Abstract: The combination of brief chemo-radiotherapy provides high cure rates and represents the first line of treatment for many lymphoma patients. As a result, a high proportion of long-term survivors may experience treatment-related toxic events many years later. Excess and unintended radiation dose to organs at risk (particularly heart, lungs and breasts) may translate in an increased risk of cardiovascular events and second cancers after a few decades. Minimizing dose to organs at risk is thus pivotal to restrain the risk of long-term complications. Proton therapy, with its peculiar physic properties, may help to better spare organs at risk and consequently to reduce toxicities especially in patients receiving mediastinal radiotherapy. Herein, we review the physical basis of proton therapy and the rationale for its implementation in lymphoma patients, with a detailed description of the clinical data. We also discuss the potential disadvantages and uncertainties of protons that may limit their application and critically review the dosimetric studies comparing the risk of late complications between proton and photon radiotherapy.

Keywords: proton therapy, lymphoma, Hodgkin, radiotherapy

INTRODUCTION

Lymphomas are the most common hematologic malignancies worldwide and, despite their different disease processes and histology, have a much more favorable outcome than solid tumors. Particularly, combined chemo-radiotherapy cures most Hodgkin’s lymphoma (HL) patients, with roughly 70–80% of them surviving many decades after treatment.^1–4 In contrast to HL, non-Hodgkin lymphomas (NHL) have less favorable outcomes but, in general, survival rates in the long term are better than those of most solid tumors.⁵ Given their favorable outcome, the reduction of treatment-related toxic effects is the cornerstone of recent advances in the treatment of HL and NHL. Specially, the likelihood of long-term survival raises the issue of long-term complications, mostly related to latent radiation injuries from combined curative treatments.⁶ In particular, long-term reports of large cohorts and national registries have produced a strong evidence that the benefits from radiation may be counterbalanced, decades later, by increased mortality and morbidity from cardiovascular events and second cancers.^7–9 This evidence lead hematologists and clinical oncologists to accept increased relapse rates as a barter for omitting radiotherapy (RT) altogether.^10,11 At the same time, efforts have been done from the whole radiation oncology community to minimize RT-related complications to organs adjacent to the target of treatment, particularly to thoracic organs at risk (OARs) as breasts, heart, and lungs by reducing the prescribed RT dose and treatment fields without compromising cure rates.¹² In particular, the new concepts of involved-site RT (ISRT) and involved-node RT (INRT) were recently developed for the definition of smaller treatment volumes. Despite marginal differences, in both concepts, the pre-chemotherapy disease involvement determines the clinical target volume, resulting in greater sparing of OARs compared to the older volumes.¹³ Proton therapy (PT), with its particular ballistic characteristics favoring a low entrance dose and a step fall-off of the dose at the end of the beam range (“Bragg peak”), offers a great opportunity to further minimize the risk of long-term complication related to photon-based radiation while keeping the increased initial cure rate offered by RT. However, PT requires a complex treatment planning, is more expensive than photons and still suffers from some uncertainties. For these reasons, the decision of PT referral should always be driven by a dosimetric comparison with an optimally planned photon treatment in order to demonstrate a clinical benefit for the patient, as already carried out for other tumors.¹⁴ In this article, 1) we review the ability of PT in reducing dose to organs at risk with an overview of the current techniques for treatment delivering and of the published clinical data, 2) we describe the actual uncertainties which may limit its application in lymphomas, 3) and we report a detailed summary of the radiation dosimetry literature comparing PT and photons.

TECHNICAL ASPECTS FOR LYMPHOMAS AND CURRENT TECHNIQUES IN DELIVERING PROTON THERAPY

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Individualized treatment planning with PT is based on various factors including patient-specific factors such as age, gender, previous treatment, disease location, baseline co-morbidities, and findings from initial disease extension, evaluated with PET/CT scan. Modern radiation planning using ISRT techniques requires appropriate image fusion with functional (usually pretreatment/chemotherapy) imaging to identify the initial sites of involvement.^13,15,16

During the CT simulation (ideally with intravenous contrast), for cases involving the mediastinum, a 4-dimensional CT scan is often utilized to determine breathing motion and the appropriate internal target volume (ITV) margin. Also, the deep-inspiration breath-hold (DIBH) technique can be used to reduce the breathing motion of the mediastinum, thus narrowing the mediastinal target, while minimizing the exposure of lung and heart. Modern studies demonstrate that the lowest doses to the nearby organs at risk are obtained for patients treated with PT and DIBH (compared to photons), if clinically available.¹⁷ Currently, there are various PT techniques clinically available for cancer patients. This includes passive scattering technique and pencil beam scanning (PBS) techniques.

Passive Scattering

Treatment planning goals for lymphomas with passive-scattered proton beams are to irradiate the target with an adequate dose while reducing the integral dose to the patient, and the commonly utilized technique is the double-scatter (DS) method. The relative size and heterogeneity of the targets can often present a challenge with the DS techniques. Limitations of the passive-scattering delivery technique include the following: field size (maximum), inability to conform the dose proximally to the target, and poor conformality distal to the target (compared to spot scanning). Advantages to passive scattering delivery include increased plan robustness to patient and target motion uncertainties relative to PBS. With appropriate margins and smearing techniques, passive scattering plans are less sensitive to motion and density changes in the beam path.

Most commonly, the treatment planning strategy for passive-scattered PT is to assign the clinical target volume (CTV) or ITV as the beam target. Many treatment planning systems allow that margins be applied for proton range uncertainties, distally and proximally, directly in the properties of each beam. Various institutions use a formula for inherent range uncertainties similar to that described by Moyers et al: (Margin = α % Range + β mm, where α is related to uncertainties in dose calculation).¹⁸ This margin accounts for various factors including relative proton stopping power conversion factor, beam-delivery reproducibility, treatment planning system commissioning accuracy, and compensator design. The effects of setup errors on the proton range are compensated by range compensator smearing (thinning) calculated using Urie et al¹⁹. Additionally, collimator margins for the lateral penumbra are set to the planning target volume (PTV) or CTV with an adequate expansion for setup variations. Appropriate margins can be set to ensure target coverage along and perpendicular to each beam. Uncertainties due to potential relative biological effectiveness (RBE) variations along the spread-out Bragg peak can be reduced by using multiple treatment fields, rather than single fields. For example, if a single field is used, a single spot of potential high RBE would be delivered to the entire prescription dose rather than a fraction of the full prescription dose.

Plan evaluation, similarly to photons, is based on target coverage goals, OAR dose constraints, and plan quality indices such as integral dose and dose conformality. Frequently, the plans are normalized to the optimal CTV coverage, but PTV coverage requirements certainly help facilitate photon and proton plan comparisons. It is important to note that the treatment time can vary from 30 to 90 mins depending on the number of isocenters and fields being treated each day.²⁰

Below is a summary of the treatment planning specifics of PT planning, specifically DS technique:

A. 3D-conformal treatment

Manually laborious, forward planned

B. CTV and normal structures are delineated in the same way as for photons.

C. For static geometries, the plan target is the CTV, while when the treatment area is affected by breathing motion an ITV that includes CTV motion is derived from the 4D-CT.

D. For lateral beam shaping, expansions for setup uncertainty and inter-fractional anatomy variability are applied to the CTV/ITV.

E. Patient-specific beam collimators conform the dose laterally to the CTV/ITV with a margin for penumbra (1 to 10 mm). Range compensators are designed for each beam to conform the dose distally to the CTV/ITV. “Smearing” is applied to compensate for proton range changes due to density changes in the beam path.

F. Additionally, along each beam, distal and proximal margins are set to the CTV/ITV to compensate for proton range uncertainties as described above.¹⁸

G. In the current practice of scatter techniques, margins to the CTV/ITV are assigned per beam:

Collimator margins for the lateral penumbra are set to the PTV with an expansion for setup variations.
Distal and proximal margins depend on depth of the distal and proximal edges of the target. This is “beam-specific planning target volume.”

H. Beam selection and orientation depend on the unique disease distribution for each patient.

I. Whenever possible, the preference is to use anterior or posterior fields, rather than both, to the same targeted area in the mediastinum.

See below examples of treatment planning in a young patient with classical HL using PT with and without DIBH (Figures 1–3).

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Proton Therapy For Lymphomas: Current State Of The Art

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