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Radiation therapy for the mediastinum and hilum of lung for malignant lymphoma


Medical editor Alexander Fosså MD
Oncologist
Oslo University Hospital

General

In the Ann Arbor system the mediastinum is one region and is separated fromthe hilar lymph nodes on each side.

For radiation therapy, it is common to view the mediastinum as:

  • the upper region above the carina.
  • the middle region around the carina which includes tracheobronchial and bronchopulmonary lymph nodes (lung hilum on both sides). 
  • lymph nodes immediately subcarinal and at the base of the heart.
  • Posterior/lower region with lymph nodes below the carina behind the heart along the esophagus, descending aorta, thoracic column, and in the carciophrenic angles.  

Lymphoma involvement in the mediastinum occurs normally as large conglomerate tumors in close proximity to the heart. In addiion to involvment in the middle and posterior mediastinum, there is often paracardial involvement along and and in the pericardium ventrally, ventrolaterally on the right or left side and in the cardiophrenic angles. Lymphoma involvement near the heart is often a challenge for planning radiation therapy. 

Indications

Curative radiation therapy

  • For localized stages of classical Hodgkin's lymphoma (stage IA/IIA), radiation therapy is given to the original area involved with margin (involved field) after chemotherapy (ABVD or equivalent). The initial tumor volume before chemotherapy is critical for field modeling, but it is important to take into account tumor reduction after chemotherapy where the lung was pushed to the side, but not infiltrated by lymphoma before chemotherapy (the balloon effect).  
  • For localized stages of nodular lymphocyte-rich Hodgkin's lymphoma (stage IA/IIA) without risk factors, radiation therapy alone is given to the involved area with margin (involved field) without previous chemotherapy. Isolated involvment of NLPHL in the mediastinum is rare.
  • Special guidelines apply for children and adolescents up to 18 years with Hodgkin's lymphoma.
  • For residual tumor of Hodgkin's lymphoma after full chemotherapy for advanced Hodgkin's lymphoma (6-8 ABVD, 8 BEACOPP or equivalent), consolidative radiation therapy to the residual tumor with margin is considered.
  • For localized stages of aggressive lymphomas (stage I-II1), consolidative radiation therapy after chemotherapy (CHOP-based or equivalent) to the original tumor-involved area with margin (involved field) is given. The initial tumor volume before chemotherapy is critical for field modeling, but it is important to take into account tumor reduction after chemotherapy where the lung was pushed to the side, but not infiltrated by lymphoma before chemotherapy (the balloon effect). With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered.
  • With residual tumor of aggressive lymphomas after full chemotherapy (6-8 CHOP-based cycles or equivalent), consolidative radiotherapy to the residual tumor with margin is considered.
  • Mediastinal tumors from lymphoblastic lymphomas/ALL, Burkitt's lymphoma and primary mediastinal B cell lymphomas are always considered for radiation therapy, even after intensive chemotherapy. This is usually done by irradiating the original tumor volume in the craniocaudal direction, but with consideration for the balloon effect in the transversal plane.
  • For indolent lymphomas with localized disease (stadium I-II1), radiation therapy alone is given to the involved area with margin (involved field).

 

 

Palliative radiation therapy

  • As palliative radiation therapy, the method is based on guidelines for curative treatment with individual modifications.

       

       

       

       

       

       


    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

    • If large parts of the lungs or heart are included inthe radiation field, lung and heart function should be evaluated before treatment.
    • Immobilization of patients for radiation therapy for the mediastinum depends on which other regions will also be treated and whether treatment will be planned by CT.
    • If parts of the neck will also be irradiated, a 3-point or 5-point mask is preferably used.
    • For simultaneous irradiation of the axilla, patient is immobilized with the arm abduced to 90º for conventional simulation. For CT planning, a wing board or 5-point mask is used with the arms slightly abduced along the upper body.
    • In women, the breasts should be moved out of the field.
    • Palpable findings and possible scarring or skin changes are marked with marking thread.

     


    Implementation

    Conventional simulation

    For direct simulation, the craniocaudal layout of the radiation field should be individualized, such that the extent of the tumor (initial or after chemotherapy) is included with the correct margin to the field border in the craniocaudal direction. Depending on the extent of the tumor in the craniocaudal direction, the field border should have a 3-4 cm margin to the initial tumor volume (for curative treatment for localized indolent lymphomas or limited chemotherapy for early stages of HL and aggressive NHL) or 2-3 cm margin to the residual tumor after full chemotherapy for advanced disease.  

    If the upper mediastinum is included in the radiation field, it is sometimes necessary to include the supraclavicular fossa bilaterally to achieve an adequate margin to the macro tumor. 

    Even after limited chemotherapy, the actual tumor volume after chemotherapy always defines the margin to the lungs, not the initial volume (balloon effect). The mediastinum is always irradiated in full width in the levels included, and if the hilum level is included, the tracheobronchial and brochopulmonary lymph nodes are also included. This means that the field borders are laterally 1.5 cm out to lung tissue and follow the hilar contours on the simulator image (see mantle field). If the extent of the tumor lies on one side of the heart or in the cardiophrenic angle on one side, modeling should take this into account to spare as much of the heart as possible. If tumor has spread in the thoracic wall, which is included in the initial tumor volume to be irradiated, the field width must be modified, or joined with an electron field (increased lung irradiation).

    CT-based simulation

    • The actual or original tumor volume (for curative treatment for localized indolent lymphomas or after limited chemotherapy for early stages of HL and agressive NHL) defines GTV.
    • CTV is generated with margin in the craniocaudal direction 2 cm (for curative treatment of localized indolent lymphomas or after limited chemotherapy for early stages of HL and aggressive NHL) or 1 cm (residual tumor after full chemotherapy). A 1 cm margin to CTV in the transversal plane, and CTV is drawn such that the entire node region is included in the areas to be irradiated. If there is not infiltration into the lungs or bone, CTV is limited with similar anatomical barriers. 
    • If the hilum of the lung is in the CT slice where CTV is drawn, the hilar regions should also be included in CTV. The reason for this is that border recurrences in the hilar areas are difficult to retreat. It is important to be aware that larger parts of the hilum appear on CT compared to X-ray, and liberal modeling of the hilar regions may result in a much better mediastinal field. 
    • ITV is generated with margin to CTV up to 1 cm craniocaudally and up to 0.5 cm in the transversal plane out to healthy lung.
    • An alternative is to first define the desired field borders in the coronal slice on the CT planning program according to the guidelines that apply for direct simulation. An ITV can then be generated by subtracting the margin from the set-up variation and penumbra (1–1.2 cm). This ITV can be modified if necessary for the situation. 
    • When evaluating the field set-up and dose plan, it is important to check the final fields in the beams eye view since they are often disproportionately large.   
    • The standard field layout is from behind and front, since this avoids sharing the dose with large volumes of healthy tissue. 
    • Moulded lung blocks give smaller doses to the lungs than leaves from multileaf collimators with standard leaf widths of 0.5-1 cm. Moulded blocks may be necessary when the axillas are included in the radiation field. 
    • When evaluating dose-volume histograms, the cumulative dose to the heart is often small, but the critical structures at the valve level/outlet of the coronary arteries often receive a full therapeutic dose. Because of this, irradiation of partial volumes of the heart and tolerance are of limited benefit in terms of heart disease.
    • In cases of paracardial lymphoma where standard anteroposterior rays give large doses to the whole heart, may represent a challenge. Individualized modification of modeling is necessary where as much of the heart is held outside ITV. Even if the distance to the field border from the tumor should be 2 cm, parts of the left stomach can usually be held out of the fields of radiation. These patients are usually also candidates for more advanced field layouts and may possibly benefit from IMRT.  

    CT dose plan, mediastinum and lung hilum  

    CT dose plan, neck region and supraclavicular fossa  

    CT dose plan, axillary region  

    Fractionation

    Standard fractionation and total dosage for curative treatment is described below. These are also normative for palliative treatment, but must be modified for each patient.

    • For Hodgkin's lymphoma stage I-IIA without risk factors: 2 Gy x 10
    • Hodgkin's lymphoma: 1.75 Gy x 17.
    • For curative treatment of indolent non-Hodgkin lymphoma: 2 Gy x 15
    • For aggressive non-Hodgkin lymphoma: 2 Gy x 20.
    • For residual lesions after CHOP-based chemotherapy with higher doses of anthracyclines, other intensive chemotherapy and HMAS (for example Hodgkin's lymphoma, primary mediastinal B cell lymphomas, lymphoblast lymphomas/ALL or Burkitt's lymphoma), lower doses than those mentioned above are considered sufficient in some cases. 

    Follow-up

    Organs at risk

    Mucosa

    Acute mucosa toxicity such as mucositis in the esophagus during treatment and closely following occurs in most patients and some have significant problems.

    Bone marrow

    Depending on bone marrow function, a fall in counts may occur and should be measured in patients during and shortly after treatment.

    Thyroid gland

    At least half of lymphoma patients with irradiation to the neck develop hypothyroidism within years. Lifetime follow-up of thyroid status is indicated. Thyroid cancer can occur years after radiation therapy.

    Lung

    Subacute radiation pneumonitis during the first months after treatment may occur. Irradiated areas of the lungs will often develop fibrosis over time.

    Heart

    Patients have increased cardiovascular mobidity after irradiation which includes the heart valve area and/or parts of the myocardium. Valve problems, coronary heart disease, heart failure, and constrictive pericarditis are the most common side effects. These side effects are especially common in patients previously irradiated with a mantle field for Hodgkin's lymphoma. Guidelines in Norway recommend yearly follow-up with a general practicioner starting 10 years after treatment focusing on reduction of other risk factors (smoking, obesity, hypercholesterolemia, high blood pressure, physical inactivity) and early evaluation of symptoms or changes that my imply heart disease. Patients should be strongly discouraged from smoking.

    Secondary cancer

    For patients treated with mantle field irradiation for Hodgkin's lymphoma, there is a significant risk for secondary cancer, especially in organs receiving full therapeutic doses. Breast cancer, lung cancer, thyroid cancer, sarcomas, and skin cancer/melanoma are the most common forms. Secondary cancer is a significant cause of death of patients cured for Hodkin's lymphoma by radiation therapy. For younger women treated with mantle field irradiation in ages under 35, it is recommended to have yearly mammography screening starting 8 years after radiation therapy was given. For other cancer forms, there are no defined follow-up routines. Patients should be strongly discouraged from smoking.


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