Joint Estimation of Cardiac Toxicity and Recurrence Risks After Comprehensive Nodal Photon Versus Proton Therapy for Breast Cancer

Abstract

Purpose: The study aims to perform joint estimation of the risk of recurrence caused by inadequate radiation dose coverage of lymph node targets and the risk of cardiac toxicity caused by radiation exposure to the heart. Delivered photon plans are compared with realistic proton plans, thereby providing evidence-based estimates of the heterogeneity of treatment effects in consecutive cases for the 2 radiation treatment modalities.

Methods and materials: Forty-one patients referred for postlumpectomy comprehensive nodal photon irradiation for left-sided breast cancer were included. Comparative proton plans were optimized by a spot scanning technique with single-field optimization from 2 en face beams. Cardiotoxicity risk was estimated with the model of Darby et al, and risk of recurrence following a compromise of lymph node coverage was estimated by a linear dose-response model fitted to the recurrence data from the recently published EORTC (European Organisation for Research and Treatment of Cancer) 22922/10925 and NCIC-CTG (National Cancer Institute of Canada Clinical Trials Group) MA.20 randomized controlled trials.

Results: Excess absolute risk of cardiac morbidity was small with photon therapy at an attained age of 80 years, with median values of 1.0% (range, 0.2%-2.9%) and 0.5% (range, 0.03%-1.0%) with and without cardiac risk factors, respectively, but even lower with proton therapy (0.13% [range, 0.02%-0.5%] and 0.06% [range, 0.004%-0.3%], respectively). The median estimated excess absolute risk of breast cancer recurrence after 10 years was 0.10% (range, 0.0%-0.9%) with photons and 0.02% (range, 0.0%-0.07%) with protons. The association between age of the patient and benefit from proton therapy was weak, almost non-existing (Spearman rank correlations of -0.15 and -0.30 with and without cardiac risk factors, respectively).

Conclusions: Modern photon therapy yields limited risk of cardiac toxicity in most patients, but proton therapy can reduce the predicted risk of cardiac toxicity by up to 2.9% and the risk of breast cancer recurrence by 0.9% in individual patients. Predicted benefit correlates weakly with age. Combined assessment of the risk from cardiac exposure and inadequate target coverage is desirable for rational consideration of competing photon and proton therapy plans.

Figure 1

The photon plan (left) delivered to a patient at XXXXXXX in 2015 and the comparative proton plan (right). Both dose washes show the 10%–107% dose range and the CT scan is obtained in deep inspiration breath hold. Note the underdosage of the internal mammary node (white arrow) in the photon plan required to comply with the protocolized maximum dose to the heart (yellow structure). On the comparative proton plan, the internal mammary node is adequately dosed at the same time as the heart is spared more than with photons. The light purple structure on the proton plan is the proton specific planning target volume.

Figure 2

Left: mean doses for various delineated structures using the delivered photon plan (x-axis) and the comparative proton plan (y-axis) for all 41 patients. Organs at risk (heart, LADCA and left lung) below the line of identity are spared with protons. IMN should ideally receive at least 45 Gy but is sometimes compromised to avoid overdosing the heart. Note that the IMN is included in the CTV. Right: dosimetric quantification of the target coverage vs. cardiac dose compromise for all 41 patients; the mean IMN dose on the y-axis vs. mean heart dose on the x-axis. The red marks are the delivered photon plans and the blue marks are the comparative proton plans (RBE corrected). Abbreviations: LADCA, left anterior descending coronary artery; IMN, internal mammary nodes; CTV, clinical target volume; RBE, relative biological effectiveness.

Figure 3

Excess absolute risk (EAR) of at least one acute coronary event (ACE) by the age of 80 years, modeled according to Darby et al. for comparative proton (y-axis) vs. the clinically delivered photon plans (x-axis) in the 41 patients. The patients’ age at irradiation is the actual age whereas all patient cases are modeled without cardiac risk factors, CRF, (blue marks) and with at least 1 CRF (red marks). Marks below the identity line indicate dosimetric superiority of the proton plan in terms of heart sparing. Error bars represent the result of the robustness analysis, i.e. the 95% CI of the risks as consequence of setup uncertainties and stopping power conversion errors as described in detail in the appendix. Note that photon plans are often at least as sensitive as protons. Note that the 2 patients with EAR above 2% for photon treatment and at least 1 CRF are 70 years. See online appendix for details about estimation of uncertainty.

Figure 4

Excess absolute risk (EAR) of breast cancer recurrence within 10 years of therapy as compared to expected risk with mean dose to internal mammary nodes equal prescribed dose (y-axis) versus EAR of at least one acute coronary event (ACE) at age 80 years due to cardiac irradiation (x-axis). Red marks are the delivered photon plans, blue marks are the comparative proton plans. Filled symbols represent no pre-existing CRF (cardiac risk factors) and open symbols represent at least one pre-existing CRF. See text for details about the recurrence and heart toxicity models.

Figure 5

EAR contours of at least one ACE by age 80 without (left) and with CRF (center) as a function of age at exposure (x-axis) and MHD (y-axis) from the photon plan. Right panel: EAR of breast cancer recurrence by 10 years after therapy as a function of the mean dose to IMN. The grey symbols in all three panels represent the age-dose data from the 41 patients. Abbreviations: EAR, excess absolute risk; ACE, acute coronary event; CRF, cardiac risk factors; MHD, mean heart dose; IMN, internal mammary nodes.