
==== Front
Phys Imaging Radiat Oncol
Phys Imaging Radiat Oncol
Physics and Imaging in Radiation Oncology
2405-6316
Elsevier

S2405-6316(24)00104-0
10.1016/j.phro.2024.100634
100634
Original Research Article
Inter-fraction motion robustness in a prospective phase II trial on dose-escalated proton reirradiation for locally recurrent rectal cancer
Truelsen C.G. chtrue@rm.dk
abc⁎
Rønde H.S. HEIDRE@rm.dk
a
Kallehauge J.F. jespkall@rm.dk
ac
Poulsen L.Ø. laop@rn.dk
d
Havelund B.M. Birgitte.Mayland.Havelund@rsyd.dk
e
Pedersen B.G. bodilped@rm.dk
f
Iversen L.H. lene.h.iversen@dadlnet.dk
g
Spindler K.G. k.g.spindler@rm.dk
bc
Kronborg C.S. camkro@rm.dk
ac
a Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark
b Department of Oncology, Aarhus University Hospital, Denmark
c Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
d Department of Oncology, Aalborg University Hospital, Denmark
e Department of Oncology, University Hospital of Southern Denmark, Lillebaelt Hospital, Vejle, Denmark
f Department of Radiology, Aarhus University Hospital, Denmark
g Department of Surgery, Aarhus University Hospital, Denmark
⁎ Corresponding author at: Danish Centre for Particle Therapy, Aarhus University Hospital, Denmark. chtrue@rm.dk
23 8 2024
7 2024
23 8 2024
31 10063420 3 2024
19 8 2024
20 8 2024
© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Highlights

• Intensity-modulated proton therapy is relevant for pelvic reirradiation.

• Pelvic proton therapy dose robustness can be challenged by inter-fraction motion.

• Inter-fraction motion robustness was quantified by weekly computed tomography scans.

• Target coverage was robust against anatomical changes.

• Dose ratios between baseline and weekly organ at risk dose varied from 0.9 to 1.3.

Background and purpose

Intensity modulated proton therapy (IMPT) enables generation of conformal dose plans with organ at risk (OAR) sparing potential. However, pelvic IMPT robustness is challenged by inter-fraction motion caused by constant anatomical variations. In this study, the dosimetric impact of inter-fraction motion on target coverage and dose to OAR was quantified in the prospective phase II study ReRad-II on dose-escalated proton reirradiation for locally recurrent rectal cancer (LRRC).

Materials and methods

The inter-fraction motion robustness was assessed for the initial twelve patients enrolled in the ReRad-II study. Patients with resectable LRRC were assessed for neoadjuvant IMPT (55 Gy(RBE)/44Fx) and unresectable recurrences for definitive IMPT (57.5–65 Gy(RBE)/ 46-52Fx). Target coverage and dose to OAR were assessed for robustly optimised three-field IMPT, on 12 plan computerized tomography (CT) scans (pCT) − and 47 repetitive control CT scans (cCTs) during the treatment. The target coverage and doses to OAR were re-calculated on each cCT and the mean dose ratio (pCT/cCT-ratio) and target coverage (V95%) was evaluated.

Results

The target coverage was robust with a mean dose pCT/cCT-ratio of 1.00 (+/-1%). The V95% target coverage for every cCT were above the accepted worst-case scenario in the robust evaluation. Considerable variation in bladder-, bowel bag-, and bowel loop volume was observed. The OAR with the largest variation in ratio was the bladder (pCT/cCT-ratio: 1.3 (range: 0.5–4.7).

Conclusions

IMPT for dose-escalated reirradiation of LRRC provided anatomically robust target coverage despite OAR changes. Inter-fraction motion resulted in OAR doses varying within clinically acceptable range.

Keywords

Locally recurrent rectal cancer
Reirradiation
Intensity-modulated proton therapy (IMPT)
Inter-fraction motion robustness
Organs at risk
==== Body
pmc1 Introduction

The risk of locally recurrent rectal cancer (LRRC) has decreased to 5–10 % due to primary pre-operative radiotherapy [1], and improved surgical techniques. The main curative approach of LRRC is salvage surgery, with survival highly dependent on radical resection (R0) [2]. However, many are unresectable or inoperable. Reirradiation of LRRC is challenging, as up to 80 % have already been irradiated as part of the initial treatment strategy [3], with 65 % of recurrences located in the previously irradiated field [4].

Reirradiation either to enhance the probability of R0 resection or as palliative symptomatic relief has been proven effective and feasible [5], [6], [7]. The limitation of reirradiation include radiation tolerance of previously irradiated tissues, increasing the risk of acute and late toxicity [8].

Reirradiation with protons could mitigate limitation as the dose deposition of protons reduce excess dose to surrounding organs at risk (OAR) enabling irradiation near sensitive structures and near tissues that have previously received maximum or near-maximum tolerance doses [9]. Proton irradiation could also allow for dose-escalation, as previous comparative dose planning studies have verified that mean doses to OAR were lower or similar with dose-escalated proton therapy (55–65 Gy relative biological effectiveness (RBE)) than with standard dose photon therapy (40.8 Gy) [10].

However, pelvic proton therapy dose robustness can be challenged by inter-fraction motion caused by constant anatomical variations ascribed to bowel- and bladder filling, intestinal displacement, density changes due to bowel gas, and shape changes which may compromise target coverage and sparing of OAR. The inter-fraction motion might also be affected by the rearranged pelvic anatomy from previous surgery.

To ensure treatment robustness, in the prospective phase II study dose-escalated proton reirradiation for locally recurrent rectal cancer, ReRad-II; we aimed to quantify the dosimetric impact of inter-fraction motion on target coverage and OAR dose.

2 Material and methods

2.1 Patients

Inter-fraction motion robustness was assessed for the initial twelve patients enrolled in the prospective phase II trial, ReRad II (Pencil beam proton therapy for pelvic recurrences in rectal cancer patients previously treated with radiotherapy) at The Danish Centre for Particle Therapy. The ReRad II study (clinicaltrials.gov (NCT04695782)) was approved by The Danish National Committee on Health Research Ethics (VEK no.: M-2020-140-20) and reported to The Danish Data Protection Agency (1-16-02-266-20). Written informed consent was obtained from all patients. Patients were diagnosed with LRRC and had previously received pelvic irradiation > 30 Gy EQD2. Patients were evaluated at a multidisciplinary team conference where resectable recurrences were assessed for neoadjuvant proton therapy and unresectable or non-operable recurrences for definitive proton therapy.

Dose-escalated reirradiation was delivered as hyperfractionated intensity modulated proton therapy (IMPT). The planned dose was 55 Gy(RBE) in 44 fractions in the neo-adjuvant arm and 57.5–65 Gy(RBE) in 46–52 fractions in the definitive arm. Concomitant peroral capecitabine 850 mg/m2 BID was administered on radiotherapy treatment days.

2.2 Proton therapy dose planning

Prerequisites for reirradiation planning were a pelvic MRI-(T2 weighted axial, sagittal, and coronal sequences) and planning CT scan (pCT, 3 mm slice thickness, with no contrast and with intravenous contrast at both 70 s and 480 s delays). Supine position on a flat tabletop with a knee-feet fixation support and arms on the chest were used. No standard bladder filling protocol was used. The MRI and CT scans were co-registered based on bony anatomy. The planning scans were also co-registered with a diagnostic PET-CT. GTV was defined based on available imaging, and if relevant proctoscopy, by an experienced radiation oncologist in collaboration with an experienced radiologist and nuclear radiologist. For the CTV an isotropic 1 cm margin was added and trimmed for anatomical barriers.

Proton plans used three posterior fields with gantry angles 150°, 180° and 210° (Eclipse, Varian Medical Systems v13.7). The gantry angles were subject to (smaller) changes due to patient-specific considerations. For each individual field, a robust target volume (RTV) was added based on the CTV with a 5 mm setup error, a calibration curve error of 3.5 %, and a 1 mm proximal and distal margin, respectively. Seldom, the RTVs could be cropped to avoid a particular OAR or the like. If the water equivalent distance was less than 4 cm to the target a range shifter of 3 cm was utilised for either all fields or the field in question.

IMPT plans were generated with multi-field optimization. The algorithms, NUPO 137 and PCS 137, in Eclipse were used for optimization and final calculation, respectively. No limits to one or more fields were used but after final calculation it was checked that one field did not deliver > 90 % of the total dose. The plans were robustly optimized (not field based) with 14 scenarios (2 scenarios with 0 mm setup error and 3.5 % calibration curve error and 12 scenarios with 5 mm setup error and 3.5 % calibration curve error). A constant RBE factor of 1.1 was applied. Bowel gas/air cavities near the target were overwritten with tissue equivalent Hounsfield units for optimization but not for final calculation. Plans were normalized to the target mean. The 14 scenarios described above were calculated for evaluation. Plans should fulfil V95% ≥ 98 % for the worst-case scenario in the robust evaluation and V95% = 100 % for the nominal plan if feasible. OAR doses were checked according to an internal OAR prioritising list [11], [12], and patient-specific prioritisations; likewise for target coverage compromises.

2.3 Treatment delivery and controls

Patients were treated twice daily with a minimum 6-hour time gap guided by a twice-daily cone beam-CT (CBCT) set-up to verify treatment position. CBCTs were registered to pCT with a 4D match on bony structures. Infrequently, a 5D or a 6D match was used but only up to 1–1.5° in pitch and roll. 5D and 6D matches were verified with an extra CBCT to check for potential counter movements of the patient. Deviations in soft tissue/body outline was checked offline before the next treatment. Control CT (cCT, also 3 mm slices, no contrast) scans were performed once weekly in the treatment position. The cCT was co-registered (6D rigid) with the pCT based on bony anatomy. If the cCT did not match the pCT, the cCT was checked for resemblance with the daily CBCT. The CTV and OARs were transferred, and each contour was manually adjusted to the cCT. On the cCT, the treatment plan was re-calculated including range uncertainty of +/− 3.5 % calibration curve error with no residual setup error, and the target coverage and doses to OARs were checked. The need for a re-plan or plan optimization was evaluated on each cCT. There was no need for replanning in this cohort.

2.4 Organs at risk and inter-fraction motions robustness

The following OARs were delineated on the pCTs and cCTs according to RTOG guidelines [13] and local atlas guidelines [14], [15]: bladder, bowel loops, bowel bag, sacrum, sacroiliac joints, cauda equina, sacral plexus, ureters, femoral heads, and vagina/penile bulb. In addition, the volume of bowel gas present within the 20 % isodose curve (iso20%BowelGas), and the variation in body outline (iso20%BodyOutline), defined as the largest distance between the posterior boundary on pCT compared to cCT within the 20 % isodose curve were contoured. Body contour was used to evaluate setup uncertainty where a maximum of 5 mm was accepted within the 20 % isodose curve. The 20 % isodose curve was generated as a region of interest (ROI), to aid the co-registration of pCT to CBCT for the IGRT strategy setup before treatment.

The target coverage robustness was evaluated by comparing the CTV mean dose on the pCTs to each cCTs for the individual patient. Further, target (CTV) coverage was also evaluated by the V95% target coverage on cCTs compared to the nominal V95% and V95% worst-case CTV target coverage on the pCTV. The CTV mean dose ratio (pCTV/cCTV) was correlated to volume differences between pCT and cCTs (Δ) for bladder-, bowel bag-, bowel loop volume, iso20%BowelGas, and iso20%BodyOutline. The dosimetric impact on OARs was estimated by comparing dose differences (ratio) between pCTs and cCTs, of all delineated OARs. This ratio was also correlated to volume changes in the bladder, bowel loops, bowel bag, and gas cavities. Clinically insignificant mean doses < 0.5 Gy(RBE) on cCTs were adjusted to ratio 1 for an equitable presentation of data. The median CTV V95% is reported with interquartile ranges (IQR), while volumes are reported as mean values with ranges to display the spread of volume changes.

3 Results

For the first 12 patients, 12 pCT- and 47 cCT scans were available for analyses (range pr. patient 3–5). Patient and CTV characteristics are presented in Table 1. The mean CTV volume irradiated was 173.1 cm3, however with considerable variation (range: 20.3–587.3). The 14 pelvic CTVs were located [16] posterior n = 9 (hereof 3 posterolateral), lateral n = 2, central n = 2, and urogenital n = 1.Table 1 Patient and treatment characteristics.

Patient and treatment characteristics	
	n = 12 (%)	
Age (years)		
 Median:	70	
 Range:	43–78	
Sex		
 Male	5 (41.7 %)	
 Female	7 (58.3 %)	
BMI		
 Median:	26.5	
 Range:	21.1–34.1	
Number of CTVs		
 Total:	14	
 Range:	1–2*	
CTV volume (cc)		
 Median:	62	
 Range:	20.3–587.3	
Planned dose (Gy (RBE))		
 Dmedian:	65	
 Definitive IMPT, n = 10	57.5–65	
 Neo-adjuvant IMPT, n = 2	55	
Number of control CTs		
 Total:	47	
 Median:	4	
 Range:	3–5	
*Two patients had two recurrences.

IMPT provided excellent anatomically robust target coverage to all recurrences with a CTV mean dose pCTV/cCTV-ratio of 1.00 (+/− 1 %), depicted in Fig. 1A. The target coverage remained excellent despite considerable variation in bladder volume (Δ mean 83.3 cm3 (range: 1.8–328.3)), bowel bag volume (Δ mean 182.4 cm3 (range: 6.5–1118.6)), bowel loops volume (Δ mean 77.2 cm3 (range: 0.7–290.5)), and minor variations in iso20%BowelGas (Δ mean 7.3 cm3 (range: 0.0–66.6)) and iso20%BodyOutline (Δ mean 1.9 mm (range: 0.5–4.7)), illustrated in Supplementary Fig. 1. On the pCTs the median CTV V95% was 100.0 % (IQR: 100.0–100.0) and the median CTV V95% worst-case scenario was 99.4 % (IQR: 98.0–99.7). For the cCTs, the median CTV V95% was 100.0 % (IQR: 99.9–100.0) and 99.8 % (IQR: 99.6–100.0) for the worst-case scenario. The V95% target coverage for every cCT was above the accepted worst-case scenario estimated by robust optimization, illustrated in Fig. 1B. Minor changes to the CTV volume between pCT and cCTs were seen mainly due to bladder/bowel filling changes.Fig. 1 A) Target coverage ratio pCT/cCT (mean dose) for CTV. B) The CTV V95 (%) for nominal dose, worst-case scenario and cCTs for each patient, with nominal V95 (%) depicted in green, worst-case V95 (%) in red, and cCT V95 (%) in grey. The worst-case scenarios below 98 %, illustrated with the yellow line, are due to deliberated target comprises, e.g., due to tumour location close to the skin, to protect the ureter in a single kidney patient and to protect the urethra after previous high-dose radiation. *Two separated target CTVs were constructed for two patients, thereof, two nominal V95 (%) depicted in green and two worst-case V95 (%) scenarios depicted in red. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

The OARs with the highest reported nominal mean dose (Dmean) on the pCT were the sacral plexes (Dmean: 20.9 Gy(RBE)), sacral bone (Dmean: 17.3 Gy(RBE)), and ipsilateral ureter (Dmean: 14.6 Gy(RBE)); attributed by the posterior beam angles, size of the OAR, and anatomical localization in or near the target volume. However, due to the large bowel bag volume, the mean dose is correspondingly lower. The mean and near max (D2%) doses for all delineated OARs is listed in Table 2 and depicted in Supplementary Fig. 2.Table 2 The mean dose (Dmean) and near-max dose (D2%) to organs at risk on the plan CT and the control CTs are presented as median values with interquartiles ranges. Inter-fraction motion robustness is evaluated by comparing the mean dose between the plan CT and the control CTs presented as the pCT/cCT-ratio.

Organ at risk	Plan CT (pCT)	Control CT (cCT)	pCT/cCT-ratio	
pCT Dmean (Gy)	pCT D2% (Gy)	cCT Dmean (Gy)	cCT D2% (Gy)	Mean dose ratio*	
	Median (IQR)	Median (IQR)	Median (IQR)	Median (IQR)	Mean (range)	
Bladder	8.1 (3.1–14.1)	58.6 (41.3–64.1)	6.0 (0.5–10.1)	59.3 (33.0–65.4)	1.3 (0.5–4.7)	
Bowel bag	1.5 (0.2–2.4)	59.4 (54.1–65.7)	1.4 (0.4–2.7)	63.6 (56.1–66.9)	1.0 (0.2–1.9)	
Bowel loops	3.8 (2.9–6.1)	58.9 (50.4–65.8)	3.7 (1.7–9.0)	59.9. (56.6–66.6)	1.0 (0.1–2.2)	
Sacrum	18.2 (11.6–22.0)	62.9 (58.0–66.8)	18.0 (10.1–22.0)	65.5 (58.7–66.8)	1.0 (0.9–1.1)	
SI joint Ipsi	4.8 (0.9–10.9)	47.7 (23.4–62.4)	5.8 (0.9–12.4)	56.0 (23.1–63.0)	1.0 (0.8–1.1)	
SI joint Con	0.0 (0.0–1.0)	7.3 (0.6–29.4)	0.0 (0.0–0.9)	2.4 (0.8–54.5)	1.0 (0.9–1.2)	
Cauda equina	3.7 (2.9–5.5)	54.5 (50.6–59.1)	4.0 (2.7–5.7)	55.4 (51.1–59.2)	1.0 (0.6–1.4)	
Sacral plexus	20.4 (12.6–25.1)	60.5 (56.1–65.6)	22.6 (12.7–29.2)	62.2 (56.2–66.1)	1.0 (0.6–1.0)	
Femoral head Ipsi	0.0 (0.0–0.0)	0.2 (0.0–10.2)	0.0 (0.0–0.1)	0.4 (0.0–12.8)	1.0 (0.7–1.1)	
Femoral head Con	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	0.0 (0.0–0.0)	1.0 (0.8–1.2)	
Ureter Ipsi	12.4 (1.5–22.2)	55.6 (4.5–62.8)	12.8 (1.3–26.1)	56.1 (4.6–65.2)	1.0 (0.5–1.7)	
Ureter Con	1.1 (0.1–6.9)	23.8 (1.1–56.7)	0.6 (0.1–12.0)	28.7 (0.4–58.0)	1.1 (0.4–1.8)	
Vagina	5.9 (0.1–22.2)	49.1 (4.6–56.9)	13.4 (0.0–24.7)	56.9 (1.5–63.5)	0.9 (0.5–1.1)	
Penile bulb	3.2 (0.1–3.2)	20.4 (0.9–31.5)	0.7 (0.0–3.1)	7.0 (0.1–24.9)	1.2 (0.8–2.7)	
*Clinically insignificant doses on cCTs below 0.5 Gy(RBE) were adjusted to ratio 1 for an equitable presentation of the ratio.

Ipsi: ipsilateral; con: contralateral.

The mean dose pCT/cCT-ratio for all OARs ranged from 0.9 to 1.3, illustrated in Table 2 and Supplementary Fig. 3. The OARs with the largest variation in ratio and volume were bladder and bowel. Minor variations were seen for the rest of the OARs, except the penile bulb. Thus, the OAR with the largest variation in dose was the bladder with a mean dose pCT/cCT-ratio of 1.3 ranging from 0.5 to 4.7. The bladder pCT Dmean was 10.3 Gy(RBE), with nominal doses ranging from 0 to 39.6 Gy(RBE). Noticeably, the largest variation in bladder ratio was seen for small absolute mean doses e.g., patient no 6, see Fig. 2A–B. The mean bladder volume on pCT was 196.6 cm3 (range: 26.0–509.9), and variations in bladder filling resulted in a mean difference (absolute) in bladder volume between pCT and cCT of 83.3 cm3 (range: 1.8–328.3), see Fig. 3A.Fig. 2 Mean bladder-, bowel loop- and bowel bag dose, as well as corresponding mean dose pCT/cCT-ratio.

Fig. 3 The impact of changes in bladder volume on mean dose bladder pCT/cCT-ratio (A). The effect of difference in bowel loop and −bag volume (B) as well as in bowel gas within the 20% isodose curve (C) on bowel loop and −bag mean dose pCT/cCT-ratio.

Changes in bowel filling, intestinal displacement, and density changes had limited dosimetric impact on dose to the bowel loop and bowel bag with a mean dose pCT/cCT-ratio of 1.0 (range: 0.1–2.2) and 1.0 (range: 0.2–1.9), respectively (Fig. 2C–F). Thus, dose to the bowel is variable within an acceptable clinical range, despite relatively large variations in bowel loops- and bowel bag volume of 77.2 cc (range: 0.7–290.5) and 182.4 cc (range: 6.5–1118.6), respectively (Fig. 3B), and a presence of gas within the 20 % isodose curve with a mean difference of 7.3 cc (range: 0–66.6) (Fig. 3C). In general, the inter-fraction motion had limited dosimetric impact on dose delivered to the delineated OARs and varied within what we considered clinically acceptable.

4 Discussion

In this prospective, phase II study of dose-escalated proton reirradiation for LRRC, the dosimetric impact of inter-fraction motion on target coverage and dose to OAR was assessed to ensure treatment robustness. This is the first study to evaluate anatomical robustness in this setting. Our study found excellent CTV target coverage and clinically acceptable OAR variation despite considerable anatomical variation.

Several studies have verified the OAR-sparing potential of protons compared with photons credited to the inverted dose profile with low dose absorption at tissue entrance and maximum dose deposition at the Bragg-peak [17]. The dosimetric advantage of proton therapy in rectal cancer has been evaluated in a recent review [18], verifying that proton plans can reproduce the dosimetric quality of conventional plans and hold the potential to increase the therapeutic tolerance [9].

In the reirradiation setting, few preliminary clinical trials have investigated proton therapy for LRRC. In a prospective study [19], 7 LRRC patients were reirradiated with once-daily standard fractionated passive scatter proton therapy to a mean dose of 61.2 Gy(RBE). In a retrospective study, 15 LRRC patients were reirradiated with accelerated hyperfractionated PBT of 1.5 Gy to a total dose of 39–45 Gy(RBE) using a passive scattering technique [20]. In another retrospective study, 18 LRRC patients were reirradiated with hyperfractionated pencil beam scanning proton therapy using two lateral fields with a single-field optimization technique with a third field and/or multiple-field optimization used in some cases [21]. Thus, planning- and delivery techniques varied in the presented studies. Noticeably, none of these studies considered that the plan robustness in proton therapy is challenged by the reproducibility of the target volume coverage and dose to OAR due to possible internal organ motion and variation in organ filling within the course of radiation. Therefore, the plańs robustness against critical parameters must be demonstrated and the clinical benefit must be proven to translate into a lower toxicity profile with better oncological outcomes.

This study demonstrated that IMPT for rectal cancer recurrences can be delivered with anatomically robust target coverage despite inter-fraction motion. This was evaluated by the mean dose pCT/cCT-ratio. However, as deliberate target compromises are inevitable in this setting, we also reported the V95% on cCTs compared to the nominal V95% and the V95% of the accepted worst-case scenario when approving the primary plan. However, aiming primarily at V95%=100 % for the nominal plan often resulted in a worst-case scenario better than V95%>98 %. This also showed that the cCT target coverages were always better than the accepted worst case. The inter-fraction motion robustness of IMPT has been evaluated in other pelvic tumour types. An in-silico planning study of twelve cervical cancer patients with indications for nodal irradiation using robust optimisation and an intermediate IGRT strategy demonstrated a robust target coverage similar to current clinical volumetric modulated arc therapy plans [22]. In another cervical cancer planning study using a mitigating strategy with four-field IMPT the dosimetric impact of gas cavities and body outline, was evaluated in 7 patients, on daily CBCTs, and showed a limited impact on accumulated dose to ITV45 [23]. Robust optimization of proton plans was not applied in that study. Instead, an ITV-to-PTV margin was set isotopically to 5 mm. In prostate cancer, the inter-fraction motion was assessed in ten patients, treated with bilateral-field single-field uniform dose PBS. Bilateral-field IMPT plans were retrospectively created to assess the inter-fraction motion on more modulated plans. The plans were evaluated against 3 mm isocentre shifts in 3 directions with no degradation in CTV coverage. For both, the CTV coverage was robust against inter-fraction motion with clinically insignificant CTV degradations [24]. In comparison, our study prospectively evaluated inter-fraction motion for 12 patients treated with IMPT robustly optimized with 14 scenarios.

Regarding dose to OAR, inter-fraction motion caused some variation in planned dose and dose on subsequent controls. However, the doses to OAR varied within a clinically acceptable range without specific correlation to volume change. The highest nominal mean doses were delivered to the sacral plexus and sacral bone. This was caused by the posterior field of the proton plans. The posterior fields were chosen to avoid end-range uncertainty caused by density changes due to bowel gas, anatomical variations in bowel- and bladder filling, and body outline due to weight loss and/or gain [19], [22] which may give a slightly higher dose to sacrum and skin but a more robust target coverage throughout the treatment.

With IMPT conformal dose distributions can be constructed along the beam path to the target volumes, but it is characterised by delivery complexity by factors such as range uncertainty, targeting uncertainty, water-equivalent thickness changes, and density changes. Therefore, robust optimization is essential for the plan quality and the plan robustness is monitored by repetitive cCTs in many cases. This study demonstrates that with the described planning process and objectives, repetitive cCTs are redundant in this setting as plans can be delivered with clinically acceptable robustness. Instead, the daily CBCTs will be systematically monitored for anatomical changes. Based on these findings, future perspectives may be a reduction of margins in the robust optimization.

The limitation of this study is the small sample size; however, the estimates are strengthened by the variation in CTV volume and different localization of the tumours. Most of the tumours were posterior or pelvic side wall recurrences, however, two were T-site/rectal recurrences, which are known to be more variable. Furthermore, a cCT only reflects the anatomy at a given time point. Therefore, it is essential that this study is based on repeated weekly control CTs throughout the course of treatment. Additionally, this study did not consider intra-fraction motion which should also be considered. In cervical cancer patients, subject to large uterus motion, intra-fraction motion was assessed through daily CBCT scans, displaying that small margins (≤5mm) are sufficient in most cases to compensate for dose degradations [25]. In prostate cancer patients, the intra-fraction effect dominated over inter-fraction effect in CTV coverage [24]. However, the total dose degradation of D99 was 2–3 % and therefore clinically insignificant.

In conclusion, this study demonstrated limited dosimetric impact of inter-fraction motion for patients included in the prospective phase II study on dose-escalated proton reirradiation for LRRC. Thus, robustly optimized IMPT can be delivered with anatomically robust target coverage with variation in doses to OAR within a clinically acceptable range despite variation in organ-filling.

CRediT authorship contribution statement

C.G. Truelsen: Data curation, Methodology, Formal analysis, Visualization, Writing – original draft, Writing – review & editing. H.S. Rønde: Conceptualization, Data curation, Methodology, Resources, Writing – review & editing. J.F. Kallehauge: Data curation, Writing – review & editing. L.Ø. Poulsen: Conceptualization, Funding acquisition, Resources, Writing – review & editing. B.M. Havelund: Conceptualization, Funding acquisition, Resources, Writing – review & editing. B.G. Pedersen: Resources, Writing – review & editing. L.H. Iversen: Resources, Writing – review & editing. K.G. Spindler: Conceptualization, Funding acquisition, Resources, Writing – review & editing. C.S. Kronborg: Conceptualization, Funding acquisition, Data curation, Methodology, Resources, Supervision, Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A Supplementary data

The following are the Supplementary data to this article:Supplementary Data 1

CTV target coverage ratio pCT/cCT (mean dose) versus difference in bladder volume (A), bowel bag volume (B), bowel loop volume (C), bowel gas within the 20% isodose curve (D), and body outline within the 20% isodose curve (E). The different symbols represent the 12 different patients.

Supplementary Data 2

The mean dose (solid colour) and near max dose (hollow red) to delineated organs at risk on pCTs and cCTs. The doses to OARs on the pCT are illustrated with a triangle, and the doses on cCTs are illustrated with a circle. The sacroiliac joints, femoral heads, and ureter are presented according to ipsilateral-contralateral anatomical location relative to target.

Supplementary Data 3

Organ at risk dose robustness depicted as mean dose pCT/cCT ratio for every delineated OAR. Clinically insignificant doses on cCTs below 0.5 Gy(RBE) were adjusted to ratio 1 for an equitable presentation of the ratio.

Acknowledgements

This study was funded by grants from 10.13039/100008363 The Danish Cancer Society (R268A15473 ). The outcome of this paper is not influenced by the financial support. No writing assistance was used.

Appendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.phro.2024.100634.
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