Patient selection, inter-fraction plan robustness and reduction of toxicity risk with deep inspiration breath hold in intensity-modulated radiotherapy of locally advanced non-small cell lung cancer

Background State-of-the-art radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC) is performed with intensity-modulation during free breathing (FB). Previous studies have found encouraging geometric reproducibility and patient compliance of deep inspiration breath hold (DIBH) radiotherapy for LA-NSCLC patients. However, dosimetric comparisons of DIBH with FB are sparse, and DIBH is not routinely used for this patient group. The objective of this simulation study was therefore to compare DIBH and FB in a prospective cohort of LA-NSCLC patients treated with intensity-modulated radiotherapy (IMRT). Methods For 38 LA-NSCLC patients, 4DCTs and DIBH CTs were acquired for treatment planning and during the first and third week of radiotherapy treatment. Using automated planning, one FB and one DIBH IMRT plan were generated for each patient. FB and DIBH was compared in terms of dosimetric parameters and NTCP. The treatment plans were recalculated on the repeat CTs to evaluate robustness. Correlations between ΔNTCPs and patient characteristics that could potentially predict the benefit of DIBH were explored. Results DIBH reduced the median Dmean to the lungs and heart by 1.4 Gy and 1.1 Gy, respectively. This translated into reductions in NTCP for radiation pneumonitis grade ≥2 from 20.3% to 18.3%, and for 2-year mortality from 51.4% to 50.3%. The organ at risk sparing with DIBH remained significant in week 1 and week 3 of treatment, and the robustness of the target coverage was similar for FB and DIBH. While the risk of radiation pneumonitis was consistently reduced with DIBH regardless of patient characteristics, the ability to reduce the risk of 2-year mortality was evident among patients with upper and left lower lobe tumors but not right lower lobe tumors. Conclusion Compared to FB, DIBH allowed for smaller target volumes and similar target coverage. DIBH reduced the lung and heart dose, as well as the risk of radiation pneumonitis and 2-year mortality, for 92% and 74% of LA-NSCLC patients, respectively. However, the advantages varied considerably between patients, and the ability to reduce the risk of 2-year mortality was dependent on tumor location. Evaluation of repeat CTs showed similar robustness of the dose distributions with each technique.


S2.1 Radiation pneumonitis (RP)
The NTCP for RP grade ≥2 was calculated using a QUANTEC model refined by Appelt  where MLD is the mean lung dose in Gy and the other parameters are assigned value 1 or 0 according to Table S2.

S2.2 2-year mortality (heart model)
The NTCP for 2-year mortality based on heart dose was calculated using a model developed by Defraene et al. and revised after external validation in several patient cohorts (3,4): where GTV is the combined GTV volume of the primary tumor and nodes in cm 3 and MHD is the mean heart dose in Gy. The GTV volume from the DIBH CT was used in the calculations for both FB and DIBH, as delineation on the DIBH CT was regarded more accurate than on the AIP (the average difference in GTV volume between DIBH and FB was 2.7%, with DIBH volumes being slightly larger).

S2.3 Acute esophageal toxicity (AET)
The NTCP for AET grade ≥2 was calculated using a model developed by Wijsman et al. and revised after external validation in several patient cohorts (3,5): where MED is the mean esophagus dose in Gy and OTT is the overall radiotherapy treatment time in days.

S2.4 2-year mortality (EDIC model)
The effective radiation dose to immune cells (EDIC) in circulating blood, estimated as the equivalent uniform dose to the entire blood during the radiotherapy course, and the corresponding 2-year overall survival (OS) were calculated based on the models of Jin et al. (6), with some adjustments to accommodate the DIBH scenario: where B1% = 0.12, B2% = 0.08, B3% = 0.45 and B4% = 0.35 represent the percentages of the total blood volume contained in the lungs, heart, great vessels, and small vessels in other organs, respectively, MLD, MHD and MBD are the mean doses to the lungs, heart and body, respectively, k1 = 0.85 is a dose effectiveness factor due to the small percentage of cardiac output for the small vessels, and n is the number of fractions.
The mean body dose was calculated as = /(61.8 • 10 3 ), where 61.8 • 10 3 cm 3 is the estimated average body volume and ID is the integral dose to the body. The ID was not straightforwardly calculated in the DIBH vs. FB scenario. The increased lung volume leads to more air and more body volume around the treatment area and therefore more low dose in the patient body ( Figure S1). This dose is, however, given to air; there is not more tissue or blood in the lungs. To correct for this, based on the fact that the amount of functional lung tissue is the same in FB and DIBH, a constant value approximating the lung volume was used for both techniques. To this purpose, the ID was split in two parts: the integral dose in the body volume included in the CT scan minus the lungs, ( − ) • ( − ), plus the integral dose in the lungs, • ( ), where the average FB value of 3800 cm 3 was used as the lung volume in both FB and DIBH for all patients.
The integral dose in the whole patient was approximated as the integral dose in the body included in the CT scan. Because the CT scans always included the whole lungs and due to limitations in the 4DCT scan length depending on the patient's breathing frequency, the DIBH scan was usually longer than the FB scan for each patient. Therefore, more of the very low doses to the patient body were included in the dose statistics with DIBH. This difference was mainly seen for doses <0.5 Gy. Doses below this were therefore not included when calculating the ID. This had only a small impact on the calculated EDIC (-0.4% for FB and -0.6% for DIBH). , with the resulting NTCP for 2-year mortality: = 1 − . Figure S1. Average DVHs for the patient body and body without lungs in FB and DIBH plans. The figure illustrates that there is an increase in the absolute body volume receiving low doses with DIBH, but that this is solely due to the increased lung volume (more air in the lungs). The volume receiving very low doses (<0.5 Gy) is larger with DIBH due to increased scan length.   Figure S2. Intra-patient changes in the mean doses to (A) lungs, (B) heart and (C) esophagus, and (D) CTV V95%, from planning to week 1 and planning to week 3 evaluated together. pp = percentage points.

S4
Patient characteristics and benefit of DIBH