Harnessing benefit of highly conformal RT techniques for lymphoma patients

Abstract

This status article describes current state-of-the-art radiotherapy for lymphomas and new emerging techniques. Current state-of-the-art radiotherapy is sophisticated, individualised, CT-based, intensity-modulated treatment, using PET/CT to define the target. The concept of involved site radiotherapy should be used, delineating the target using the exact same principles as for solid tumours. The optimal treatment delivery includes motion management and online treatment verification systems, which reduce intra- and interfractional anatomical variation. Emerging radiotherapy techniques in lymphomas include adaptive radiotherapy in MR- and CT-based treatment systems and proton therapy. The next generation linear accelerators have the capability to deliver adaptive treatment and allow relatively quick online adaptation to the daily variations of the anatomy. The computer systems use machine leaning to facilitate rapid automatic contouring of the target and organs-at-risk. Moreover, emerging MR-based planning and treatment facilities allow target definition directly from MR scans and allow intra-fractional tracking of structures recognisable on MR. Proton facilities are now being widely implemented. The benefits of proton therapy are due to the physical properties of protons, which in many cases allow sparing of normal tissue. The variety of techniques in modern radiotherapy means that the radiation oncologist must be able to choose the right technique for each patient. The choice is mainly based on experience and standard protocols, but new systems calculating risks for the patients with a specific treatment plan and also systems integrating clinical factors and risk factors into the planning process itself are emerging.

Introduction

The technological development within imaging, computerised planning systems, and treatment delivery has been incredible in recent decades. First of all, the development in imaging techniques has dramatically improved the ability to define the target for radiotherapy; from standardised regional targets based on bony landmarks to individualised volumes based on the actual lymphoma location. Secondly, the technological progression has changed treatment planning of radiotherapy from calculations based on assumptions on body size and composition to planning based on calculations of absorbed dose based on CT scan of the actual patient. Thirdly, delivery has progressed from 2D delivered radiation with different attenuation devices delivered to large targets to very precisely delivery intensity modulated doses to the defined target volumes. Fourthly, verification of treatment delivery using modern imaging ensures that radiation is delivered correctly at every treatment fraction.

The aim of this paper is to briefly describe the current state-of-the-art radiotherapy for lymphomas and to outline the current development in treatment technologies and the clinical perspectives hereof.

Current state-of-the-art

Radiotherapy for lymphoma has evolved significantly from the days of extended fields, using large anterior and posterior fields based on bony landmarks. The most important development has been the reduction in the size target volumes, reducing the radiation delivered to normal tissues without compromise of tumour control. We also have superior imaging techniques, allowing for better targeting and better patient selection for treatment. Finally, we have improved RT technology as will be described in this paper.

Current optimal treatment is individualised and highly conformal, delivering a homogeneous dose to well-defined target volume, with as low dose as possible to normal tissues. In most situations, the concept of involved site radiotherapy (ISRT) should be applied.¹ ISRT has replaced extended or involved field radiotherapy (IFRT) and means treatment of the original tissue volume which contained lymphoma before systemic therapy, adjusted to changes in anatomy and differences in patient position on imaging as per ILROG guidelines. If RT is the only modality used with no prior systemic therapy, considerations should be given to including adjacent areas at high risk of having subclinical disease. An ISRT treatment volume will usually be smaller than traditional involved field RT (IFRT), as the whole anatomical region does not always need to be included.

Involved node radiotherapy (INRT) is a special case of ISRT, where pre-chemotherapy imaging is optimal, allowing only inclusion of the involved nodes with no additional extension.

The delivery of optimal RT for lymphoma depends on the availability of contemporary and high-quality diagnostic imaging. Most lymphomas are FDG avid, so 18FDG PET-CT is the imaging modality of choice, if not available otherwise CT with contrast should be used.² For certain sites, such as head and neck, central nervous system and bone, MR may give additional useful clinical information. The baseline imaging should be coregistered with planning CT scans, to aid delineation of the target volume. Ideally, diagnostic imaging should be performed in the RT treatment position as possible. This allows more accurate image fusion and thus less positional uncertainty but requires close collaboration between the radiotherapy and diagnostic imaging services and anticipation of RT as a part of the treatment plan from early in the patient’s management pathway.

RT treatment should be CT planned using IV contrast if renal function permits this. For gastric and upper abdominal treatment volumes, a fasting protocol is advisable to reduce variation due to gas and gastric fluid.

The patient should be immobilised according to the site, for example with a thermoplastic mask for head and neck treatments. Patients receiving mediastinal radiotherapy will typically be treated on a thoracic board, with arms above head. On occasion, it may be preferable to treat a female with arms by the side or inclined on a breast board. Both of these manoeuvres move the breast tissue down and laterally and potentially away from the target volume.

Motion management

Motion management should be considered for mediastinal and upper abdominal treatment sites. There are several methods of managing respiratory motion, but in lymphoma radiotherapy, DIBH (Deep Inspiration Breath Hold) appears to be the most beneficial. Treating the patient in DI (Deep Inspiration) as opposed to using other techniques such as 4DCT, gating or end expiration breath hold (EEBH), has two main advantages. Firstly, by eliminating respiratory motion, it is possible to reduce internal margin and thus the overall PTV volume, which in turn will decrease the volume of normal tissue irradiated.³ Secondly, the anatomical changes during DI are favourable to organ sparing. For example, the lung expansion during DI means that relatively less lung tissue is irradiated, resulting in lower lung doses, particularly for the low doses (V5). The heart moves downwards during inspiration; for upper mediastinal target volumes, this will result in less overlap between the PTV and the heart, again allowing a reduction in dose to a critical structure^4–8 (Figure 1). However even in DIBH, there will be some displacement of the heart and its substructures during the phases of cardiac cycle. This should be taken into account during planning, with consideration of the use of expansion margins for substructures such as the coronary arteries.⁹

Figure 1.

Illustrating the volume of the lungs and heart receiving 20 Gy or more with free breathing (FB) and deep inspiration breath-hold (DIBH) in a patient treated with parallel opposing fields (upper panel) and a patient treated with intensity-modulated radiotherapy (lower panel). These coronal views illustrate the increased lung volume with deep inspiration breath-hold and that the heart is pulled caudally with deep inspiration.

DIBH can also be used in upper abdominal irradiation (gastric lymphoma, for instance), as can EEBH. The advantage of DIBH over EEBH in this situation is that during DIBH, the heart becomes elongated and pulls away from the diaphragm, thus again increases the separation between the heart and the treatment volume, reducing dose to the inferior part of the heart.^10,11 Whichever technique of motion management is used, it is imperative that there is robust monitoring and verification.

Treatment planning

To achieve the high level of conformity and organ sparing desired in lymphoma RT, an intensity-modulated radiotherapy (IMRT) solution is preferable in most situations. With IMRT, homogeneous coverage of the target volume, high conformity and a rapid dose gradient is readily achievable, even with complex volumes. It is also possible to deliver simultaneous boosts to high-risk tumour subvolumes. Modern software systems, and the transition from static field IMRT techniques to rotational based therapies, such as volumetric modulated arc therapy (VMAT) and helical tomotherapy, have further increased dosimetric capabilities, with reduced optimisation and treatment times.

The disadvantage of IMRT is the inevitable low-dose bath to normal tissues, particularly with full-arc VMAT. Lymphoma patients receive treatment in their 20 s and 30 s, this is of particular concern, due to the risk of second malignancy,^12,13 most notably breast cancer in young females.¹⁴ The incidence of pneumonitis, rarely a potentially life threatening side-effect of mediastinal radiotherapy for lymphoma, is also related to the proportion of lung tissue within the low-dose bath, with risk significantly increased with lung V5 >55%.¹⁵ This means that, during plan review, it is important not only to evaluate target volume coverage and OAR dose constraints assessment but also to carefully review the distribution of the lower isodoses and to ensure the optimal compromise with an ‘intelligent’ plan.

An example of intelligent IMRT is the ‘butterfly technique’, used for treating mediastinal volumes.¹⁶ This has been described using both static field IMRT and VMAT.^16,17 Butterfly VMAT comprises multiple partial arcs, including at least one non-coplanar anterior arc (Figure 2). This main dosimetric advantage of this beam arrangement, as opposed to full arc VMAT, is the relative sparing of breast tissue and reduction in lung exposure. The downside is a small loss of conformity around the heart, with a possible increase in cardiac exposure, although newer adaptations of butterfly VMAT, such as full arc butterfly ‘FaB VMAT’, along with substructure contouring and avoidance may improve cardiac sparing.^8,9,18

Figure 2.

Dose distributions for coronal and axial planes are shown with doses >3.06 Gy displayed (10% of the prescription dose). a and c: DIBH Butterfly - VMAT; b and d: DIBH Full arc-VMAT. The figure is adapted from reference (3) after permission from the publisher, Elsevier.

3D conformal RT (3D-CRT) retains a place in modern lymphoma RT in special cases. For certain sites/indications, there may be little dosimetric benefit from using a more complex technique, such as when treating the breast, bilateral parotid glands and orbits. There are also situations in which a 3D-CRT solution may be preferable, to allow maximal sparing of an adjacent body region or organ. This includes the patient who has had prior radiotherapy to the contralateral side, or the young patient receiving unilateral pelvic radiotherapy, for whom preservation of gonadal function is a goal.

Dose constraints

Dose constraints in lymphoma RT should be individualised and tailored in the individual patient to achieve a balance between the benefit from RT and the risk of toxicity. Acute toxicity is rarely a significant concern in lymphoma RT due to the lower doses needed compared to solid tumours and more attention is paid to long-term toxicity. Therefore, QUANTEC dose constraints are not relevant in most cases and dose constraints should be individually decided according to the ALARA principle (as low as reasonably achievable), with consideration given to the benefit from RT versus estimated long-term toxicity based on the disease location, patient age and sex, and comorbidities. For example, breast constraints are less relevant in the post-menopausal female when the risk of radiation-induced breast cancer is low. Another example is the consideration of the purpose of treatment. For early-stage disease, the addition of RT to systemic treatment in responding cases offers a small but well-defined improvement in disease control and in these cases prevention of long-term toxicity should be a priority. On the other hand, when treating refractory disease, the main concern is controlling the resistant lymphoma and therefore target volume coverage takes the priority and higher dose constraints for OAR would be accepted. An example of applied dose constraints are shown in Table 1.

Table 1.

Suggestions for radiation dose constraints in lymphoma patients. Adapted from Dabaja¹⁹ et al 2018 and Wirth A et al 2020¹.

Organ	Optimala	Acceptableb	If necessaryc	Avoid
Heart
Mean (Gy)	<5	5–10	10–18	Coronary arteris and left ventricle
V15d	<10%	10–25%	25–35%
V30		<15%	15–20%
Lung
V5	<35%	35–45%	45–55%
V20	<20%	20–28%	28–35%
Mean (Gy)	<8	8–12	12–15
Thyroid				Whole thyroid
V25	<62%
Breast
Mean (Gy)	<4	4–15	>15
V4	<10%	10–20%	>20%
V10		<10%	>10%

^aFavourable disease, small volume early stage lymphoma.

^bFor bulky mediastinal lymphoma.

^cRelapse/refractory setting.

^dV₁₅: Voume treated to a dose of 15 Gy or more.

Treatment delivery and verification

To ensure accuracy of treatment delivery, it is important to have robust systems in place for verification. As the complexity of treatment has increased, so has the need for more advanced monitoring techniques to guarantee our treatment is on target.

Image-guided radiation therapy (IGRT) uses imaging obtained immediately before, during or immediately after radiation delivery to evaluate and correct set up errors. Online imaging, when images are reviewed before or during treatment, is optimal in modern lymphoma RT, as this allows intervention before delivery is completed. Images may be acquired using CT (KV or MV), planar images (KV) or portal imaging (MV).

CT imaging provides better assessment of soft tissue structures such as the mediastinum or abdomen, allowing easier evaluation of the target volume and organs at risk. Given the complexity of many lymphoma target volumes, daily cone beam CT imaging is often required to ensure consistent coverage of the target.^2,20 For the more stable set up such as when treating the head and neck, less frequent imaging or KV planar images may suffice. With any verification schedule, it is important to balance potential risk from geometric error, to that of additional radiation exposure from the imaging used.

Use of a BH monitoring system such as surface tracking or real time position management (RPM) should be complimentary to, but not replacing verification, as the external anatomy is not a reliable surrogate for changes in internal geometry.

New emerging techniques

The technology has changed substantially during the past 20 years, so therapeutic radiation has now developed from 2D photon or electron beam radiation to sophisticated computerised 3- or 4D IMRT. More recent developments include the use of adaptive radiotherapy, using both MR- and CT-based imaging systems. There has also been an expansion of the number of centres delivering proton therapy, and significant interest in the use of protons in the treatment of many tumour types. Here, we describe some of these advances and their current and potential role in the treatment of lymphomas.

CT based adaptive photon treatment

The next-generation linear accelerators have the capability to deliver 3D adaptive treatment and are being installed in many academic centres across the world. These systems allow relatively quick online adaptation to the daily variations of the anatomy. The computer systems use machine leaning to facilitate rapid automatic contouring of the target and organs at risk.²¹ For this, the target and the organs at risk must be visible and recognisable on a cone-beam CT. The system does allow respiratory gating but does not allow tracking during treatment.

Adaptative radiotherapy is relevant if tumour shrinks, (response adapted radiotherapy (R-ART)) or if the anatomical variations due to changes in surrounding organs at risk, for example, bowel filling/emptying or pleural effusion (anatomy-adapted radiotherapy (A-ART)).²² In both situations, the aim of adaptive radiotherapy is to ensure delivery of prescribed dose to the tumour and to keep dose to the organs at risk as low as possible despite the anatomical variations.²²

A variety of studies have shown different approaches to re-planning of radiotherapy during the course of radiation in a variety of cancers. Dose sparing of salivary glands has, for example, been shown in head and neck cancer.²³ Re-planning in lymphoma treatment is sometimes required if there has been a substantial change in anatomy, or the tumour has responded with significant shrinkage. However, this has seldom been done systematically with predefined criteria. Modern radiotherapy units now allow a daily online re-planning after a CBCT. The units have computer programs with artificial intelligence, which allows for automatic contouring of target and organs at risk.

Clinical aspects

No studies have been published in lymphomas and currently we have no evidence for clinical benefit of CT-based treatment with daily online adaptation of the treatment to variations in anatomy, but the impact of R-ART on local control and toxicity outcomes is actively being investigated in several currently accruing trials, for example bladder and lung cancers.^24,25

In lymphomas, the main benefit from this technology would be to reduce dose to organs at risk, without compromising dose to the target, with the aim of decreasing the risk of late effects whilst maintaining disease control. Given the relatively low doses used in lymphoma, acute toxicity is rarely a significant clinical problem. A challenge when using adaptive RT in lymphoma treatment might be the complex geometry of some of the treatment volumes, compared to a prostate or bladder. It may also be limited by the fact that many patients are treated post-chemotherapy, without a visible treatment target for the software to identify on the online imaging; however, A-ART might most useful in patients with large variation in anatomy for example abdominal volumes, affected by bowel gas, gastric or bladder filling, but the technique must still be used primarily in clinical studies. R-ART may be relevant in cases where there is significant tumour bulk at the outset, with shrinkage anticipated on treatment, especially if the volume is close to an OAR, for example, in large mediastinal lymphomas close to the heart, especially as the technique allows treatment in DIBH.

MR-guided adaptive radiation therapy

Facilities for MR-based planning and treatment are now being installed in some academic centres. These machines allow target definition directly from a planning MR and allow tracking of structures recognisable on MR. In addition, adaptation of the treatment to daily variations in anatomy is possible.²⁶

The improved visualisation of the gross tumour and adjacent normal tissues and MR done during the course of radiotherapy and even during each radiotherapy fraction may improve the ability to adjust treatment to variations in anatomy. Therefore, radiation treatment systems based on onboard MR imaging has been developed.

Workflow

A CT scan is done for electron density and a 3D planning MR-scan is done in order to plan the treatment. The MR-scan can be done in breath-hold or sampled in a certain part of the breathing cycle in order to improve the quality of the imaging. Contouring is then based on MR and CT is used only for dose calculations, both primarily and during adaptation. IMRT planning is then done using a Monte Carlo dose calculation with magnetic field corrections.

The process of adaptation includes deformation of electron density and auto-segmentation. A re-optimisation of the treatment plan is based on the actual anatomy of the day. In addition, some systems allow for continuous tracking of the target during treatment, which will enable gating of the radiation beam. A tracking region of interest is applied and the gating is based on the percentage of the tracking area which stays within this region.²⁷

Clinical aspects

This treatment technique has shown to be feasible in pancreatic tumours,²⁸ liver metastases and prostate cancer,²⁹ but is not tested in randomised studies. Currently, most studies have looked at large fraction dose to limited size tumours and shown ability to limit radiation to organs at risk, contributing to the improved safety of hypofractionated schedules.

One gastric lymphoma case has although been published, clearly illustrating the problems in gastric lymphoma radiation.²⁷ Gastric lymphoma radiotherapy might be improved with MR-guided adaptive radiation therapy because the target is visible on MR scans and a large interfraction stomach deformation can happen and both factors can be handled with this technique allowing us to limit the dose to surrounding organs. The future role of this technique in lymphoma depends on whether further development will create a quicker treatment delivery and improve the dose delivery (better treatment plans). Currently this technique is exploratory in lymphomas.

Proton radiation therapy

Over the past 20 years, there has been a significant rise in the capacity to treat patients using particle therapies (protons and light ions). Facilities have developed from big scientific facilities with limited clinical use, to commercial clinical units, and particle facilities are now becoming available to patients in most industrialised countries (https://www.ptcog.ch/). The physical properties of protons and light ions allow sparing of radiation to organs at risk in many situations and limits low dose bath compared to modern photon IMRT. However, particle radiation delivery is very sensitive to anatomical changes such as tumour shrinkage and respiratory movements and measures to correct for these factors are not always available clinically. As lymphoma particle treatment experience is limited to proton treatment, we discuss this below.

Physical properties

The main advantage of proton over photon RT is the concentrated deposition of the dose at a narrow depth range, known as the Bragg-Peak, which is determined by the beam energy. This results in complete fall-off of dose beyond the Bragg-Peak and low dose in the beam path towards the peak. Protons are also assumed to cause double-DNA strand-break due to the higher energy transfer and thereby cause cell death directly. Radiation relative biological effectiveness (RBE) is assumed to have an average value of 1.1 compared to photons; however, this value changes along the beam path and increases towards the Bragg-Peak. Care should be taken if the distal edge of the tumour is immediately adjacent to an OAR as the Bragg Peak, with its increased RBE, could extend to OAR with minor changes in tissue density and/or organ displacement.

Beam types

Currently, three types of beams are used in proton therapy, passive scattering, uniform scanning beam and pencil beam scanning:

Passive scattering uses one thin beam line through a scatter foil to widen it to fit the tumour. A modulator or range shifter is used to create a range of beams with different depth. Passive scattering requires custom-made collimator to shape the beam and compensator to fit the beams to the depth, but this treatment is relatively fast.

Uniform scanning uses magnets to scan a broad beam across a treatment field. This type of scanning still requires the use of collimators to shape the beam and compensator to fit the beam to the depth; however, treatment is relatively fast.

Pencil beam scanning delivers the radiation with a small beam which is steered by magnets, thus eliminating the need for the collimator and compensator; however, this treatment is relatively slow and is more sensitive to anatomical changes and variations both during and between treatment fractions. This means that organ motion needs to be addressed very carefully.

Multifield optimisation improves conformity compared to single-field optimisation at the expense of robustness and resource requirements. Intensity-modulated proton therapy (IMPT) (like IMRT for photon treatment) integrates pencil beam scanning fields into an integrated treatment plan to cover a target with pre-specified doses and to avoid dose to organs at risk. IMPT increases robustness at the expense of larger low dose volumes to organs at risk.

Uncertainties

One major source of uncertainty in proton therapy is calculating the range of the protons in tissue. This is due to both the uncertainty in the conversion of computed tomography (CT) number to proton linear stopping power and differences in the anatomy during treatment relative to the anatomy of the planning CT. These anatomical differences can include changes due to patient positioning, organ motion (e.g., respiratory and cardiac motion) and other changes such as tumour shrinkage. Together, these factors result in uncertainty in the exact range of the protons in the patient and could result in a difference between the simulated and actual-delivered proton dose.¹⁹

These uncertainties are kept as low as possible by relevant imaging, by careful motion management (e.g., 4-D imaging, breath hold), and by creating robustness analysis of different scenarios of positioning and movement.

The biological effect (the relative biological effectiveness [RBE]) of protons along the beam path, which affects targets and normal tissue, is also uncertain. It is suggested that the RBE is higher in the range of the Bragg-Peak, but still uncertain how much higher. Furthermore, the RBE is often assumed to be 1.1 relative to photons, but in fact we do not have the clinical data to assess the RBE precisely in different tissues.

Clinical aspects

So far, no clinical Phase 2/3 studies have investigated outcome of proton therapy in lymphomas, compared to photon radiotherapy.³⁰ The largest prospective cohort study of selected Hodgkin lymphoma patients (n = 138, 42% paediatric) getting consolidation proton therapy after standard chemotherapy found similar results to photon radiotherapy with excellent relapse-free survival with a favourable acute toxicity profile including very low rates of pneumonitis.³¹ A comprehensive review of implementation of proton therapy in lymphomas and of the clinical data finds that proton therapy may reduce long-term toxicity in selected patients. Based on the limited clinical data, on the limited availability, the patients shall be selected carefully after comparative treatment planning with photon therapy.³² A number of dosimetric studies have shown overall favourable dose distributions to organs at risk in terms of good dose coverage and better sparing of organs at risk^33–37 (Figure 3). The magnitude of the dosimetric benefit depends on the selection of cases, which means the size and location of the lymphomas. Studies have shown that treatment in deep inspiration breath hold is important in radiation treatment of mediastinal lymphomas and that at least for some patients the benefit from DIBH is in the same magnitude as the benefit from proton treatment.^33–35 However, for tumours extending to the inferior part of the mediastinum, the dosimetric benefit of protons seems more pronounced.^38,39 The studies also show that the magnitude of benefit from proton treatment varies significantly between patients.³⁹

Figure 3.

Illustrating the dosimetric benefit of intensity modulated proton therapy (right) in a case of mediastinal Hodgkin lymphoma compared to volumetric arc photon therapy (left). The volume receiving 30% or more of the prescribed 30.6 Gy is shown.

Whether a dosimetric benefit from particle therapy translates into a clinical benefit, basically should be tested in randomised trials. However, because tumour control is generally excellent in lymphomas and acute toxicity modest, the endpoints for such trials needs to be long-term toxicity with many participants. Therefor, we for now need to rely on the dosimetric comparisons and calculation of benefit from known relations between dose and long-term toxicity to choose modality.

Selection of patients for Proton therapy

As proton therapy is less available and more expensive, clinicians need to select which patients to refer to proton treatment. In many situations, the final decision is made on the basis of comparing two plans for the same patient, protons and photons, to decide if there is a significant dosimetric benefit from protons for the specific course of treatment. However, there are no agreed criteria for the magnitude of benefit that would justify proton treatment and more studies are needed.

In this respect, ILROG has issued consensus guidelines to help define which patients may benefit from protons for mediastinal RT. The guidelines suggest that lymphoma patients who can greatly benefit from proton therapy include¹ patients with mediastinal disease that spans below the origin of the left main stem coronary artery and is anterior to, posterior to, or on the left side of the heart²; young female patients for whom proton therapy can reduce breast dose and risk for secondary breast cancer; and³ heavily pretreated patients who are at higher risk for radiation-related toxicity to the bone marrow, heart, and lungs.

Proton therapy might also spare the testes of young males treated with radiotherapy for inguinal lymphoma.

Guidelines for other lymphoma sites are currently lacking but in clinical practice protons are commonly used for craniospinal irradiation, some head and neck sites, paediatrics and for retreatment.

How to choose the optimal treatment

Radiation oncologists make decision about individual plans every day. The choice of a treatment plan for an individual patient is mostly based on experience, implemented treatment protocols and guidelines, for example, ILROG guidelines.

The factors included in this decision are dose coverage to the target, dose to surrounding organs and dose homogeneity. Also, clinical factors of the disease, of comorbidity and the patient’s age are important factors, for example, the benefit of breast sparing is important in young female but not in elderly patients, and heart sparing is more important in patients with cardiac disease or patients who have received certain chemotherapy agents. So, in everyday practice, radiation oncologists must make individualised compromises between dose coverage and limiting dose to organs at risk and must prioritise dose to different organs at risk. In most cases, the current state-of-the-art treatment is an excellent treatment.

In lymphoma radiotherapy, acute toxicity is rare due to the moderate dose levels needed, so the focus for new technologies is mostly to limit long-term toxicities such as cardio-vascular disease, renal failure, second cancers and less often CNS toxicity. A large report has reviewed the knowledge of dose and toxicity from a variety of organs⁴⁰ and probability for a given toxicity is estimated from dose-response estimates based on previous studies, for example, heart toxicity.^41,42 Calculation of life years lost is also used in studies comparing different techniques.⁴³ This principle is based on dose-response calculations for risk of death due to specific organs, for example, risk of cardiac death due to a spectrum of cardiac radiation dose. Tools to predict the risk of life years lost in an individual case has been suggested.³³ With such a tool, the radiation oncologist could prioritise the dose to organs at risk from estimates on the death from different reasons, for example, the combination of the risk of dying due to cardiac disease and a second breast or lung cancer.^33,43 In most cases, no reliable long-term data exist to establish a precise normal tissue complication model, however modern planning allows sampling of precise dose estimates for virtually every organ, so in the future such data will be available, if precise data on long-term effect are collected.

The special issue of BJR on lymphoma radiotherapy has a paper that describes the idea to integrate patient-specific factors such as patient-specific risk factors and patient preferences, lymphoma subtype, anatomic location and extend of disease, response to chemotherapy and normal structure radiation tolerances directly into the treatment planning using automatic processes (ref: Arezoo Modiri, BJR)

Conclusions

Lymphoma RT is unique in the variability of target volumes, purpose of treatment and risks of toxicity in individual patients. The use of technological advances should be optimised to maximise the benefit-risk balance for the individual patients. This requires adequate clinical experience and understanding of disease, patient and technological factors. Current state-of-the-art radiotherapy for lymphoma provides excellent balance in most cases. New technologies in RT, including the adaptive radiotherapy, using both MR and CT based imaging systems and protons, may have a role in lymphoma RT. Early evidence shows dosimetric advantage however with the relatively low doses used in lymphomas, improvements are modest and are limited to a proportion of cases. More research is required into patient selection for newer technologies and into quantifying long-term reduction in clinical complications.