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Radiation therapy of non-Hodgkin lymphoma

B-cell Lymphomas

B-lymphoblastic leukemia/lymphoma

B-cell lymphoblastic leukemia/lymphoma is treated using ALL protocols where use of radiation therapy is often applied. For many patients, radiation therapy is not indicated. Radiation therapy is relevant for CNS manifestations in combination with other CNS-directed treatment or as part of CNS prophylaxis for certain subgroups of patients. Radiation therapy for testicular involvement prevents local recurrence. Total body irradiation may be used for certain patients who are candidates for stem cell transplantation. Whether radiation therapy is given to areas of B-lymphoblastic lymphoma with initial bulk and whether residual lesions are irradiated (with CR in bone marrow) is considered on an individual basis.

Indolent non-Hodgkin B-cell lymphomas

Radiation therapy alone is considered potentially curative only for localized stages of indolent lymphomas (stage I/PeI and localized stage II1/PeII1). Radiation therapy is generally given to the involved lymph node region/involved organ (involved field). At Oslo University Hospital, the nearest draining uninvolved lymph node region is included as part of this.

The involved area of the lymph node region includes visible tumor (GTV) with at least 1 cm margin to CTV in the transversal plane. In the craniocaudal direction, there should be at least 2 cm to CTV and CTV should generally include the involved lymph node region in the transversal plane. ITV is generated based on internal movement of CTV. The field borders are then around 3-5 cm from the macrotumor in the craniocaudal direction and at least 2 cm from the macrotumor in the transversal plane. For extranodal involvement (for example the eye, salivary glands, stomach, skin), the definition of target volume may vary from organ to organ. If the nearest draining lymph node region or parts of this are included, this is modeled in CTV.

Direct modeling on the simulator follows equivalent guidelines for determination of field borders. The margin for ITV to field border is 1-1.5 cm for setup uncertainty and and penumbra.

Standard fractionation for most patients is 2 Gy x 15.

Small cell lymphocytic lymphoma/lymphoplasmocytic lymphoma

If the disease is in a localized stage, radiotherapy to the involved lymph node area is recommended and possibly including the nearest draining neighboring region. Modeling and contouring follows the same principles as for indolent lymphomas.

Fractionation is 2 Gy x 15.

Solitary plasmocytoma in bone

This diagnosis is made from a bone biopsy or aspirate dominated by mature, partially atypical plasma cells, and makes up 5% of plasma cell neoplasias. The presence of lytic solitary destruction of bone is common and evident by X-ray. Certain patients may have monoclonal gammopathy at serum protein electrophoresis. Myeloma should be excluded by standard examinations.

Treatment consists of curative radiation therapy. The prognosis is relatively good, but over half of patients develop generalized disease (myeloma) within 5-10 years after treatment.

Using 3D dose-planned treatment, the visible tumor is GTV. There is often soft tissue spreading outside the bone, therefore adequate imaging is necessary (CT or MRI) for evaluation. CTV should be modeled with at least 1 cm margin to GTV. If there is tumor involvement in vertebrae, all involved vertebrae and transverse processes should be included in CTV, with field borders lokated on the vertebral discs including one uninvolved vertebrae above and one below in the radiation field. The border to CTV in long bones should be 2-3 cm lengthwise in the marrow to be treated. Additional margin to ITV depends on the localization of the tumor, for example the thoracic wall.

Total dose and fractionation are normally 40 Gy as 2 Gy x 20. Data show that 59 Gy in fractions of 2 Gy gives a high rate of local control. 

Extraosseous plasmacytoma cell lymphomas

This diagnosis is made by a histological examination of an extraosseous neoplasm and constitutes 3-5% of plasma cell neoplasias. This disease is mainly (about 80%) localized to the upper respiratory tract. Some patients may have monoclonal gammopathy. Treatment consists of radiotherapy, and the prognosis is very good since few patients develop generalized disease.

With 3D dose-planned treatment, the visible tumor is GTV. CTV should be modeled with at least a 1 cm margin. An additional margin to ITV depends on the localization of the tumor. For tuning on the simulator, the field borders are located 2-3 cm from the macrotumor. It has been discussed in the literature whether one draining regional lymph node should be included, but Oslo University Hospital  has not done this routinely in recent years. (Thomas Broe Christensen, Århus)

Total dose and fractionation are normally 40 Gy given as 2 Gy per fraction. Data suggest that this treatment gives a high rate of local control.  

Marginal zone B-cell lymphoma

These lymphomas often occur as extranodal lymphomas and are often confined at the time of diagnosis. Marginal zone lymphomas are considered very radiosensitive. Radiotherapy for this diagnosis follows the same principles as for indolent lymphomas, but extranodal forms may be technically challenging to treat (such as stomach lymphomas). 

Total dose and fractionation is 2 Gy x 15.

Follicular lymphoma grade 1, 2 and 3A

Less than 1/3 of patients are in stage I or II when diagnosed. Localized disease, or potentially localized disease rather, can be defined as stage I and stage II1 where only two neighboring lymph node regions are involved, which can be included in a suitable radiation field.  

Treatment according to the Nordic lymphoma group's recommendation (www.nordic-lymphoma.org) is local radiotherapy with curative intention.

The involved area of the lymph node region includes visible tumor (GTV) with at least 1 cm margin to CTV. In the craniocaudal direction, (direction of lymph drainage) there should be at least 2 cm to CTV (3 cm in according to Nordic Lymphoma group's guidelines) and CTV normally includes all of the involved lymph node region in the transversal plane. ITV is generated based on assumed internal patient movement of CTV. Field limits will then be 3-5 cm from the macrotumor in the craniocaudal direction and at least 2 cm from the macrotumor in the transversal plane. For extranodal involvement, such as the eye, salivary glands, stomach, or skin, the definition of target volume will vary from organ to organ. If the nearest draining lymph node region or parts of this are included, this is modeled in the CTV. There is no convincing data to indicate extending the fields beyond this.

For direct modeling on the simulator, equivalent guidelines are followed for choice of field borders with margins 1-1.5 cm for setup error and penumbra.

The recommended total dose and fractionation are 30 Gy given as 2 Gy x 15.

Less than half of patients will develop recurrence outside the radiation field and systemic treatment is appropriate when necessary. 

Radiation therapy is limited for stages II2-IV. In multiple palliative situations, radiotherapy may be a good alternative for tumor masses that threaten organ function such as obstruction of the bronchial tree, ureters, spinal compression, or venous stasis, or those causing pain. It is important to consider radiotherapy also in patients with advanced, chemo-resistant disease. Effects can be achieved with much lower doses than those usually applied for follicular lymphomas. A common fractionated regimen for palliative treatment of large fields is 2 Gy x 2. Radiotherapy is considered for some patients with residual lesions after effective chemotherapy such as patients with remaining transformed follicular lymphomas after instensive chemotherapy/HMAS.

Follicular lymphomas grade B

Follicular lymphomas grade B are treated as DLBCL, and radiotherapy is used in combination with chemotherapy as for DLBCL.

Aggressive B-cell lymphomas

Many studies that support the use of radiotherapy for aggressive B-cell lymphomas are antiquated and do not use current classification or systemic treatment with combined immuno-chemotherapy. For DLBCL, the guidelines are relatively well documented by some randomized studies, while for other lymphomas, guidelines are based more on analogical assessments.

Mantel cell lymphomas

Patients in stages I/PeI and patients with localized stages II (II1/PeII1) are considered for treatment analogous to strategies for early stages of DLBCL. Whether radiotherapy alone should be recommended is less certain, if so 2 Gy x 20 is recommended as for follicular lymphomas.

Diffuse large cell B-cell lymphoma

For localized disease (stage I/PeI and stage II1/PeII1) 3–6 CHOP21 + rituximab cycles are given followed by local radiotherapy, most often 2 Gy x 20. Six cycles are given for stage I bulky disease and/or elevated LDH and stage II1, otherwise 3 cycles. With elevated LDH, a sign of high rate of proliferation in the tumor, CHOP14 with rituximab may be used. In cases where 6 cycles are given and there is complete remmission after 3 and 6 cycles, radiotherapy may be avoided. It is possible to replace radiotherapy by giving more cycles (total 6-8) in situations where irradiation will cause high morbidity (for examplel to the oral cavity) or unwanted doses to organs at risk (for example kidneys or heart). A new study possibly indicates there is no benefit to giving radiation therapy after 4 CHOP cycles for patients over 65-70 years. Where radiation therapy is assumed to cause bothersome side effects, it is recommended to avoid radiation therapy after 4 cycles, especially in patients over 70 years. 

When radiation therapy is given after limited chemotherapy mentioned above, CTV is defined as the original tumor volume with 2 cm margins in the craniocaudal direction. In the transversal plane, the original tumor volume is defined as CTV, but usually includes the full width of the entire region. If the original tumor volume has pushed aside healthy organs without infiltration and the organs have relocated to their original location after chemotherapy (lungs, kidney, intestines), it is correct to use the tumor's expansion in the transversal plane after chemotherapy for modeling of CTV (balloon effect). Margins for ITV will depend on the assumed internal movement of the area giving margins to field borders 3-4 cm in the cradiocaudal direction and 2-3 cm in the transversal direction.  

Modeling of fields on the simulator will follow the same principle, that is, 3-4 cm from the macrotumor before chemotherapy to the field border in the craniocaudal direction and 2-3 cm in transversal direction.

Radiation therapy has a limited role for advanced stages (stages II2-IV). Some recommendations suggest that originally bulky lesions and extranodal manifestations should be irradiated after chemotherapy, but the benefit of this is unclear. This is not generally recommended. Localized residual lesions after adequate chemotherapy (6-8 CHOP + rituximab-based cycles) should be considered for biopsy and/or PET examination. Radiation therapy is considered consolidative. For positive biopsy of residual areas, younger patiens should be evaluated for 2nd line chemotherapy and consolidative therapy with HMAS. Residual tumor with 1 cm margin is defined as CTV, but the full width of the entire region is normally included. Margins for internal movement (ITV) are additional depending on localization. For direct modeling on a simulator, equivalent guidelines are followed. Bone involvement, if there are 1 or 2 bone manifestations, should normally be consolidated with radiotherapy. Original size in bone with 1 cm margin represents CTV. Original testicular involvement leading to irradiation of the scrotum with remaining testicles is done even after full chemotherapy with complete response.

Standard fractionation for DLBCL after full chemotherapy is 2 Gy x 20. For large volumes, there are limitations regarding organs at risk especially after HMAS where somewhat lower doses are considered, preferably 2 Gy x 16-18. Hyperfractionated treatment may also be considered with dose fractionation of 1.8 Gy with equivalent change in total dose if late toxicity from critical organs with high α/β ratio indicates that this is sensible.

Radiotherapy may be considered when starting primary treatment, especially with threatened organ function and pain caused by local growth. Radiotherapy can give good response and better quality of life even in lymphoma patients with advanced, chemo-resistant disease. If expected survival time is short, one should consider reduction of dose or fewer fractions with larger fractionations than normal. 

Mediastinal B-cell lymphomas

Mediastinal (thymic) large cell B-cell lymphoma is a subentity of DLBCL that occurs in the mediastinum and has distinct clinical immunophenotypical and genetic characteristics. The clinical profile may be dominated by local aggressive growth with a tendency for vena cava superior syndrome and thrombosis of large veins in the mediastinum, the neck, and lower extremities. The biopsies may be dominated by fibrosis, and gene expression profiles of PMBCL have shown relationships between this entity and Hodgkin's lymphoma of nodular sclerosizing type.

Treatment follows guidelines as for DLBCL otherwise. There will usually be residual lesions in the medistinum even after 6 or 8 CHOP-rituximab cycles, and many patients must be considered for irradiation of these lesions. The role of radiation therapy in treatment of PMBCL is still uncertain, and since patients are often young, late toxicity in the form of cardiotoxicity and secondary cancer is significant. As a practical solution to this dilemma, radiation therapy should be avoided in patients in CR or CRu. Patients with PR but without sign of vital tumor (by biopsy or PET) are considered for radiation therapy (tumor-directed) after 6 cycles, when the cumulative anthracycline dose is still low at the time of radiotherapy. The total dose may be reduced to 32-36 Gy, and hyperfractionated treatment in fractions of 1.8 Gy is a possibility.

Burkitt's lymphoma

Treatment of Burkitt's lymphoma in adults 18-55 years follows the GM-ALL B-ALL/NHL 2002 protocol.

In this protocol, radiotherapy is recommended on residual tumor after 6 cycles (CRu and PR) with 36 Gy. Patients in CR will continue after 6 cycles, but initial mediastinal tumor or CNS involvement will be irradiated to the mediastinum to 36 Gy or total brain with 24 Gy. Patients in CR after 6 cycles, but initial extranodal involvement may be considered for consolidating radiotherapy to these areas, but this is not specified in the protocol. Patients with stage I or II without mediastinal tumor and without extranodal involvement which are in CR after 4 cycles should not have radiotherapy.

T-cell non-Hodgkin lymphomas

T-lymphoblastic leukemia/lymphoma

These patients are treated from ALL protocols where use of radiotherapy is often specified. For many patients, radiotherapy will not play a role in treatment. Radiotherapy is appropriate for CNS manifestations in combination with other CNS-directed treatment or as part of CNS prophylaxis for certain subgroups of patients. Radiotherapy for the testicles with testicular involvement is debated. Total body irradiation is also appropriate for some patients who are candidates for stem cell transplantation. There are retrospective data indicating the mediastinum should be irradiated with initial tumor involvement, probably also when CR is reached with chemotherapy. The dose should be upward to 30 - 36 Gy, but at Oslo University Hospital a maximum of 2 Gy x 15 after HMAS is used.

With irradiation of the mediastinum, it is often normal to define the intial tumor volume with a 1 cm margin in the craniocaudal direction. In the transveral plane, the residual tumor after chemotherapy is used as the basis (balloon effect), but the entire mediastinum/hilum is normally modeled in the CTV in the transversal plane. Margins are allowed for internal movement of the mediastinum. Modifications may be appropriate with tumor which has infiltrated for example the lungs or thoracic wall. Modifications may also be necessary to avoid too large a dose to organs at risk. It is often necessary to deviate from irradiation of the entire original craniocaudal mass and instead focus of the location of the residual tumor. 

Mature T/NK-cell lymphomas

Aggressive T/NK-lymphomas (peripheral T-cell lymphomas without closer specification, anaplastic large cell T/0 cell lymphoma, etc.) rarely occur in localized stages (stage I/PeI – II1/PeII1). If this is the case, they may be treated according to guidelines analagous to confined stages of DLBCL. It may then be appropriate to irradiate to the involved field as for DLBCL. Standard fractionation is 2 Gy x 20.

For patients with advanced disease, radiation therapy to residual lesions is considered after adequate chemotherapy. Considerations are the same as for DLBCL.

Special extranodal lymphoma localizations

Primary PCNSL lymphomas

Radiotherapy to the brain, especially with PCNS lymphomas enhances dementia. Newer protocols strive to avoid or postpone radiotherapy until possible recurrence. When radiotherapy is indicated, 2 Gy x 20 is given to the total brain field. 

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