Potential Morbidity Reduction With Proton Radiation Therapy for Breast Cancer☆
Introduction
Adjuvant radiotherapy (RT) confers significant local control and overall survival benefits for breast cancer patients, in both the breast conservation and postmastectomy settings.1, 2, 3 However, despite clinical and technological improvements in RT delivery, there remains a measurable risk of adverse effects that stems largely from the obligate exposure of adjacent normal structures, either directly to the radiation beam or indirectly to scatter. For example, conventional photon-based breast radiation necessarily exposes the lungs and heart to some degree, resulting in pneumonitis within months of treatment in a small percentage of patients,4, 5 or long-term cardiac injury (eg, cardiomyopathy, valvular dysfunction, coronary artery disease, and cardiac death) within years.6, 7, 8, 9, 10 To counter this physical shortcoming of X-ray radiation, proton-based RT was developed, employing this charged-particle beam that has physical properties permitting coverage of a deep target with essentially complete avoidance of exit dose to underlying structures beyond the target volume(s). The clinical, dosimetric, and physical properties of proton RT in the treatment of breast cancer will be discussed in detail later.
Importantly, however, proton RT is also more costly than comparable photon-based technologies. As a result, proton treatment centers have historically been limited to major institutions within the largest population centers. More recently, however, data have begun to emerge demonstrating the significant clinical advantages of protons in select settings. Single room proton facilities have also emerged, markedly decreasing the initial capital cost to enter the market and allowing smaller hospital systems that serve smaller patient populations to consider proton therapy. This has prompted a rise in global interest11 and a rapid expansion in the number of centers that has broadened the availability of this technology.12 This surge of interest, coupled with market forces and contemporary resource constraints, make it imperative that clinical leaders carefully evaluate the implications, costs and benefits of proton therapy, particularly in an era of advanced photon and electron-based alternatives.
Emerging data suggest the potential for protons to mitigate the toxicity of RT in select settings. In contrast to megavoltage photon-based radiation, a proton beam is comprised of particles with mass and charge that exhibit distinct tissue interactions. A proton beam, upon encountering tissue, deposits a moderate and constant dose until nearing the end of its range where most dose is deposited within a short distance. The dose deposition profile of a proton beam is, therefore, characterized by a long plateau followed by a sharp peak (the “Bragg peak”) and an abrupt drop-off. As a result of the abrupt halt in the terminal portion of the proton range, nearly no dose is delivered beyond a given depth. Therefore, whereas photon radiation necessarily confers an “exit dose”, protons yield no such additional exposure beyond the target. This physical property is of particular significance for breast cancer patients as it permits mitigation of both high and low dose exposure to pulmonary and cardiac structures among other adjacent tissues (Figure 1). These physical properties, and the absence of exit dose in particular, confer the major advantages of proton therapy in limiting exposure to adjacent normal tissues and, in turn, potentially reducing the overall likelihood of toxicity. Several trials are currently underway to assess the clinical significance of these physical and dosimetric advantages, including a large-scale randomized national study which seeks to compare proton vs photon outcomes (RADCOMP—Clinicaltrials.gov: NCT02603341).
In the setting of historically low recurrence rates and the rising prevalence of early-stage disease largely owing to widespread screening, the reduction of treatment-associated morbidity is of particular importance. Rising mastectomy rates and enhancements in reconstructive approaches also now challenge the most advanced photon-based approaches to optimize conformality while minimizing toxicity. Moreover, with the recent publication of MA.2013 and EORTC 22922,14 two trials that demonstrated the benefits of regional nodal irradiation in patients with high risk, early stage breast cancer, comprehensive regional RT including the internal mammary nodes, is increasingly being employed and further pushing the technical boundaries of traditional radiotherapeutic approaches. The physical properties of protons allow for the targeting of the whole breast, chest wall, regional nodal basins, or implant reconstruction while simultaneously minimizing dose to adjacent normal tissues. With the anticipated favorable outcomes for most breast patients, proton radiotherapy heralds an opportunity to deliver comprehensive treatment while optimizing iatrogenic risk.
Indeed, among the most concerning late effects for this population is cardiac morbidity.15 Insult to the heart from radiation has been reported in many forms, including direct injury to the myocardium or coronary vessels that lie adjacent to the target chest wall.16 Premature coronary disease has been seen in the mid and distal left anterior descending artery among those with left-sided lesions, and right coronary disease for those with right-sided tumors.17, 18 Cardiac dose and therefore, risk, is elevated among those who must receive treatment to the internal mammary nodes, which often lie in direct apposition to the pericardium. In a landmark study that elucidated cardiac risk, Darby et al19 demonstrated that mean heart dose is directly associated with cardiac outcomes, with the relative risk of a major cardiac event increasing linearly by 7.4% per Gray increase in mean heart dose. Of note, there appeared to be no lower bound for this association, suggesting that even at low mean heart doses, subsequent cardiac risk was elevated above baseline. In addition, although cardiac morbidity often manifests >10 years after treatment, the increased cardiac risk appears significant even in the early years following treatment.
It is important to note that contemporary photon-based approaches have seen considerable advances in treatment conformality. Among the most revolutionary of these has been intensity modulated radiation therapy (IMRT), which leverages computational modeling to develop treatment plans of increasing complexity, conformality, and homogeneity. These improvements are enabled by algorithms that iteratively modulate treatment beams to optimize the plan around defined targets and organs-at-risk. However, by employing multiple beams and subfields to convert high dose regions into lower-dose swaths, IMRT necessarily increases the volume of tissue receiving low-dose exposure. This increase in volume of exposed tissue is of particular significance among young patients who will face the risk of secondary malignancies several decades following treatment.20, 21, 22, 23
In treating breast cancer, IMRT typically increases the low-dose exposure of the heart and lungs with limited short-term consequences,24 but with unclear long-term implications which remain under study. A recent study showed that even low-dose exposure to the left ventricle (V5) may lead to serious cardiac morbidity, raising concern about the increased volume of the low-dose IMRT region.25 This low-dose spread can ultimately be limited by simplifying IMRT plans to include fewer fields, or by using 3D-conformal therapy (3D-CRT), although at the expense of target conformality and coverage. Deep inspiratory breath hold (DIBH) has also emerged as an effective technique to limit unwanted cardiac exposure.
Because of the difference in physical interactions between proton and photon beams, proton treatments are prescribed in Relative Biologic Effectiveness; Gy[RBE] (Gray-RBE), in contrast to the conventional Gray. This annotation denotes the higher biologic effectiveness per unit of proton radiation and is used throughout this discussion. To calculate this biological dose, the physical dose is multiplied by a factor of 1.1 in contemporary practice, largely based on prior radiobiologic studies in animal models. Indeed, RBE may vary with α/β, with fractionation, or at the distal edge of the Bragg Peak. In the future, LET-based planning may be possible, but the 1.1 factor has been in clinical use for decades with reproducible outcomes. As defined, a given photon dose in Gy is expected to yield similar cell-kill as the same numeric proton dose in Gy(RBE).
Section snippets
Dosimetric Assessments of Proton Radiotherapy
As discussed above, protons have the unique physical ability to deliver a homogeneous and conformal prescription dose to the target volume while sparing distal structures. This property is particularly relevant in the treatment of breast cancer where the avoidance of underlying cardiac and pulmonary tissues may improve survival. Indeed, early radiation studies revealed an increase in death from ischemic heart disease, which may have negated the survival benefit of eradicating the breast cancer
Accelerated Partial Breast Irradiation
While multiple reports have shown the dosimetric superiority of protons, fewer studies have focused on evaluating long-term clinical outcomes. As discussed above, several early protocols employing protons for breast cancer focused on APBI where recurrence risk is low and treatment-related toxicity is less tolerable in weighing the putative risk:benefit ratio. Among these studies was a phase I/II multi-institutional study of 3D-conformal proton PBI, using a regimen consisting of 32 Gy(RBE) in
Planning Considerations
Three main proton delivery technologies have been employed for breast radiotherapy: passive scattering, uniform scanning and pencil beam scanning (PBS). The maximum field size for a passively scattered beam is around 25 cm in diameter by projection, although the effective field size with less than 2% dose heterogeneity is 22-23 cm. For APBI, these dimensions typically allow for encompassing the entire target; however, for irradiation of the intact breast or chest wall or both including regional
Ongoing Clinical Trials
A surge in interest surrounding proton radiotherapy is evidenced by the increase in studies at leading international proton facilities. There are currently 9 randomized trials in various stages of activation, each comparing protons vs photons across multiple disease sites, including 1 study in breast cancer. The clinical trial registry of the National Institutes of Health (http://www.clinicaltrials.gov) lists 8 open protocols aimed at assessing various facets of proton radiotherapy for breast
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Cited by (22)
Model-Based Selection for Proton Therapy in Breast Cancer: Development of the National Indication Protocol for Proton Therapy and First Clinical Experiences
2022, Clinical OncologyCitation Excerpt :Treatment planning comparative studies showed that proton therapy plans usually yield a lower dose to the heart, lungs and contralateral breast [6,9–11]. In a specific subset of patients, i.e. in patients with an adverse anatomy (e.g. like a pectus excavatum), patients not being able to hold their breath or patients to be irradiated to the (left-sided) internal mammary chain [12–15], it is sometimes difficult to adequately spare simultaneously heart, lungs and contralateral breast even with the most advanced photon techniques. In these patients, proton therapy may offer the opportunity to yield lower doses to multiple organs at risk, which are expected to translate into a clinical benefit.
What can space radiation protection learn from radiation oncology?
2021, Life Sciences in Space ResearchCitation Excerpt :For sparing the heart in breast cancer and lymphoma patients, particle therapy can be used rather than X-ray radiotherapy. Several clinical trials are ongoing with promising initial results (Braunstein and Cahlon, 2018; Hug, 2018; Malouff et al., 2020b; Plastaras et al., 2014; Tseng et al., 2017), but many years will be necessary to verify the putative reduction in CVD among the survivors. For space travel, the question is whether CVD risk is increased also at doses <1 Gy, and what is the RBE at low doses for CVD induction (Sylvester et al., 2018).
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2021, Cancer/RadiotherapieCitation Excerpt :In addition, the results showed that PT_PBS should be one of the treatment options considered. It is already known that proton therapy can improve OAR sparing because of the physical characteristics of protons [13]. All dosimetric studies that have compared proton therapy to IMRT or conformational 3D radiotherapy showed that proton therapy allows better coverage of PTVs and better OAR sparing [14].
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2020, Physica MedicaCitation Excerpt :Radiotherapy plays a major role in the treatment of breast cancers. Although proton therapy is a relatively new application, interest in its use for breast cancer treatment has been drastically increasing due its ability to reduce the volume of the heart and lungs exposed to radiation and its potential for reducing morbidity [1–7]. In proton treatment planning, the pencil-beam (PB) algorithm assumes that the material on the central axis is laterally infinite.
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2019, JOGNN - Journal of Obstetric, Gynecologic, and Neonatal NursingOptimise not compromise: The importance of a multidisciplinary breast cancer patient pathway in the era of oncoplastic and reconstructive surgery
2019, Critical Reviews in Oncology/HematologyCitation Excerpt :Ongoing modelling of optimal radiation dose in the context of tissue expanders is being undertaken to improve dosing calculations (Yoon et al., 2018). Proton therapy might overcome this disadvantage, however, this is lacking clinical validation and is not readily accessible (Braunstein and Cahlon, 2018). The availability of these techniques is dependent on local technical expertise and resources, and hence the value in extrapolation of single institution reports is limited.
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Conflict of interest: none.