas is normally 2 Gy x 15 or 3 Gy x 8, and for aggressive lymphomas, 2 Gy x 20. For palliation of advanced mycosis fungoides, 2 Gy 4 is also used.


Follow-up

Risk organs will depend on the area treated, field size, and range of depth for the chosen treatment.

Skin

A certain degree of acute dermatitis in healthy skin within the radiation field can be expected. 


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