Patients with Hodgkin lymphoma have a very favorable prognosis. In limited stages, with and without risk factors, patients are treated with a short course of chemotherapy followed by radiotherapy. In advanced stages chemotherapy is usually given alone, except in rare cases where there is a PET positive remnant after treatment.

With a favorable prognosis and long life expectancy, patients may be at risk of developing late treatment adverse effects from radiotherapy. Therefore it is important to minimize radiation dose to normal tissue.

This is a description of the radio therapeutic part of the Hodgkin lymphoma treatment for both photon- and proton therapy. The protocol can also be used for primary mediastinal B-cell lymphoma, with several features in common with Hodgkin lymphoma, and for other lymphomas, but often with other doses and fractionation.

Patient pre-treatment preparation

Due to the localization of the target, different immobilization devices can be used.

Targets in the neck and supraclavicular fossae A thermoplastic five point mask-mould or equivalent immobilization device ensuring satisfying reproducibility shall be used for supine patient position.  
Targets in the mediastinum Arms should preferably be akimbo, i.e. arms placed on the hips with elbows bowed outward, or placed on the sides of the body, gripping indexed handles. To be able to use frontal fields the chin should be slightly elevated. Deep inspiration breath hold (DIBH) can be beneficial for targets in mediastinum (8). If DIBH is not used a 4DCT must be performed to ensure that the motions are within limits for proton therapy. Patients suitable for proton therapy but not eligible for DIBH should preferably be immobilized with a thermoplastic three or five point mask-mould or equivalent immobilization device ensuring satisfying reproducibility.  
Targets in the abdomen Arms can be either above the head or on the chest due to target location (should not be “in field”).

Appropriate leg/foot support shall be used for all patients. The patient reference coordinate system can be defined by using pen markers or tattoos. Specific demands for proton therapy on fixation devices: materials used must not disturb or make the dose distributions uncertain, particularly regarding range. Identical fixation must be used for imaging and treatment.

Pre-treatment imaging

For proton and photon treatment planning, dose calculations must be performed on a CT study without contrast. Therefore a native CT study should be performed before any contrast enhanced study. The CT scanning protocol must be validated for protons and photons. For better target definition, CT imaging with i.v. contrast agent could also be performed. If a contrast-CT is performed the patient should be positioned in the same way as on the CT without contrast. The CT slice thickness should not exceed 5 mm for photons and 3 mm for protons. Treatment in DIBH is recommended. The advantage of treatment in DIBH is not only a reduction of target motion but also anatomical advantages. The lung volume increases, the mediastinum gets narrower and the heart is pulled caudally which may translate into a reduction of dose to healthy tissue. If DIBH is not possible a 4DCT is recommended for photons and mandatory for protons in order to determine movements of the target. If target movements exceed 5 mm in thorax, treatment with scanned protons is not recommended unless DIBH is used. Target motion is measured in a centrally located point along the anterior-posterior (AP), superior-inferior (SI) and left-right (LR) axes. A visual assessment of the 4DCT is also done to eliminate the risk of an excess motion in one part of the target volume.

Treatment in DIBH A CT scan without i.v contrast agent including total lung volume in DIBH (CT-DIBH) should be performed. A CT-DIBH with i.v. contrast could also be performed for more accurate target definition. To evaluate anatomical DIBH variations (inter breath-hold variations), it´s recommended to acquire two additional CT-DIBH during the planning CT simluation. The CT-DIBH must be performed with low-dose CT protocols (7, 8).  
Treatment in free breathing (FB) If the DIBH is not possible a CT in free breathing (CT-FB) without i.v contrast and a 4DCT including the target area with sufficient margins should be performed. Alternatively, if it is possible to create an average CT image for planning from the 4DCT acquisition, the CT-FB scan without contrast can be omitted.

For structure delineation, it is preferred that the diagnostic FDG-PET/CT is performed with the patient immobilized for radiotherapy using a flat table top and a head and neck support. The image sets from the different modalities should be registered in the treatment planning system.

Specification of treatment prescription

Volume specification

The recommendations made by ICRU (ICRU Report 83 2010 (2)) shall be followed. The volumes shall be delineated with tissue specific window level. For protons, if DIBH is not used, the target volumes must be delineated in the different respiratory phases, creating internal target volume(s) (ITV) according to applied technology at the department. Delineation of organs at risk (OARs) in different respiratory phases is optional. All naming of structures should follow the recommendations from the Swedish Radiation Safety Authority (SSM 2016:18 (5)). The target definition is based on the ILROG guidelines (Maraldo et al 2015 (4)).

The gross tumor volume(s) (GTV) is the same for photons and protons and is defined if there is a visible tumor remnant before radiotherapy.
The clinical target volume(s) (CTV) is the same for photons and protons and is determined by the tumor extent at the prechemotherapy FDG-PET/CT. The CTV is limited laterally by the borders of the affected lymph node area and anatomical barriers. Craniocaudally no extra margin is added if the anatomical registration between the prechemotherapy FDG-PET/CT and the treatment planning CT is satisfactory. An extra margin of approximately 1 cm is otherwise added craniocaudally.
When a 4DCT is performed the ITV includes the CTV in all different respiratory phases and is the same for photons and protons. ITV is not necessary to outline in sites that are unlikely to change shape and position during treatment. When DIBH is used the ITV encompasses information from multiple CT-DIBH taking the inter-breath-hold variation into account.
The planning target volume(s) (PTV) is defined for photons and is a geometric expansion of CTV or ITV to take into account for uncertainties in immobilization, daily patient positioning and image registration. The PTV margin must be determined locally according to the locally estimated uncertainties mentioned. For example, the PTV margin for photons is often 0.3-0.5 cm in all directions when a thermoplastic five point mask-mould or equivalent immobilization is used and 0.5-1 cm for targets in the mediastinum, thorax and abdomen, depending on the geometric precision of the applied technology. For protons, a PTV will be defined by the same principles as for photons and used for prescribing and reporting dose according to the recommendations of ICRU (2). During treatment optimization help structures with customized margins to the CTV can be created in order to include range uncertainties and to ensure homogeneous and robust dose delivery to the CTV.
All possibly involved OARs must be identified and delineated, in particular: SpinalCord, Parotid_L, Parotid_R, Submandibular_L, Submandibular_R, Thyroid, Esophagus, Heart, ValvularPlane, A CoronaryD-L, Kidney_L, Kidney_R, Lung_L, Lung_R, LungTotal, Breast_L, and Breast_R.
For protons, artifacts in the tissue as well as clips, markers, etc. must also be contoured and replaced with appropriate Hounsfield unit (HU).

Absorbed dose prescription

The prescribed absorbed dose should be specified to a dose reference point/volume.
For proton therapy, the dose prescriptions should be in both physical dose and in relative biological effectiveness absorbed dose (RBE-weighted) and with dose–volume constraints specified accordingly (See ICRU 78 (2007) (2) for naming conventions on reporting RBE-weighted absorbed dose). The RBE value/model 1.10 should be used.
For treatment planning optimization, physical and/or biological dose-volume objectives and constraints shall be prioritized according to table 1.

Fractionation and treatment time

Radiotherapy is in primary treatment either given daily, 5 days/week with the normal fractionation scheme with 17 fractions of 1.75 Gy (RBE), i.e. total 29.75 Gy (RBE) or with 10 fractions of 2 Gy (RBE) to a total of 20 Gy (RBE). The prescribed dose at relapse and palliative treatment may vary. A boost can be given but due to different protocols and response the fractionation scheme can vary.
Interruption due to holidays, equipment failure etc. should not exceed 4 consecutive days. Overall treatment time should not exceed the planned with more than one week. For proton patients a backup photon plan should be used if the interruption exceeds 4 days.

Relation to other concomitant therapies

Radiotherapy is given after chemotherapy and should start approximately 3-4 weeks after completion of chemotherapy.

Table 1. Prioritized dose volume objectives and constraints expressed in EQD2 (9, 10). RBE value/model 1.10 is used.

Priority	Volume	Objective/constraint in biological doses Gy (RBE)	Objective/constraint in physical doses Gy
1	Spinal cord	D_0.5cc ≤ 48 Gy (RBE)	D_0.5cc ≤ 43.6 Gy
2	GTV	D_100% ≥ 98%	D_100% ≥ 98%
3	CTV	D_98% ≥ 95%	D_98% ≥ 95%
4	PTV¹	D_2% ≤ 105% D_98% > 95%	D_2% ≤ 105% D_98% > 95%
5²	Bilateral Kidneys	Mean dose<15-18 Gy (RBE) V_{12 Gy (RBE)}<55% V_{20 Gy (RBE)}<32% V_{23 Gy (RBE)}<30% V_{28 Gy (RBE)}<20%	Mean dose<13.6-16.4 Gy V_{10.9 Gy}<55% V_{18.2 Gy}<32% V_{20.9 Gy}<30% V_{25.5 Gy}<20%
	If mean dose to 1 kidney >18 Gy	V_{6 Gy (RBE)(remaining kidney)}<30%	V_{5.5 Gy (remaining kidney)}<30%
	ValvularPlane	V_{30 Gy (RBE)} as low as possible	V_{27.3 Gy} as low as possible
	A CoronaryD-L	D_2% as low as possible	D_2% as low as possible
	Heart	D_2% as low as possible V_{15 Gy (RBE)} as low as possible Mean dose < 5 Gy(RBE)¹	D2% as low as possible V _{13.6 Gy} as low as possible Mean dose < 4.6 Gy³
	Breast_L and Breast_R (women < 30 years)	V_{2.5 Gy (RBE)} as low as possible V_{20 Gy (RBE)} as low as possible Mean dose < 4 Gy(RBE)³	V_{2.3 Gy} as low as possible V_{18.2 Gy} as low as possible Mean dose < 3.6 Gy³
	LungTotal	D_2% as low as possible V_{5 Gy (RBE)} <55% V_{5 Gy (RBE)}as low as possible V_{20 Gy (RBE)} < 30% V_{20 Gy (RBE)} as low as possible Mean dose < 10 Gy(RBE)³	D_2% as low as possible V_{4.5 Gy} <55% V_{4.5 Gy}as low as possible V_{18.2 Gy} < 30% V_{18.2 Gy} as low as possible Mean dose < 9.1 Gy³
	ValvularPlane	D_2% as low as possible	D_2% as low as possible
	Muscle	D_2% as low as possible	D_2% as low as possible
	Thyroid	D_2% as low as possible	D_2% as low as possible
	SalivaryGlands	V_{26 Gy (RBE)} < 40% V_{30 Gy (RBE)} as low as possible	V_{23.6 Gy} < 40% V_{27.3 Gy} as low as possible
	Esophagus	D_2% as low as possible V_{34 Gy (RBE)} < 50%	D_2% as low as possible V_{30.9 Gy} < 50%
	Body	D_0.5cc ≤ 110%	D_0.5cc ≤ 110%

¹ Dose volume objectives and constraints to PTV may be disregarded if other strategies like robust optimization are used to ensure CTV coverage.
² The dose volume objectives and constraints of priority 5 is listed in an order of recommendation, however, for each patient, the responsible physician decides how the individual priority among the structures with priority 5 should be employed during treatment plan optimization.
³ Ideal

Treatment planning and delivery

Treatment technique

The radiation treatment can be given with photons (3DCRT/IMRT/VMAT) or protons.

Dose computation and optimization

Dose calculation
– Reference dosimetry is carried out according to the IAEA report TRS 398 (2000) (1).
– The absorbed dose in the patient geometry shall be calculated by using validated algorithms.
– The calculation grid shall be at a maximum of 3 mm.
In order to facilitate the optimization procedure, help structures and volumes may be defined.
For proton treatments, see treatment planning and optimization guidelines in the Skandion Clinic treatment planning instruction manual (Delprocess 5).
When DIBH is used see “Riktlinjer för andningsanpassad protonstrålbehandling av Hodgkin lymfom”(8).

Treatment plan evaluation

A robustness test should be performed for each proton treatment in 12 test cases according to the recommendations in the Skandion clinic treatment planning instruction manual. Tolerance levels that should be fulfilled in the robustness test for treatments with the prescribed dose of 29.75 Gy (RBE) are described in table 2.

Table 2. Tolerance levels that should be fulfilled in the robustness test. RBE value/model 1.10 is used.

	Tolerance levels
CTV: all test cases	D_90% ≥ 95%
CTV: for at least 10 of 12 robustness test cases	D_98% ≥ 95%
GTV: all test cases	D_100% ≥ 98%
Spinal cord: all test cases	D_0.5cc ≤ 48 Gy (RBE)
DVH parameters of OARs used for definition of objectives and constraints (table 1)	According to clinical judgement

Image guided and adaptive treatment delivery

Repainting or other motion mitigating techniques could be considered.
The position of the patient shall be verified based on MV imaging, CBCT, in-room CT, kV imaging and/or surface imaging.
– For photons, the position of the patient shall be verified daily or at least the first 3 days and then at least weekly during the treatment. A statistical analysis shall be performed after the first 3 treatments. Based on the analysis, the treatment delivery shall be adapted according to protocol for corrective action. In case of DIBH and/or VMAT, the position should be verified before each treatment.
– For protons daily imaging is required.
– The additional absorbed dose contribution due to imaging procedures should not exceed 0.1 Gy for the whole treatment.
A new CT (for proton treatments without DIBH in the thoracic region both 3D- and 4DCT) should be performed after one week with the possibility of adaptive re-planning if the difference between the dose distribution of the original treatment plan and the dose distribution based on this new CT is not in accordance with the tolerance levels specified for the robustness test (see table 2) A new assessment, individually for each patient, is made to determine whether additional CT scans are needed during the course of the treatment.
When DIBH is used see “Riktlinjer för andningsanpassad protonstrålbehandling av Hodgkin lymfom”(8).

In-vivo dosimetry

The absorbed dose to the patient shall be estimated based on in vivo measurements according to clinical routine procedures.
If in-vivo dosimetry is not applicable, pre-treatment patient specific quality assurance (QA) must be performed.

Quality Management

Preparatory

For protons, a new CT scan in DIBH or a 4DCT for patients not eligible for DIBH should be performed at the proton center prior to treatment to verify the calculated dose distribution. The tolerated difference between the dose distribution of the original treatment plan and the dose distribution based on this new 3DCT should be in accordance with the tolerance levels of the robustness test (see table 2).

Pre-treatment specific dosimetry

For IMRT/VMAT or proton treatment techniques, or if in-vivo dosimetry is not applicable, pre-treatment patient specific quality assurance (QA) must be performed based on independent calculations or measurements, for IMRT/VMAT treatments according to Swedish recommendations (6) and for proton treatments according to the clinical routine procedures at the Skandion clinic.

– Acceptance criteria should be determined locally according to the equipment and QA procedure used and should for protons fulfill dose tolerance levels in accordance with the tolerance levels specified for the robustness test (see table 2).

– In case a plan is not passing the acceptance criteria, the reasons shall be further analyzed, and replanning/change of technique shall be considered.

References

International Atomic Energy Agency. Absorbed Dose Determination in External Beam Radiotherapy. An International Code of Prattice for Dosimetry Based on Standards of Absorbed Dose to Water. IAEA TRS 398 2000
International Commission on Radiation Units and Measurements. Prescribing, Recording and Reporting Proton-Beam Therapy. ICRU Report 78 2007
International Commission on Radiation Units and Measurements. Prescribing, Recording, and Reporting Photon-Beam Intensity-Modulated Radiation Therapy (IMRT). ICRU Report 83 2010
Maraldo M V, Dabaja B S, Filippi A R, et al Radiation therapy planning for early-stage Hodgkin lymphoma: experience of the International Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys 2015; 92(1): 144-152
Montelius Anders, et al. En standardiserad svensk nomenklatur för strålbehandling. Strålsäkerhetsmyndigheten Rapport SSM 2016:218 (2016).  Available from www.stralsakerhetsmyndigheten.se
Olofsson J, Gustafsson M, Isacsson U, Olevik-dunder M, Westermark M, Benedek H och Hållström P. Strategier vid kvalitetssäkring av intensitetsmodulerad strålbehandling. Svensk förening för radiofysik Rapport 2014:1 (2014).  Available from http://www.radiofysik.org/
Chang Joe Y., et al Consensus Guidelines for Implementing Pencil-Beam Scanning Proton Therapy for Thoracic Malignancies on Behalf of the PTCOG Thoracic and Lymphoma Subcommittee. Int J Radiat Oncol Biol Phys 2017; 99(1): 41-50.
“Riktlinjer för andningsanpassad protonstrålbehandling av Hodgkin lymfom”. Guidelines for implementing DIBH-PBS from a national working group within the Skandion framework. 2018. Available from Skandion quality system RMT+.
Proton therapy for adults with mediastinal lymphomas: the international lymphoma radiation oncology group (ilrog) guidelines.  Blood 2018: blood-2018-03-837633.
Pinnix CC, Smith GL, Milgrom S, et al. Predictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2015;92(1):175-182.

History of versions

Page/item

Corrections

Version/Date

Table 1

Spinal cord maximum dose volume changed from 2% to 0.5cc
GTV constraint changed from D_100% ≥ 100% to D_100% ≥ 98%
Heart, mean dose constraint added
Breast, mean dose constraint added
Lung, mean dose constraint added
Body constraint D_0.5cc ≤ 110% added

Version 2-

2020-10-05

Table 2

Tolerance level for robustness tests:
GTV changed from 10 of 12 D_98% ≥ 100% to all test cases D_98% ≥ 100%
Spinal cord changed to D_0.5cc ≤ 48 Gy (RBE)

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