Intensity modulated proton therapy planning study for organ at risk sparing in rectal cancer re-irradiation

Background

Advanced rectal cancers are treated with neo-adjuvant (chemo)radiotherapy followed by surgery, but 5–10% experience locoregional recurrence after initial treatment. Radical (R0) salvage surgery is the main treatment and the most important prognostic factor for overall survival [1,2]. Neo-adjuvant re-irradiation has been introduced to increase R0 resection rates [3,4].

Several, mainly retrospective, studies have described re-irradiation of localized rectal cancer recurrences [5–8]. Two systematic reviews have evaluated toxicity and outcomes of re-irradiation in rectal cancer [9,10]. Re-irradiation doses were generally around 40 Gy. The studies report similar levels of grade 3–4 toxicity, (Guren: 9–20% grade 3–4 acute toxicity; Lee: grade ≥ 3 acute and late toxicities in 11.7% and 25.5% for resected and non-resected patients, respectively).

Proton therapy allows for highly conformal treatment. The absence of the low-dose-bath reduces excess dose to surrounding organs at risk (OAR).

Only a few clinical studies have published data on re-irradiation for rectal recurrence with proton therapy [11–13], with doses ranging from 16 Gy relative biological effectiveness (RBE) to 64.8 Gy RBE. All reported acceptable toxicities; Acute toxicity grade 1–3 (14–60%), late toxicity grade 1–4 (14–43%).

The risk of toxicity is the dose-limiting factor in re-irradiation. In this study we compared intensity modulated proton therapy (IMPT) with volumetric modulated arc photon therapy (VMAT) for re-irradiation of pelvic recurrences from rectal cancer with the aim of decreasing dose to surrounding OARs.

Material and methods

Patients

All patients enrolled in the Re-RAD-I study (External beam radiotherapy for pelvic recurrences in rectal cancer patients previously treated with radiotherapy) (VEK no: 1-10-72-417-14) were eligible for comparative IMPT planning. One patient was excluded due to insufficient retrieval of photon plan. Patients were treated at Aarhus University Hospital, Denmark and Oslo University Hospital, Norway. The primary neo-adjuvant radiotherapy included 3 D conformal technique (n = 11), 5-field IMRT (n = 2), and 2-arc VMAT (n = 2). Primary dose was 25 Gy in 5 fractions (n = 4), 48 Gy in 24 fractions (n = 1), 50 Gy in 25 fractions (n = 5), 52 Gy in 26 fractions (n = 4), or 60 Gy in 30 fractions (n = 1).

Re-irradiation was planned with 40.8 Gy in 1.2 Gy per fraction, twice-a-day and concomitant capecitabine 825 mg/m² twice daily. Planning CT scans were done in supine position (2.5–3 mm slices) with intravenous contrast. MR scans in treatment position included T2 weighted axial and sagittal sequences. Clinical target volume (CTV) was delineated according to the protocol, a symmetrical margin of 10 mm (trimmed to anatomical barriers) was added for the internal target volume (ITV) plus an additional 7 mm margin for the planning target volume (PTV). OARs were delineated according to RTOG guidelines [14] or anatomy. The re-irradiation photon plans included VMAT techniques; 1 arc (n = 2), 2 half-arcs (n = 1), and 2 arcs (n = 12), Eclipse (Varian Medical Systems, Inc, Palo Alto, CA, USA). The plans were normalized to target (PTV) and PTV dose was between 95–107% of the prescribed dose.

The Re-RAD-I study was approved by the local ethical committee and The Danish Data Protection Agency. In Norway, by the Regional Ethical Committee South-East (2015/1527) and the Institutional Protocol Review Board. All patients gave written informed consent.

Proton therapy dose planning, IMPT

Three posterior fields (gantry angles 150°, 180° and 210°) were used for IMPT plans. A 5 cm range shifter was used depending on the water equivalent thickness (WET) to the CTV (<4 cm) for individual fields.

To steer the optimization, relative tumor volumes (RTVs) based on the CTVs were used. RTVs take into account a 5 mm setup error, a calibration curve error of 3.5% and 1 mm proximal and distal margin, respectively.

IMPT with multi field optimization (MFO) robust optimization and evaluation was done for 14 scenarios; 2 scenarios with 0 mm and 12 scenarios with 5 mm setup error and, all with 3.5% calibration curve error. An RBE factor of 1.1 was used. CTV dose coverage criterion for the 14 robust optimized scenarios fulfilled a worst-case scenario of V95%≥98%.

IMPT plans were optimized in Eclipse v13.7 (Varian Medical Systems, Inc, Palo Alto, CA, USA) and normalized to target (CTV) mean of 40.8 Gy (RBE). Dose to OAR was kept as low as reasonably possible.

Data analysis

The mean and near maximum (D_0.03ccm) organ doses were compared for VMAT vs. IMPT plans including: bowel loops, bladder, sacral bone, penile bulb and vagina. Ureter and femoral heads were analyzed as ipsilateral and contralateral structures. CTV volumes differed considerably, therefore we compared benefit of IMPT for CTVs < or ≥ the median CTV volume of 115 cm³.

Wilcoxon's signed rank test or Wilcoxon's rank sum were used for comparison (MATLAB ver. R2020b). A Bonferroni corrected p-value of ≤0.0024 (0.05/21) was considered statistically significant.

Results

Comparative dose planning was done for fifteen patients (8 males, 7 females).

Median CTV volume for re-irradiation was 115 cm³, but with considerable variation (range: 19.5–1080.6 cm³).

For the VMAT plans the median target (PTV) coverage was D_98% = 94.4% (interquartile range (IQR): 90.1–96.7%); for the IMPT plans the median worst-case scenario target (CTV) coverage was D_98% = 96.0% (IQR: 95.3–96.8%).

Mean doses (D_mean) were lower with IMPT compared to VMAT for all delineated OARs. For bowel loops, bladder and sacral bone, median D_mean was significantly reduced from 3.2 Gy to 0.4 Gy, from 8.2 Gy to 1.7 Gy, and from 8.7 Gy to 4.2 Gy, respectively. For ureters D_mean was lowered from 10.6 Gy to 9.3 Gy ipsilaterally and significantly from 5.7 Gy to 0.03 Gy, contralaterally. Near max doses (D_0.03ccm) differed according to OAR position relative to target. For OARs close to the target, no difference in maximum dose was seen. All OAR D_mean and D_0.03ccm doses are presented in Table 1. Figure 1 shows mean dose-volume histograms (DVHs) for bowel loops, bladder and sacral bone including standard deviations for VMAT versus IMPT plans.

Figure 1. (a) Mean DVHs and standard deviations (SD) of bowel loops, bladder, and sacral bone. VMAT photon (red), IMPT proton (blue). (b) Box plots for the Δ mean-dose (Δ mean-dose = VMAT – IMPT dose) for bowel loops, bladder and sacral bone for recurrence CTV volume < (red) or ≥ (blue) than the median volume of 115 cm³. Box plots define the interquartile range (IQR) with the 25th and 75th percentile as top and bottom. The whiskers length is defined as 1.5 times the interquartile range and outliers beyond are marked.

Table 1. Organ at risk doses for the recurrence treatment plans, VMAT vs. IMPT.

	(Dmean, Gy)			(D0.03ccm, Gy)  (median, IQR)
	(median, IQR)
OAR	Photon VMAT	Proton IMPT	p Values^†	Photon VMAT	Proton IMPT	p Values^†
Bowel loops	3.2 (1.5–15.5)	0.4 (0.0–6.9)	<0.001*	41.9 (19.3–42.6)	41.5 (2.7–42.6)	0.015
Bladder	8.2 (5.3–10.7)	1.7 (0.6–3.8)	<0.001*	40.5 (38.6–42.6)	40.1 (30.2–41.8)	0.018
Ureter (ipsilateral)	10.6 (7.9–17.8)	9.3 (5.8–18.9)	0.016	41.8 (40.8–42.1)	41.7 (39.6–42.3)	0.135
Ureter (contralateral)	5.7 (1.6–9.2)	0.03 (0–1.5)	<0.001*	16.3 (10.0–28.1)	0.5 (0.0–8.2)	<0.001*
Sacral bone	8.7 (2.0–14.1)	4.2 (1.4–13.0)	<0.001*	42.3 (33.9–42.9)	42.0 (37.6–42.3)	0.658
Vagina	15.5 (7.1–24.7)	8.8 (5.5–17.3)	<0.001*	39.7 (32.5–41.8)	39.3 (26.5–41.6)	0.063
Femoral head (ipsilateral)	6.6 (4.3–7.2)	0.01 (0.0–0.02)	<0.001*	17.3 (13.5–22.1)	0.7 (0.0–2.1)	<0.001*
Femural head (contralateral)	4.7 (2.3–6.8)	0.0 (0.0–0.0)	0.004	12.8 (9.3–14.3)	0.0 (0.0–0.0)	<0.001*
Penile bulb	1.0 (0.7–2.5)	0.0 (0.0–0.0)	0.031	1.4 (0.9–5.0)	0.0 (0.0–0.1)	0.008

Organs At Risk (OAR), Interquartile range (IQR) defining the 25th and 75th percentile.

^†Wilcoxon's signed rank test.

*Bonferroni corrected significant values (p ≤ 0.0024).

Comparing CTVs < or ≥115 cm³, a non-significant benefit of IMPT (Δmean-dose = VMAT – IMPT dose) was seen for CTVs >115 cm³ for bowel loops (8.2 Gy versus 1.3 Gy, p = 0.04), bladder (7.7 Gy versus 4.6 Gy, p = 0.15), and sacral bone (3.7 Gy versus 0.7 Gy, p = 0.09), as illustrated in Figure 1.

Figure 2 displays a scatter plot for mean photon (Gy) versus mean proton (Gy/RBE) dose for bowel loops, bladder and sacral bone. All but two are below the identity line, and in favor of protons.

Figure 2. Scatter plot for mean photon dose (Gy) versus mean proton dose (Gy/RBE). Bowel loops (blue circle), bladder (red triangle), sacral bone (grey cross).

Discussion

We report the results of comparative VMAT and IMPT dose planning for re-irradiation of rectal cancer pelvic recurrences. This is the first comparative dose planning study for this patient group, and allows us to assess the potential benefit of IMPT relative to VMAT. We found that mean doses to delineated OARs were lower with IMPT and allowed for sparing of OARs. D_0.03ccm was also lower for OAR not in the vicinity of the target, otherwise comparable between the two groups. Larger recurrences showed a trend for greater dosimetric benefit.

Proton therapy can be relevant for re-irradiation when the surrounding healthy tissue has received maximum or near maximum tolerated doses. There are limited data on normal tissue tolerances for pelvic re-irradiation [15,16], but it is probable that any dose sparing achievable with IMPT could contribute to a decreased toxicity due to high cumulative doses. Protons do, however, not reduce maximum dose to OAR in close proximity of the target, as our finding supports. It is the low dose bath to the OARs surrounding the target volume that can be reduced with IMPT.

Only few studies on proton re-irradiation of rectal cancer recurrences have been published. The studies are heterogeneous with a mixture of rectal and other pelvic cancers, different re-irradiation doses (16–64.8 Gy (RBE)), schedules, and both neo-adjuvant or definitive intent. Generally, acute and late toxicities seemed manageable [13,14]. Re-irradiation doses for both the proton and photon re-irradiation studies are often kept around 40 Gy, to minimize combined doses to OARs. However, higher doses are associated with better pathological response in rectal cancer [17]. As studies indicate that toxicity after re-irradiation is acceptable, dose-escalation with proton therapy might be relevant, in order to increase the R0 resection rates or as an option for definitive treatment for the un-resectable recurrences.

Posterior fields are often used in pelvic proton therapy, to reduce impact from changing bowel gas/fillings, weight and other variable conditions [13,18]. This can result in slightly higher dose to the parts of the sacral bone close to the CTV. However, we found comparable D_0.03ccm and lower D_mean with IMPT.

In conclusion, IMPT for pelvic re-irradiation resulted in lower mean doses to OARs, which could translate into clinical benefit with decreased side effects, or enable dose escalation regimens in future trials.

Acknowledgements

The authors would like to thank Espen Rusten for assistance with extracting dose data from the treatment planning system for the Norwegian patients.

Disclosure statement

The authors report no conflicts of interest