1 INTRODUCTION

Radiation therapy is a major treatment option for patients with prostate cancer. However, variations in the patients’ anatomy during radiotherapy treatment can present challenges. Numerous studies show that the variable location of the prostate, bladder filling, and pockets of gas often present in the rectum might significantly compromise dose coverage of the target structure and increase the dose delivered to critical organs.1-5

Hypo-fractionated radiotherapy, delivering fewer, higher fraction doses increases the dosimetric impact of anatomic variability compared to conventional fractionation schemes. For prostate cancer patients, moderate hypofractionated (70 Gy in 28 fractions, 2.5 Gy/fraction) intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) were proven to keep early normal tissue toxicity at acceptable levels.6, 7 More aggressive hypofractionation delivering 33.5–37.5 Gy in five fractions has also been shown to achieve acceptable toxicity and quality of life,9, 10 even for high risk and very high risk (including node-positive) prostate cancer patients.

The safe and effective delivery of high radiation doses in hypofractionated schemes requires a high level of precision, but inter- and intra-fractional patient anatomical variation is present and known to compromise dosimetric aspects of the treatment.8, 9 Adaptive radiation therapy (ART) strategies, in particular on-line ART, have the ability to account for systematic anatomic changes of prostate swelling as well as random anatomic changes such as inter- and intra-fraction bladder and rectal filling, in addition to independent movement and deformation of multiple targets.8, 10 The necessity and the benefits of ART application in stereotactic body radiation therapy (SBRT) prostate treatments have been shown in other recent studies.9-12 It should also be noted that existing image guided radiation therapy (IGRT) techniques, although allowing for prostate motion management, have some limitations. For example, they might require an invasive procedure carrying the risk of bleeding, infection, and discomfort for the patient (radiopaque intraprostatic fiducial markers method). Another prostate IGRT example is a technique that utilizes inserted electromagnetic transponders. In this case, patient eligibility criteria are very strict as only patients without hip prosthesis, metal implants, peacemaker, or other electromagnetic devices are eligible, as well as relatively thinner patients due to the maximum range of the beacon detection by a required external array (reading) device.13

Adaptive radiation therapy is currently an active area of research, and there are still many novel ART approaches that have not been explored yet but could make a significant contribution to the field. The current study focuses on a comprehensive evaluation of several ART methods that have not been explored for the prostate VMAT hypofractionation schemes examined here. The purpose of this research was to retrospectively investigate eight adaptive radiation therapy strategies (including both online and offline scenarios) for hypofractionated VMAT treatments based on imaging and treatment plan data of 20 prostate cancer patients with the application of deformable image registration (DIR). The online and offline adaptations considered were compared to the non-ART (not adapted) delivery scenario.

2 MATERIALS AND METHODS 2.1 Patient data

The imaging and treatment planning data for twenty prostate cancer patients, with an average age of 77 (±7) years were retrospectively used for this study. The study was approved by the local research ethics board (University of Manitoba).

All 20 patients had previously received a 40 Gy/5 fraction treatment regimen and were treated at CancerCare Manitoba. One pre-treatment, planning computed tomography (pCT) imaging scan, and five sets of on-treatment cone beam CT (CBCT) imaging scans were obtained for each patient. CBCT images were acquired during each treatment fraction right before radiation delivery to ensure proper patient positioning. Anatomic structures considered in the dosimetric analysis included the clinical target volume (CTV), the planning target volume (PTV = CTV+0.5 cm margin) as well as organs-at-risk (OARs) - bladder, rectum, and femoral heads. An experienced radiation oncologist segmented these structures on both CT and CBCT imaging data sets. These structures were also used for plan adaptation and optimization purposes.

The pCT images, at 512 × 512 pixels, were obtained with a spatial resolution of 1.17 mm × 1.17 mm per pixel and 3.0 mm slice thickness (total of ∼210 slices) on a Philips Brilliance Big Bore CT scanner. The CBCT images, at 384 × 384 pixels, were obtained with a spatial resolution of 1.17 mm × 1.17 mm per pixel and 2.5 mm slice thickness (total of 64 slices) using an OBI Cone-Beam CT unit (Varian Medical Systems, Palo Alto, CA).

2.2 Dose delivery and treatment planning

The treatment was delivered using VMAT with two full arcs. Every patient was treated with a full bladder and empty rectum as per local clinical protocol. The intent of the radiation therapy was curative for all patients. Treatment plans were created in the external beam planning module of the eclipse treatment planning system, version 13.6 (Varian Medical System, Palo Alto, CA, USA). Dose and dose-volume objectives for the radiation treatment are summarized in Table 1. The beam energy and the maximum dose rate for both arcs were 6MV and 1000MU/min (SRS mode). All the non-ART plans were normalized to the dose received by 95% of the PTV volume. Specifically, the dose was determined based on the 95% of the PTV volume on the dose volume histogram of the original treatment plan. The non-ART plans were not normalized.

TABLE 1. Treatment planning objectives for target and organs-at-risk (OARs) structures Structure Prescription Fraction dose (cGy) Total dose (cGy) Planning objective symbols* CTV At least 99.0 % receives more than 800.0 4000.0 D99% > 4000 cGy PTV At least 99.0 % receives more than 760.0 3800.0 D99% > 3800 cGy PTV Maximum dose is 856.0 4280.0 Dmax < 4280 cGy Rectum At most 15.0 % receives more than 640.0 3200.0 D15% < 3200 cGy Rectum At most 20.0 % receives more than 560.0 2800.0 D20% < 2800 cGy Bladder At most 15.0 % receives more than 640.0 3200.0 D15% < 3200 cGy Bladder At most 20.0 % receives more than 560.0 2800.0 D20% < 2800 cGy Femur-RT At most 5.0 % receives more than 560.0 2800.0 N/A Femur-LT At most 5.0 % receives more than 560.0 2800.0 N/A *The percentage deviations from these objectives for all adaptive radiation therapy (ART), planned and non-ART plans have been illustrated in Figure 6b for CTV and PTV as well as in Figure 7b for Bladder and Rectum. Femoral heads (right - RT; left - LT) were not included in the plan evaluation as the radiation doses for all plans were significantly below the planning objective thresholds. Abbreviations: CTV, clinical target volume; PTV, planning target volume. 2.3 Adaptive radiation therapy 2.3.1 DIR

Daily CBCT images were acquired before the delivery of every fraction. Planning CT images were then registered to CBCT data sets using a Bspline-based14 automated DIR algorithm available in Velocity AI, version 3.2 (Varian Medical System, Palo Alto, CA, USA). Deformed pCT images (‘dCT’) were then used for daily dose estimation with respect to the treatment plan (adapted and non-adapted) that was delivered to the patient during a particular fraction. Since our study was retrospective, the plan delivery was simulated (i.e., it was not actually delivered to the patient). Contours that allowed for the estimation of the dose delivered to the considered anatomical structures were delineated by an experienced physician on CBCT and then propagated to daily dCT image scans. To adapt to the current patient anatomy, and as needed for some of the strategies studied here including adaption while accounting for the dose delivered in the previous fraction(s), the subsequent fraction treatment plans were re-optimized simulating offline or/and online scenarios.

2.3.2 Plan optimization

For the optimization of VMAT plans in this study, the progressive resolution optimizer,15 version 10.0.28 was used, while for dose calculation, the AAA algorithm (v.10.0.28) was utilized with a 0.25 cm calculation grid resolution. The total dose delivered to the patient after performing a given plan adaptation was estimated by mapping daily doses back to the reference (planning CT) image using an inverted deformation vector field obtained through DIR and then by performing dose accumulation using the Velocity AI software. The objectives were consistent and unmodified throughout the optimization process relative to the Planned plans.

2.3.3 Adaptive radiation therapy strategies For this study, online, offline, and dose feedback (DF) approaches were examined by simulation using the available daily anatomical CBCT data set. Online plan adaptations were simulated to occur immediately before a dose delivery while offline modifications were simulated to occur between fractions n and n+1. DF adaptation was simulated as an offline strategy and utilized the dose delivered in the previous fraction to guide a plan adaptation (re-optimization) for the next fraction. Overall, eight adaptive radiation therapy strategies were simulated for all patients as described below.

DF 2–4 – A combination of the non-ART treatment plan and DF adaptation. In the 1st, 3rd, and 5th fraction, the non-ART plan was delivered. In the 2nd and 4th fraction, the non-ART plan was re-optimized based on the dose delivered during the previous fraction. The reasoning behind performing re-optimization only during the 2nd and 4th fraction is as follows: The second fraction is the first fraction that can use the feedback from the dose delivered in the previous (1st) fraction. During the third fraction, the non-ART treatment plan was delivered because the dose delivered during the 2nd fraction accounted for dose discrepancies resulting from dose delivery during the first fraction, and thus up to the 3rd fraction the plan was assumed to be delivered optimally. Therefore, the time-consuming DF adaptation was not used during the 3rd fraction. To examine the performance of DF applied to every fraction (for example with the availability of in vivo patient dosimetry), we have also tested a continuous DF adaptation (Cont.+DF approach).

The dose delivered in the previous fraction was incorporated in the optimization process for the current fraction using the “dose-based” plan optimization module of eclipse. Before the start of the optimization process, the dose delivered in the previous fraction was mapped to the patient's anatomy of the current fraction using DIR. Once the optimization was initiated, the optimizer compensated for regions of lower than or higher than intended dose by delivering a higher/lower dose to those regions, so that the total accumulated dose delivered during the previous and the current fraction would meet the treatment plan objectives. The application of the DF in the subsequent plan adaptation scenarios was performed in the same manner.

Offline – based on the offline adaptation of the non-ART treatment plan. In the 1st fraction, the non-ART plan was delivered. To deliver the dose during the 2nd, 3rd, 4th, and 5th fraction, the treatment plan was adapted by plan re-optimization using the dCT from the previous fraction (obtained based on the previous fraction's CBCT). As it implies, in this adaptation scenario, only changes in the patients’ anatomy detected on the daily CBCT image data set relative to the planning CT images were accounted for. The dose delivered during the previous fraction was not considered as described in approach (i).

Offline + DF – based on the combination of offline adaptation of the non-ART plan and DF adaptation. In the 1st fraction, the non-ART plan was delivered. In the 2nd fraction, the treatment plan was re-optimized using the daily image data sets (daily dCT) and the dose delivered during the previous fraction (DF adaptation). In the 3rd fraction, the dose was delivered using an offline adapted plan (based on the previous fraction image data sets). In the 4th and 5th fractions, DF and offline adaptation were applied, respectively.

Online – based on the daily online adaptation of the non-ART plan. In all fractions, before the daily dose was delivered, the treatment plan was re-optimized according to the patient's anatomy just before treatment delivery.

Online + DF – based on the combination of daily online adaptation and DF adaptation. In the 1st, 3rd, and 5th fraction, online adaptation was performed, while in the 2nd and 4th, fraction DF adaptation was performed.

Cont. + DF – based on the combination of continuous DF adaptation. In the 1st fraction, the non-ART plan was delivered. During the remaining, 2nd–5th fractions, the treatment plan was adapted using the patient's daily anatomy. The plan re-optimization was performed based on the total dose delivered over all the previous fractions.

Online 1-3-5 – based on the daily online adaptations and non-ART treatment plan. In the 1st, 3rd, and 5th fraction, the treatment plan was adapted using an online approach, while in the 2nd, and 4th fraction, the non-ART treatment plan was delivered.

Offline+Online – based on the combination of online and offline adaptations. In the 1st, 3rd, and 5th fraction, the treatment plan was adapted using an online approach while in the 2nd, and 4th fraction using offline plan adaptation.

The purpose behind creating various adaptive radiation therapy strategies was to find an optimal solution for treatment plan adaptation which minimizes the negative impact of changes in the patient's anatomy on the accuracy of the delivered dose, while also minimizing the time it would take to perform such adaptations in a clinical environment. For example, the rationale behind examining the Online 1-3-5 strategy, where online adjustments of the treatment plan were performed every second fraction instead of every fraction, was to decrease the total time of adaptation relative to a full Online strategy, where online adjustments of the treatment plan were performed every fraction. Another example is a DF 2–4 strategy (where DF = DF). Incorporating a DF step allows accounting for potentially inaccurate dose delivery in the previous fraction and the change in the patient's anatomy because optimization involving the DF step is performed on the daily imaging data. Although the implementation of those steps will increase total treatment time, it is expected that the improved accuracy in the dose delivery will justify the additional workload.

In this study, we define the reference non-ART plan as the one that was created based on the pCT data and was delivered at every treatment fraction without modifications (dose delivered was calculated based on the CBCT and mapped back to the reference pCT image). This is an estimate of what dose is actually delivered by the conventional non-ART approach.

Planned delivery reflects the intended (ie. prescribed) dosimetry of the treatment plan, as approved by the radiation oncologist.

2.4 Evaluation of adaptive radiation therapy strategies

The dosimetric effectiveness of adaptive radiation therapy strategies was evaluated using a variety of dose and dose-volume metrics for target and OARs as specified in Table 2. Metrics were selected based on the relevant literature to ensure general applicability.16-23 The values of each metric were associated with anatomic structures, ART strategies, and the reference plan. Where applicable, the evaluation metrics for ART plans were presented relative to the reference plan as well to quantify the dosimetric benefit of applying plan adaptations compared to the situation where the adaptations were not incorporated in the treatment process.

TABLE 2. Quantitative metrics used for evaluation of adaptive radiation therapy strategies. Apart from all listed metrics, maximum dose (Dmax), mean dose (Dmean), and minimum dose (Dmin) for each structure were determined as well Bladder & Femur-LT & CTV & PTV Rectum Femur-RT D1% (cGy) D1% (cGy) D1% (cGy) D2% (cGy) D1cc (cGy) D1cc (cGy) D5% (cGy) D2% (cGy) D2% (cGy) D50% (cGy) V15%(6 Gy) D5% (cGy) D95% (cGy) V20%(8 Gy) D98% (cGy) V50%(20 Gy) D99% (cGy) V80% (32 Gy) V100% V95% (32 Gy) V105% HI* (%) CI** (%) (PTV only) V95% (PTV only) Dv% - minimum dose delivered to the “hottest” v% of the volume, D1cc – minimum absolute dose for the “hottest” 1cm3 of the volume, Vd% - a volume that received d% or more of the prescription dose expressed as a percentage of volume, HI – homogeneity index calculated as a ratio (D2% - D98%)/D50%,24 CI – conformity index calculated as a ratio V95%/Volume of PTV.25 Abbreviations: CTV, clinical target volume; PTV, planning target volume.

The calculation of the percentage of plans that passed the treatment planning criteria for CTV, PTV, and OAR structures was reported as well. Due to their clinical relevance, the percentage deviations from the treatment planning objectives were also reported. Importantly, our conclusions with respect to superiority and inferiority of particular ART strategies relative to other dose delivery approaches were mostly driven by analysis of treatment planning objectives. Specifically, the larger the passing rate, the more clinically feasible we considered a given ART approach. For CTV and PTV, the smaller the absolute percentage deviations from the planning objectives were considered better. For OARs, the smaller percentage deviations were considered better. The large number of other dose-volume metrics (Table 2) that we have included in our study provide a more comprehensive view on the dosimetry of all considered plans but were not considered in the exact treatment planning objectives used to derive the plans (these are included in Table 1).

The statistical significance of the results comparing the non-ART plan to all the other plans was determined using paired t-tests, using the p-value associated with a 95% confidence level. The time efficiency of the best performing ART method was also reported. The time required for each ART strategy was estimated with the consideration of plan optimization, dose calculation, and DIR procedures.

2.5 Qualitative assessment of image registration

In order to ensure that the image registration did not introduce any major errors in terms of the patient's anatomy deformations, a qualitative (i.e., visual) evaluation of deformed images and deformable vector fields was performed. In particular, the deformed images were compared to the target images by using image overlays, checkboard filters, dynamic magnifying window focusing on soft tissue and bone tissue alignment as well as external body contour, for every registration. The analysis of the vector fields included the inspection of the deformed grid that reflected the magnitudes and directions in the field. The inspection was conducted using tools available in the commercial image registration software Velocity AI (as specified in the Section 2.3.1).

3 RESULTS 3.1 Maximum, minimum, and mean doses

Figure 1 shows the percentage differences relative to the non-ART (i.e., reference, not adapted) plan in Dmax, Dmean, and Dmin for CTV, PTV (Figure 1a) as well as in Dmax and Dmean for OARs (Figure 1b). Dmin for OARs was calculated as well but due to their limited applicability were not included in the results. Appendix (Table A1) contains the detailed tabular data for Figure 1 including Dmin for OAR and standard deviations for all metrics.

Comparison of Dmax and Dmean, and Dmin metrics between the Planned plan as well as non-adaptive radiation therapy (ART) and adapted plans for (a) target structures and (b) for OARs. Bars represent percentage differences (averaged over 20 patients) in particular metrics relative to the Planned treatment. The measure of 0% on the y-axis is the reference point reflecting the value of a given metric for the Planned plan (i.e., reference plan).

All the metrics in Figure 1a indicate that values of Dmax, Dmean, and Dmin in the case of CTV and PTV for adapted plans were closer to the original (Planned) plans compared to the unadapted reference plan. Overall, in terms of dose metrics reported in Figure 1a, continuous DF adaptation outperformed other ART strategies and had a performance close to online adaptations. The Online and Online 1-3-5 plans scored as well as Planned plans in terms of the maximum dose delivered to PTV. The most apparent difference between adapted plans and the dose delivered by the non-adapted plan was reflected in the value of the minimum dose to PTV. In particular, the unmodified plan resulted in the delivery of approximately 17% lower Dmin to PTV compared to the planned minimum dose. Most adapted plans significantly improved the delivered dose in terms of this evaluation metric. Overall, it can be noticed that non-ART plans delivered a lower radiation dose to both CTV and PTV in terms of Dmax, Dmean, and Dmin.

Figure 1b for the OARs shows that Dmax for both bladder and rectum in the non-ART plan differed from the planned dose by around 5% (decrease). However, adapted plans were able to closely match the Planned plans decreasing the difference in Dmax to around 1%–2%. In contrast, the mean dose for bladder and rectum showed larger variations for the adapted plans relative to the non-ART plan. In the case of the bladder, the majority of adaptations increased the Dmean by less than 5%. Only Cont.+DF plans escalated the mean dose by around 6%. Online and Online 1-3-5 plans were able to slightly reduce the Dmean for the bladder relative to the planned dose. The rectum received approximately 5% lower mean dose upon delivery of the non-ART plan compared to the planned dose. As can be seen, Cont.+DF, Offline+DF, and online strategies were able to decrease that difference to roughly 0.5%–2%. The dose to the femoral heads was spared the most through the application of Online and Online 1-3-5. As for the right femoral head, those two online adaptation techniques delivered maximum doses significantly smaller even compared to the planned dose. However, the Cont.+DF adaptation resulted in higher than intended dose to both left and right femoral heads – a 6% and over 10% increase in the mean dose, respectively.

3.2 Dose-volume metrics 3.2.1 Target structures

Figure 2 shows the relative values of dose-volume metrics that were calculated within the evaluation of adaptive radiation therapy strategies for the CTV and PTV. Overall, the dose delivered with the various adaptive strategies was consistently closer to the planned dose compared to the non-ART approach. In that regard, Offline+Online and Offline plans demonstrated the lowest while Cont.+DF and online adaptations demonstrated the highest dosimetric performance for both target structures. The PTV benefited from ART more than CTV as shown by D95%, D98%, and D99%, metric. Notably the values of these three metrics for non-ART plans were approximately 4% lower for CTV and as much as 11% lower for PTV compared to Planned plans. Tabular data for Figure 2 with standard deviations are included in the Appendix (Table A2).

Comparison of dose-volume metrics between the Planned plan as well as non-adaptive radiation therapy (ART) and adapted plans for the clinical target volume (CTV) and planning target volume (PTV). Bars represent percentage differences (averaged over 20 patients) in particular metrics relative to the Planned treatment. The measure of 0% on the y-axis is the reference point reflecting the value of a given metric for the Planned plan.

When it comes to homogeneity index (HI) for CTV (Figure 3), the majority of adapted plans improved the homogeneity (i.e., a lower HI indicates a higher homogeneity level) of the dose distribution relative not only to the non-ART plan but also to the Planned standard treatment. Online and Online 1-3-5 delivered the highest benefit. For PTV, HI was also improved among all adapted plans. Specifically, online and DF plans performed similarly and outperformed offline strategies by around 20%–40%. Compared to the non-ART dose delivery, CI for the planning target volume was approximately 10% higher when adapted plans were utilized. Online ART, in particular, very closely matched the Planned treatment. According to most metrics presented in Figure 3, Offline and Offline+Online adaptations were not meaningfully beneficial to the radiation treatment dosimetry.

Comparison of homogeneity index (HI) and conformity index (CI) between the Planned plan as well as non-adaptive radiation therapy (ART) and all adapted plans for clinical target volume (CTV) and planning target volume (PTV). Bars represent percentage differences (averaged over 20 patients) in the particular metrics relative to the Planned treatment. The measure of 0% on the y-axis is the reference point reflecting the value of a given metric for the Planned plan.

3.2.2 Organs at risk

Figure 4 illustrates the dose-volume metrics for the bladder and rectum. In the case of the bladder, D1%, D1cc, and D2% did not differ significantly from the planned dose for adapted plans but were lower by approximately 7% for non-ART plans. Only Cont.+DF, and a few Offline adaptations, showed slightly higher values compared to the Planned delivery. Larger variations in magnitude were observed in V15%, V20%, and V50% metrics. The most desirable results were obtained through Online and Online 1-3-5 strategies. Cont.+DF adaptive plans showed poor performance with large volumes receiving 15%, 20%, and 50% of the prescription dose as can be seen in Figure 4a. The same observation can be made in Figure 4b showing V80% and V95% metrics for the bladder. Considering results for the rectum, most ART strategies were able to closely match Planned values of D1%, D1cc, and D2% (Figure 4a) as well as values of V80% and V95% (Cont.+DF, Online+DF, Online and Offline+DF in Figure 4b). For V15% and V20%, the majority of adapted plans delivered nearly the same results except for Cont.+DF for which approximately 2% volume increase was noted for 15% and 20% dose prescription levels. Compared to adapted, the non-ART plans were closer to the Planned plans for those two volume metrics. V50% for Planned treatment was approximately the same as for DF 2–4 and Online+DF adaptations. The Cont.+DF approach resulted in V50% being around 7% lower compared to the Planned delivery.

Comparison of dose-volume metrics between the Planned plan as well as non-adaptive radiation therapy (ART) and all adapted plans for bladder and rectum. Bars represent percentage differences (averaged over 20 patients) in particular metrics relative to the Planned treatment. The measure of 0% on the y-axis is the reference point reflecting the value of a given metric for the Planned plan. The charts (a) and (b) were separated for better visualization of the results due to the large differences in y-axis values between V80%, V95%, and the rest of the metrics.

Figure 5 demonstrates that for the left femoral head only the Online 1-3-5 plans were able to keep the D1%, D1cc, D2%, and D5% at the level close to the Planned treatment. All the other plan modifications, except for non-ART resulted in doses higher than the Planned plans by around 4%–11%. In contrast, the majority of adapted plans (except for Cont.+DF and DF 2–4), especially Online and Online 1-3-5, deliver a lower D1%, D1cc, D2%, and D5% by up to 5% to the right femoral head compared to Planned dose delivery.

Comparison of dose-volume metrics between the Planned plan as well as non-adaptive radiation therapy (ART) and all adapted plans for left and right femoral heads. Bars represent percentage differences (averaged over 20 patients) in particular metrics relative to the Planned treatment. The measure of 0% on the y-axis is the reference point reflecting the value of a given metric for the Planned plan. The lack of expected symmetry in the dose delivered by adapted plans to both femoral heads is explained in the Discussion section.

3.3 Comparison to treatment planning criteria 3.3.1 Target structures

Figure 6a demonstrates the percentage of patients for whom a given treatment plan met the treatment planning objectives specified in Table 1 (Section 2.2) for CTV and PTV structures. For CTV, all plans had at least a 90% passing rate except for non-ART plans for which no patients passed CTV or PTV planning objectives. One hundred percent of patients passed the CTV criteria in the case of DF 4-2 and three Online adaptations. For the PTV, these same four strategies were able to achieve a 60%–80% passing rate for the Dmax objective, while other ART approaches received 50% and lower rates. The D99% criterion for PTV was very hard to reach even for well-performing Online adaptations. The maximum passing rate was achieved by Online ART and was equal to slightly above 20%.

(a) Passing rates for clinical target volume (CTV) and planning target volume (PTV) for three treatment planning objectives. (b) Dose differences between the planning objectives and the dose delivered by the specific treatment plan.

Figure 6b details the dose difference, ΔD, between the considered criteria and the value achieved by the plan. For the CTV, nearly all the plans were able to meet the treatment planning objective, and ΔD is positive ranging from 1%–4%. The dose difference in Dmax for the PTV was approximately 1% for investigated ART approaches. It is noted that even though the passing rate for offline adaptations was lower in comparison to the rest of the ART strategies, the ΔD is, on average, positive for Offline+DF, Offline+Online, and Offline plans. This clearly shows that several patients delivered higher doses to the CTV so that it was able to cause the increase in the dose averaged over all 20 patients. The ΔD for D99% objective for PTV ranged from around −4% in the case of Offline plans to approximately −2% for Online adaptations. Compared to all the ART approaches the non-ART plans differs significantly from the Planned plans by −4% to −11% depending on the planning criteria.

In summary, the implementation of the majority of the ART strategies improved the overall passing rate and ΔD for most of the plans, especially for daily online adaptations compared to the delivery of an unchanged non-ART treatment plans.

3.3.2 Organs at risk

The passing rate presented in Figure 7a is equal to 100% across all the plans for the bladder in the case of both plan objectives. Consistently, Figure 7b shows that ΔD for the bladder is significantly (around 60%) below tolerance doses (D15% and D20%). In the case of the rectum, the passing rate for three Offline adaptations and the non-ART plan was in the range of 60%–85% for the D20% metric and from 80% to 100% for the D15% metric. For Online plans, the analogous range was from 80% to 95% for D20% and from 95% to 100% for D15%. ΔD was negative for all the plans and had nearly the same magnitude (of 10%) for most of the adaptations for the D15% and D20% criteria. The absence of femoral heads in this analysis is addressed in the discussion section.

(a) Passing rates for organs at risk (OARs) in relation to the treatment planning objectives. (b) Dose differences between the planning objective and the dose value delivered by the specific treatment plan.

3.4 Statistical significance

As mentioned in the Materials and Methods section, the statistical significance of the results was calculated using paired, two-tailed t-tests. The analysis was based on the comparison of dose and dose-volume metrics for target and OARs structures between the non-ART plan and the other treatment strategies for all 20 patients. The relevant p-values with a 95% confidence level are presented in Table 3 for Dmax, Dmin, and Dmean as well as in Appendix (Table A3) for the remaining metrics. Both tables also summarize the total number of metrics for which the test determined the statistical significance at the level of p < 0.05.

TABLE 3. The results of paired, two-tailed t-test for Dmax, Dmin, and Dmean. The fields for which 0.01 < p ≤ 0.05 are highlighted in green (i.e., significant), while those with p ≤ 0.01 were highlighted in red (i.e., strongly significant)

Cont.

Online

Online

Offline

Offline

Structure Metric non-ART

+DF

DF 2–4

+DF

Online

1-3-5

+DF

+Online

Offline CTV Maximum dose (%) 0.0000 0.4591