Introduction These guidelines are intended to direct the treatment of patients with lymphoma with radiotherapy. They have been developed from guidelines already in existence at Barts Health NHS Trust, University College London Hospitals NHS Foundation Trust, Royal Free London NHS Foundation Trust, Princess Alexander Hospital, North Middlesex Hospital and Barking, Havering and Redbridge University Hospitals NHS Trust. They should be read and used in conjunction with other guidelines covering the investigation and management of Hodgkins and NonHodgkins Lymphoma. They also do not remove the need to follow the Local Rules and Work Instructions that have been developed at individual radiotherapy departments 2. CANCER DEFINITION 2.1. Staging System (Ann Arbor Staging Classification for Lymphoma) Stage I Involvement of a single lymph node region (I); Single extra nodal site (IE) Stage II Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) Localised involvement of an extra lymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE) Stage III Involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by localised involvement of extra lymphatic site (IIIE) or spleen (IIIS) or both (IIIES) Stage IV Diffuse involvement of one or more extra lymphatic organs with or without associated nodal involvement or distant nodal involvement. Any liver / bone marrow disease X Bulk disease>10cm A =absence of B symptoms B =presence of either unexplained fever>38○C; drenching night sweats; weight loss>10% in the 6 months prior to diagnosis 2.2. Histological Classification WHO Classification (Full extent is beyond the scope of this document). Non-Hodgkins Lymphoma (NHL)  Low Grade / Indolent (e.g. Follicular, MALT)  High Grade (e.g. Diffuse Large B-Cell Lymphoma; Primary Mediastinal; NK/T Cell Lymphoma) Hodgkins Lymphoma (HD)  Classical HD: Nodular Sclerosing; Mixed Cellularity; Lymphocyte Deplete; Lymphocyte Rich  Lymphocyte Predominant HD (LPHD) Early stage HD Favourable o Clinical Stage I/II and no risk factors Unfavourable o Clinical Stage I/II with one or more of the following risk factors:  Large mediastinal mass (>10cm)  Extranodal involvement  Elevated ESR (>30mm/h for B stage; >50mm/h for A stage)  3 or more lymph node regions involved  B symptoms 2.3. Advanced stage HD 2 Favourable  Clinical Stage III/IV with 0-3 adverse risk factors (listed below) Unfavourable  Clinical stage III or IV with four or more adverse risk factors o Albumin level of <4.0 g/dL. o Hemoglobin level of <10.5 g/dL. o Male sex. o Age of ≥45 years. o Stage IV disease. o White blood cell (WBC) count of ≥15,000/mm3. o Absolute lymphocytic count of <600/mm3 or a lymphocyte count that was <8% of the total WBC count. 3. INDICATIONS and INTENT Radical intent o Following short course chemotherapy o As single modality therapy e.g. localized stage I Lymphocyte Predominant HD; o Consolidation following chemotherapy o Chemotherapy refractory disease Palliative Intent 4. TIMING  Radiotherapy to start 4 weeks from time of decision to treat. Following chemotherapy recommended starts at maximum within 3 months of completing chemotherapy (e.g. patient factors) but ideally to start 4 weeks following completion.  Lymphoma falls into Category 2 patients 4.1. Radiotherapy Dose schedules Classical Hodgkin Lymphoma  Favourable Early Stage after 2 cycles ABVD 20Gy / 10 fractions over 2 weeks  Unfavourable Early Stage after 4 cycles ABVD 30Gy / 15-17 fractions  Unfavourable Early Stage after BEACOPP Dose may be reduced to 20Gy / 10 fractions  35-40Gy / 20 fractions may be considered in certain instances e.g. chemotherapy refractory disease. LPHD  Early stage, sole therapy 30-35Gy / 15-20 fractions (dependent on bulk and site) Non-Hodgkin Lymphoma  High grade Lymphoma 30Gy / 15-17 fractions  NK/ T cell Lymphoma requires higher doses of at least 50Gy in 2Gy/fraction  Primary CNS Lymphoma - Post chemotherapy 35-40Gy in 1.8-2Gy/fraction with boosting of residual volume to total of 45-50Gy  Low grade Lymphoma (e.g. Follicular Lymphoma) 24-30 Gy / 12-15 fractions 3 Examples of Palliative Schedules:  20-30Gy / 5-10 fractions  12Gy / 4 fractions  8Gy / single fraction  4Gy / 2 fractions 5. ESSENTIAL INVESTIGATIONS AND INFORMATION REQUIRED PRIOR TO DECISION TO TREAT FOR EBRT The following investigations should have been performed with results available before planning commences:  Clinical history  Baseline clinical examination and Performance Status  Histology  FBC, U+E’s, biochemical profile, LDH  Bone marrow evaluation  Results of staging investigations: CT and or FDG PET-CT. In some instances MRI may be of value e.g. Primary CNS lymphoma; disease in head and neck region  For patients receiving radiotherapy after chemotherapy, PET-CT / CT scans before and after treatment are used to determine the involved sites and residual disease. PET-CT pre and post chemotherapy is advised for ISRT (Involved Site Radiotherapy). 6. INFORMATION FOR PATIENTS Patients should be given an appropriate patient information leaflet about their treatment and have access to a lymphoma nurse clinical nurse specialist or other specialist practitioner. 7. CONSENT All patients must have given written informed consent before radiotherapy planning commences. Consent is to be taken by a practitioner who is familiar with lymphoma radiotherapy planning and administration. 8. TRIALS  IELSG 32 Randomised Phase2 trial of primary chemotherapy with high dose Methotrexate and high dose Cytarabine with or without Thiopeta and with or without rituximab followed by brain radiotherapy vs High dose chemotherapy supported by Autologous stem cell transplant for immune-competent patients with newly diagnosed primary CNS Lymphoma  UK Haplo v1.0 A UK multi-centre phase 2 trial of haplo-identical stem cell transplantation in patients with haematological malignancies  RIC UCBT Transplantation of umbilical cord blood from unrelated donors in patients with haematological diseases using a reduced intensity conditioning regimen 9. RADIOTHERAPY TREATMENT PLANNING: 9.1. POSITION / IMMOBILISATION  Patients to be planned and treated in the supine position.  Chin up position for neck and SCF sites. For head sites clinician to indicate appropriate neck position.  Appropriate immobilization for the site being treated is required. In head and neck regions this should include a customized immobilization shell. 4 9.2. IMAGE ACQUISITION  Patients are 3D-planned using data from a CT planning scan.  Contiguous slices with slice thickness of no more than 3mm taken through the region of interest.  i.v. contrast is recommended to improve identification of nodal chains unless there are specific contraindications. With common treatment planning systems, dosimetric calculations should not be influenced, except in sites such as mediastinum and para-aortic region where blood, volume is relatively large. Pre and post i.v. contrast planning CT scans are then required. It is recommended that each centre carry out a dosimetric analysis of the effects of contrast on the treatment planning calculations for individual anatomical sites. 9.3. VOLUME DELINEATION AND NOMENCLATURE Lymph node region atlases for CT planning have been published for major regions in the head and neck; trunk and pelvis and these should be referred to when outlining nodal regions. Involved Field Radiotherapy (IFRT) has been the standard with equivalence to wide field radiotherapy when used in combination with chemotherapy. Involve Site Radiotherapy (ISRT) has been utilized in recent paediatric Hodgkin Lymphoma protocols and in the recent 18-30 trial as a step to further reduce the radiation volume treated and hence probability of late effects. Validation from large datasets is awaited from the current clinical trials. Hoskin et al, (2013) recommended the adoption of ISRT for patients receiving combined modality treatment as long as appropriate pre-chemotherapy imaging is available. In this instance, FDG PET-CT would be advisable. If imaging is not available or radiotherapy is being used as sole therapy, IFRT should be used instead. Use of ISRT remains at clinician discretion with the patient fully counselled. GTV – Gross tumour volume CTV – Clinical Target volume IFRT – CTV definition  Involved field CTV (IF-CTV) will include the anatomical nodal region affected by lymphoma defined by the clinician as that which should be treated by radiotherapy.  IF-CTV will be outlined to include the involved nodal region, the margins of any tumour mass (primary or residual) in all dimensions, & the contigual nodal regions.  For patients who have had prior chemotherapy, the post chemotherapy volume is used in all directions except cranio-caudal direction where the pre-chemotherapy volume is used  There may be instances where it will be desirable to modify the IF–CTV to limit toxicity. This will be performed under the clinician’s discretion taking into account site of involvement. Involved nodal regions are described with summary as follows: Neck ipsilateral neck (mastoid – suprasternal notch) including supraclavicular fossa (SCF) Mediastinum lower neck (from top of thyroid cartilage), bilateral SCF to 5cm below lower extent of disease Mediastinum + hilum as for mediastinum but includes bilateral hilar nodes; Inferior border (INF) to bottom of T10 SCF includes ipsilateral neck. If mediastinum involved pre-chemo extend INF as per mediastinum node region Axilla includes ipsilateral lower neck, SCF and infra-clavicular fossa (ICF) (top of thyroid cartilage to axillary fold) Inguinal ipsilateral femoral, inguinal and external iliac node region; from bifurcation of common iliacs to Sartorius muscle (at approx. inferior border of lesser trochanter) External iliac ipsilateral inguinal, external iliac, internal iliac, obturator and common iliac node regions (from aortic bifurcation to inferior border of superior pubic ramus) 5 Femoral ipsilateral femoral and inguinal nodes; sup border = where external iliac becomes most superficial; INF border to Sartorius muscle Para-aortics bottom T10 to aortic bifurcation ISRT – CTV definition: CTV for Involved Site radiotherapy (IS-CTV) includes all initially involved sites. Pre-chemotherapy imaging is used to define the superior and inferior extent of the original disease. This is expanded cranio-caudally by 1.5cm in the direction of lymphatic spread to form the superior and inferior levels of the IS-CTV. In transverse plane, the IS-CTV includes the nodal chain (or organ) and any residual disease. It is not necessary to encompass entire nodal regions (or adjacent ones either). CTV is modified by hand to notextend into air, muscle planes or bones unless evidence of direct invasion. CTV delineation of Extra-nodal Sites: Maxillary antrum CTV = whole ipsilateral antrum. If disease extends beyond it CTV = prechemotherapy GTV + 10mm Waldeyer’s ring (WR) Conventionally lymphoma in any part would be treated with inclusion of all sites of the WR in the radiotherapy field and risks a dry mouth. Following the principles for nodal lymphoma the following is considered: CTV = pre-chemo GTV + 10mm, except 15mm cranio-caudally. If multiple contiguous sites affected, follow margins above. If other areas within the WR also suspicious, treat the whole ring. Orbit Conjunctival tumours: electrons or superficial X-rays with corneal shielding. Some form of eye fixation recommended. CTV = GTV+5mm. GTV=whole conjunctiva also option as difference in volume minimal. Lachrymal gland: CTV = entire gland, no margin. Orbit: Most will be marginal zone or diffuse large B-cell lymphomas. CTV=whole orbit, constrained to bone. Particularly localised tumours may have a partial orbit treated. Brain High Grade lymphoma. Phase 1 CTV = whole brain from frontal, parietal and occipital lobes down to the C1-C2 junction. The IELSG PCNSL trial treats whole brain post-chemotherapy to 36Gy and boosting the phase 2 residual volume with 1-2cm margin to 45Gy. Low grade lymphoma localised irradiation may be used. CTV = GTV+10 mm expansion constrained to bony and lobular anatomy. Shield the eye after 30Gy. Palliative elderly patients consider 30Gy / 15 fractions Parotid CTV = entire ipsilateral gland. Extra-capsular spread pre-chemotherapy: GTV = pre-chemotherapy volume; CTV = GTV+10 mm expansion Bone Conventionally whole bone irradiated after chemotherapy but not necessary in many cases. MRI is used to define pre-chemotherapy volume = GTV. CTV = 15 mm cranio-caudally along the bone marrow cavity and 10 mm in all other directions. Skin Low grade lymphoma: GTV=pre-chemotherapy volume. CTV=GTV with a 10 mm expansion. 6 Complete excision biopsy will not require radiotherapy. If positive excision margin, treat as above with the scar as GTV. Localised low grades may be treated using superficial techniques. Diffuse large B-cell lymphoma: more aggressive on leg than upper body. Outlining is same as for low-grade lymphoma but to a different dose. T-Cell lymphoma: Outlining is same as for low-grade lymphoma but to a different dose. Mycosis Fungoides: referral for TSEBT to be considered Palliative treatment: residual disease post-chemotherapy=GTV. CTV=same as for low grades. For multiple sites radiotherapy will be given to up to 4 sites. Stomach CTV = whole stomach. Patient preparation recommended e.g. fasting from midnight the day before. Treat earlier rather than later in the day. Testis CTV= whole sac. Electrons to be used wherever possible setting the testis in wax block for irradiation Lung Most will be MALT lymphoma. GTV=pre-chemotherapy volume. CTV=GTV+10mm expansion. Breast CTV = whole breast. Small, low-grade lesion may be treated with partial breast irradiation CTV = GTV + 10mm, constrained to tissue planes. Other organs e.g. thyroid, prostate and bladder CTV outlining is as for parotid. PTV – Planning target volume CTV is expanded in 3D to create the PTV to account for organ motion and set-up error. These are to be defined individually for each disease site and treatment centre. For guidance typical margins are as follows.  Head and Neck: 5 – 10mm  Mediastinum: 10mm transversely and 15mm cranio-caudally  All other sites: 10mm Organs at Risk: Organs at risk (OARs) depend upon the area to be treated. Tolerance doses must be defined for OARs DVH constraints for OAR OAR Limiting Dose / Volume Brain stem If whole organ irradiated, Dmax < 54Gy to any part of the volume. If partial volume D1-10cm3 < or = 59Gy Breast Minimise volume inside PTV, particularly in young women < or = 30 years. Mean dose< or = 2Gy Cochlea Mean dose < or = 45Gy Coronary artery Minimise volume inside treatment field and keep doses as low as possible without compromising on PTV coverage Heart Mean dose < 26Gy; D100 < 30Gy. V30 <46%; V33 <60%; V38 <33%; V42 < 20% Kidney Single kidney irradiated: V15 65-70% Both kidneys irradiated: V15 20-25% for each kidney; mean dose < 18 Gy Partial kidney irradiation (all constraints are for combined kidneys): mean doses < 18Gy, V28 <20%; V23 <30%; V20 <32%; V12 <55%. If mean dose to one kidney>18Gy, V6 for remaining kidney <30% Lens Maximum dose of 6Gy to any part of the volume, unless compromising PTV coverage Liver Mean dose < 32Gy; V40 of 30-35% D100 of 20Gy, D66 of 28Gy, D33 of 38Gy Lung (whole) V20 < or = 30%. Mean lung dose (MLD) < or = 20Gy 7 Oesophagus Mean dose < 34 Gy, V35 < 50% Optic Chiasm Maximum dose of 55Gy to any part of the volume Optic nerve Maximum dose of 55Gy to any part of the volume Ovary Maximum dose of 10Gy to any part of the volume outside the PTV. If inside the PTV discuss individual case with clinician Parotid Bilateral irradiation: mean dose <25 Gy Unilateral irradiation: mean dose <20Gy to the contra-lateral parotid Small bowel For individual loops V15 < 120cm3 For whole peritoneal cavity V45 <195cm3 Spinal cord Dependent on length of field. D max < or =50Gy to any part of the volume. For neck + mediastinum field D max < or = 42Gy Testis Maximum dose of 2Gy to any part of the volume Thyroid D100<45 Gy 9.4. PLANNING / TECHNIQUE 3D planning using CT data Consider 4D imaging or deep inspiratory breath-hold technique for disease sites significantly affected by respiratory motion. 9.5. TREATMENT TECHNIQUE Conformal plan with field arrangements devised according to treatment site. A parallel-opposed field arrangement often remains the preferred beam arrangement. IMRT may be found beneficial for head and neck sites e.g. NK-Tcell lymphoma of nasopharynx. Inspiratory breath-hold techniques and image guided radiotherapy may offer advantage in certain scenarios and to be considered. 9.6. TREATMENT VERIFICATION Linac Verification Image guided verification desirable particularly for sites adjacent to critical dose limiting OAR and in the retreatment setting. 9.7. ON TREATMENT REVIEW DEFINITION AND SCHEDULE GAP CATEGORY FOR MANAGEMENT OF UNSCHEDULED INTERRUPTIONS Weekly review for assessment and documentation of toxicity Toxicity - according to site and extent of OAR exposure. All toxicities to be explained to the patient at time consent obtained. In addition, irradiation of lymph node sites may lead to lymphedema. Acute Toxicities: Head and Neck sore throat Dysphagia Mediastinum Pneumonitis Skin Erythema Hair loss Abdomen and pelvis Nausea Loose stools Cystitis Late Toxicities Neck hypothyroidism Mediastinum Pulmonary fibrosis Cardiac effects – ischaemic heart disease; heart valve toxicity; pericarditis; pericardial effusion; 8 Pelvic Infertility Early menopause Late bowel and bladder toxicity Second malignancy Breast cancer in young women Follow up  OPA 4-6 weeks following completion of radiotherapy