The safety of online contouring and planning for adaptive radiotherapy is unknown. This study aimed to evaluate the dosimetric difference of the organ-at-risk (OAR) according to the extent of contouring in stereotactic magnetic resonance image-guided adaptive RT (SMART) for pancreatic cancer.
We reviewed the treatment plan data used for SMART in patients with pancreatic cancer. For the online contouring and planning, OARs within 2 cm from the planning target volume (PTV) in the craniocaudal direction were re-controlled daily at the attending physician's discretion. The entire OARs were re-contoured retrospectively for data analysis. We termed the two contouring methods the Rough OAR and the Full OAR, respectively. The proportion of dose constraint violation and other dosimetric parameters was analyzed.
Nineteen patients with 94 fractions of SMART were included in the analysis. The dose constraint was violated in 10.6% and 43.6% of the fractions in Rough OAR and Full OAR methods, respectively (p = 0.075). Patients with a large tumor, a short distance from gross tumor volume (GTV) to OAR, and a tumor in the body or tail were associated with more occult dose constraint violations—large tumor (p = 0.027), short distance from GTV to OAR (p = 0.061), tumor in body or tail (p = 0.054). No dose constraint violation occurred outside 2 cm from the PTV.
More occult dose constraint violations can be found by the Full OAR method in patients with pancreatic cancer with some clinical factors in the online re-planning for SMART. Re-contouring all the OARs would be helpful to detect occult dose constraint violations in SMART planning. Since the dosimetric profile of SMART cannot be represented by a single fraction, patient selection for the Full OAR method should be weighted between the clinical usefulness and the time and workforce required.
Among hundreds of cancers, pancreatic cancer has one of the worst prognoses. The median overall survival is approximately 13–24 months in patients with localized disease and 9–16 months in locally advanced cases [
Among many radiation therapy (RT) techniques, stereotactic ablative radiotherapy (SABR) offers many advantages compared to conventional fractionated RT, such as a high radiation dose [
In the current practice of SMART to the pancreas at our institution, only a portion of the OARs close to the planning target volume (PTV) is re-contoured because OARs near the PTV are enough to produce an online adaptive plan, and its safety and reproducibility were also published to reduce the most time-consuming step of the treatment [
We retrospectively reviewed the medical records and treatment plans of 19 patients who received SMART at our institution from February 2018 to May 2019. The Institutional Review Board of Seoul National University Hospital (IRB No. 2003-094-1109) approved the study and waived the requirement for informed consent. All patients were treated using the ViewRay MRIdian system (ViewRay Inc., Oakwood Village, OH, USA), which incorporates a 0.35T MRI scanner with three cobalt-60 γ-ray sources [
The simulation process of SMART included MRI simulation with corresponding non-enhanced computed tomography (CT) simulations. Each scan was obtained in the end-expiratory phase to minimize respiratory motion. After simulation, we contoured the target volume and OARs and performed treatment planning. We defined the clinical target volume (CTV) as the pancreatic mass and its infiltration to neighboring structures. A 3–5 mm margin was expanded to all directions from the CTV to make up the PTV. The prescription dose for PTV was 40–50 Gy in 5 fractions, which was adjusted considering the relative location and distance from the surrounding OARs.
The OARs for the treatment course included the stomach, duodenum, and bowel. The institutional dose constraint policy required the V35 of each OAR to be less than 0.5 mL in the initial planning process. Also, in the re-optimization process for SMART, the constraint required the V35 of each OAR to be less than 1 mL. The UK consensus on normal tissue dose constraints for stereotactic radiotherapy [
All treatment plans consisted of 5 fractions of SMART. In each fraction, a daily set-up MRI was obtained using the same protocol as for the simulation. The attending physician decided whether to proceed to the treatment without making amendments to the OAR contours by comparing the anatomy between the MRI taken during the simulation and daily set-up. If the contours needed adjustment, the physician re-contoured them in real-time. For re-contouring, our institutional policy is to adjust OARs within 2 cm from the PTV in the craniocaudal direction or 3 cm, depending on the situation. Also, the attending physician decided which OARs to re-contour, considering the inter-fractional variation and proximity to the PTV. The initial plan was immediately re-optimized based on the daily contours by modifying the dose rate and beam angle.
The entire OAR was re-contoured retrospectively for every fraction of SMART regardless of the distance from the PTV (Full OAR). We contoured the duodenum from the pylorus of the stomach to the fourth portion, where it merges with the bowel. We defined the contour of the bowel as the sum of bowel loops, excluding the duodenum. It was delineated distally to the inferior aspect of the third portion of the duodenum and had no limits proximally. A representative image of the daily MR image with OAR contours using both of the contouring methods is shown in
Statistical analysis was performed using SPSS 26.0 (IBM SPSS Statistics for Windows; IBM Corp, Armonk, NY, USA). The chi-square test was used for comparing categorical variables, and the paired t-test was used for comparing continuous variables. A p-value of less than 0.05 was considered statistically significant. Side effects were graded according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE v5.0). Side effects assessed in grade 3 or higher were termed “severe side effects.”
When the three OARs were evaluated together, the dose constraint was violated in 10 fractions (10.6%), and 41 fractions (43.6%) out of 94 fractions in the Rough OAR and Full OAR methods, respectively (p = 0.075). Detailed descriptions of the violation of the dose constraint evaluated by individual OARs are listed in
In addition, various clinicopathologic factors were analyzed, and BRPC (p = 0.023), tumor size of 2 cm or more (p = 0.027), and stage group I or II (p = 0.008) were associated with a higher proportion of dose constraint violation in Full OAR. Similarly, other factors such as a distance from GTV to OAR of less than 5 mm (p = 0.061) and primary tumor in the body and tail (p = 0.054) were associated with a higher proportion of dose constraint violations in Full OAR with marginal significance.
After considering the clinical context and applicability, tumor size, distance from GTV to OAR, and primary tumor site were chosen as factors for the subgroup analysis. Analyses were performed by dividing the factors into subgroups grouped by two of the three factors and comparing the V35 of each subgroup. The V35 was used in place of dose constraint violation to evaluate the dosimetric difference more comprehensively with a continuous variable. The results are shown in
Other dosimetric parameters, including dose constraint, were investigated for the individual OARs. For each OAR, the differences of dose constraint violations, Dmax, D1cc, V35, and V33 between two contouring methods were investigated (
In SMART, daily re-contouring of the OARs provides an accurate evaluation of the intra-abdominal OARs, in which significant inter- and intra-fractional variability exist. To the best of our knowledge, this is the first study to investigate the safety of SMART for pancreatic cancer by comparing different extents of OAR re-contouring. An ideal method to evaluate dose distribution would be to draw Full OARs for all patients. However, in practice, issues such as time constraints and patient compliance (i.e., unable to maintain a supine position) are challenging. Accordingly, this study evaluated the dosimetric difference between the two distinct OAR contouring methods and investigated which patient population differed using Full OAR contouring. We could find some significant clinical factors that can be used for patient selection for the time-consuming procedure, such as tumor size, stage, distance from the GTV to OAR, and tumor location. The dosimetric difference was evident in the subgroups defined by two of the factors listed and suggested patient subgroups that could benefit from the extensive re-contouring. Regarding the individual OARs, the dosimetric parameters did not differ significantly between contouring methods for the stomach. However, there were significant differences in the duodenum and bowel. Therefore, for patients with the risk factors described above, the duodenum and bowel rather than the stomach could benefit from Full OAR contouring.
In reviewing the dose distribution of the cases that violated the dose constraint in the Full OAR, but not in the Rough OAR, we found that violations were located solely within 2 cm from the PTV contour. This indicates that the additional detection of dose constraints in the Full OAR were not due to the delineation of the contours outside the 2 cm distance from the PTV, but could rather be attributed to the re-contouring of all of the OARs, regardless of the physician's decision. The sparing of the areas outside the 2 cm distance from the PTV is due to the co-planar technique and the steep dose gradient of SABR planning system, making delivery of high dose to remote areas unlikely [
We evaluated the dosimetric profiles for each fraction. Ten of 94 fractions (10.6%) showed a violation of dose constraints, even in the Rough OAR. However, one SMART course is usually made up of 5 fractions, and a dose constraint violation in a single fraction does not necessarily result in a violation for the whole treatment course. Areas that received the highest level of radiation may differ throughout the treatment course. Thus, there may not have been a violation in terms of the entire course. Daily anatomic variations of the OAR should be considered to make an accurate evaluation of the accumulated dose of the treatment course. Dose accumulation of all the fractions using deformable image registration (DIR) would be helpful. Bohoudi et al. [
Recently, auto-segmentation for OARs using deep learning for RT has gained attention in the field, and techniques are evolving [
The current study's analysis is based on our institution's dose constraint (V35 <1 mL). Thus, when we apply a different dose constraint, it would alter the proportions of the violation. Several published dose tolerance guidelines for abdominal OARs exist for 5 fraction-SABR, each employing various dose parameter [
This study had several limitations. First, this study was designed as a retrospective review and contains the inherent potential for selection bias. To minimize selection bias, we included 19 consecutive patients without further selection. Secondly, the Rough OARs were occasionally omitted for some OARs under the judgement of the attending physician, thus hindering clear comparison between the two distinct re-contouring methods. Third, to apply the results of the current study to clinical practice, clinical evidence with a high level of relevance is needed for the dose constraint of SMART. We could generate more solid factors associated with OAR contouring from the prospective data with a larger number of patients. In addition, as mentioned above, the dose constraint violation from a single fraction does not necessarily translate to a violation of the total treatment. Therefore, it is ambiguous to interpret dose constraint violations concerning clinical adverse events. No severe side effects were observed among the patients in the study, even in the group with a violation. Therefore, further analysis of dose constraint violation using DIR-based dose accumulation is warranted. Moreover, the clinical significance of dose constraint violation should be clarified by assessing how many adverse events occur.
In conclusion, Full OAR differed in the proportion of violated fractions from the Rough OAR in SMART for pancreatic cancer. Patient groups with a large tumor, a short distance from the OAR to GTV, and a tumor in the body or tail showed benefit in further discriminating occult dose constraint violations and should be considered for Full OAR contours, especially in the duodenum and bowel. Also, delineating all of the OARs within 2 cm from the PTV, rather than outside 2 cm from the PTV, would help to discover occult violations. However, it should be weighted between the clinical usefulness and its cost as the dosimetric profile of SMART cannot be represented by a single fraction.
The Institutional Review Board of Seoul National University Hospital (IRB No. 2003-094-1109) approved the study and waived the requirement for informed consent.
No potential conflict of interest relevant to this article was reported.
None.
Conceptualization: HCK, YJJ, YAK, JYS; Investigation and methodology: HCK, YJJ, YAK, SHK, JYS; Project administration: EKC, HCK; Resources: EKC, SHK, HCK; Supervision: HCK; Writing of the original draft: YJJ, YAK, JYS; Writing of the review and editing, JYS, HCK; Software: SHK; Validation: SHK, JYS; Formal analysis: JYS; Data curation: YJJ, YAK, JYS; Visualization: YJJ, YAK, JYS. SHK. All the authors have proofread the final version.
The data that support the findings of this study are available from the corresponding author upon reasonable request.
MR image of OAR contours according to methods of re-contouring of one treatment fraction, with PTV (light blue) and the contours of Rough OAR (red) and Full OAR (yellow). MR, magnetic resonance; OAR, organ-at-risk; PTV, planning target volume.
Box-and-whisker plots showing values of V35 (mL) of individual OARs (A) and maximum V35 values of overall OARs (B) for all the adaptive fractions according to contouring methods. V35, volume receiving 35 Gy or more; OAR, organ-at-risk.
MR image of OAR contours according to methods of re-contouring of one treatment fraction Showing V35 discrepancy, with PTV (light blue) and the contours of Rough OAR (red), Full OAR (blue) and isodose line of 35 Gy (light green). MR, magnetic resonance; OAR, organ-at-risk; PTV, planning target volume; V35, volume receiving 35 Gy or more.
Patient and treatment characteristics (n = 19)
Characteristic | Value |
---|---|
Age (yr) | 62 (46–77) |
Sex | |
Male | 10 (52.6) |
Female | 9 (47.4) |
Site | |
Uncinate, head | 8 (42.1) |
Body, tail | 11 (57.9) |
Resectability (NCCN, 2021) | |
Resectable | 0 (0) |
Borderline resectable | 10 (52.6) |
Locally advanced | 6 (31.6) |
Distant metastasis | 3 (15.8) |
Tumor size (cm) | 3 (2.2–13.2) |
Stage | |
I–II | 7 (36.8) |
III–IV | 12 (63.2) |
Radiotherapy aim | |
Preoperative | 12 (63.2) |
Radical | 6 (36.8) |
Salvage | 1 (5.3) |
Radiotherapy fraction | |
4 | 1 (5.3) |
5 | 18 (94.7) |
Radiotherapy dose (Gy) | 45 (42–50) |
Distance from GTV to OAR (mm) | 3.5 |
Range | 0–11.9 |
Values are presented as number of patients (%) and median (range).
NCCN, National Comprehensive Cancer Network; GTV, gross tumor volume; OAR, organ-at-risk.
Dose constraint violation by OAR re-contouring method
n | Rough OAR | Full OAR | p-value | |
---|---|---|---|---|
All fractions | 94 | 10 (10.6) | 41 (43.6) | 0.075 |
Resectability | ||||
Borderline resectable | 49 | 5 (10.2) | 27 (55.1) | 0.033 |
Locally advanced | 30 | 5 (16.7) | 8 (26.7) | 0.460 |
Distant metastasis | 15 | 0 (0.0) | 6 (40.0) | N/A |
GTV to OAR distance (mm) | ||||
≥5 | 25 | 1 (4.0) | 8 (32.0) | 0.484 |
<5 | 69 | 9 (13.0) | 33 (47.8) | 0.054 |
Site | ||||
Uncinate, head | 39 | 4 (10.3) | 15 (38.5) | 0.617 |
Body, tail | 55 | 6 (10.9) | 26 (47.3) | 0.061 |
Tumor size, pre-RT (cm) | ||||
≥2 | 35 | 5 (14.3) | 19 (54.3) | 0.027 |
<2 | 59 | 5 (8.5) | 22 (37.3) | 0.896 |
Stage group | ||||
I, II | 35 | 5 (14.3) | 16 (45.7) | 0.008 |
III, IV | 59 | 5 (8.5) | 25 (42.4) | 0.911 |
Values are presented as number of patients (%).
OAR, organ-at-risk; GTV, gross tumor volume; RT, radiotherapy.
Mean value of V35 by OAR re-contouring method in subgroups
Subgroup | n | Rough OAR |
Full OAR |
p-value | ||
---|---|---|---|---|---|---|
V35 (mL) | 95% CI | V35 (mL) | 95% CI | |||
All patients | 94 | 0.748 | 0–9.50 | 2.101 | 0–18.31 | <0.001 |
‘Tumor size ≥2 cm’ and ‘GTV to OAR distance <5 mm’ | 43 | 1.030 | 0–9.50 | 2.211 | 0–16.43 | 0.063 |
‘Tumor size ≥2 cm’ and ‘Tumor site body & tail’ | 25 | 0.398 | 0–1.27 | 1.488 | 0–7.75 | 0.017 |
‘GTV to OAR distance <5 mm’ and ‘Tumor site body & tail’ | 44 | 0.510 | 0–1.59 | 1.994 | 0–7.75 | <0.001 |
OAR, organ-at-risk; GTV, gross tumor volume; V35, volume receiving 35 Gy or more; CI, confidence interval.
Comparison of dosimetric parameters calculated by using each re-contouring methods
n | Rough OAR | Full OAR | p-value | |
---|---|---|---|---|
All OARs | ||||
Violated fractions | 94 | 10 (10.6) | 41 (43.6) | 0.075 |
Dmax (Gy) | 35.21 ± 7.81 | 37.73 ± 7.73 | <0.001 | |
D1cc (Gy) | 30 | 5 (16.7) | 12 (40.0) | 0.009 |
V35 (mL) | 59 | 5 (8.5) | 25 (42.4) | 0.04 |
V33 (mL) | 5 | 0 (0) | 4 (80.0) | 0.039 |
Duodenum | ||||
Violated fractions | 92 | 0 (0) | 12 (13.0) | N/A |
Dmax (Gy) | 35.21 ± 7.81 | 37.73 ± 7.73 | <0.001 | |
D1cc (Gy) | 28.87 ± 6.13 | 30.08 ± 6.40 | 0.009 | |
V35 (mL) | 0.22 ± 0.26 | 0.60 ± 1.80 | 0.04 | |
V33 (mL) | 0.57 ± 0.52 | 1.02 ± 2.22 | 0.039 | |
Stomach | ||||
Violated fractions | 87 | 9 (10.3) | 14 (16.1) | 0.597 |
Dmax (Gy) | 35.07 ± 10.36 | 34.98 ± 9.84 | 0.949 | |
D1cc (Gy) | 30.44 ± 9.40 | 29.37 ± 9.43 | 0.393 | |
V35 (mL) | 0.55 ± 1.52 | 0.66 ± 1.42 | 0.628 | |
V33 (mL) | 1.16 ± 1.81 | 1.30 ± 2.08 | 0.629 | |
Small bowel | ||||
Violated fractions | 67 | 1 (1.5) | 19 (28.4) | 0.109 |
Dmax (Gy) | 36.64 ± 4.62 | 38.98 ± 7.11 | 0.006 | |
D1cc (Gy) | 31.63 ± 4.75 | 32.28 ± 5.89 | 0.077 | |
V35 (mL) | 0.31 ± 0.31 | 1.50 ± 2.95 | <0.001 | |
V33 (mL) | 1.12 ± 0.90 | 2.57 ± 4.14 | <0.001 |
Values are presented as number (%) or mean ± standard deviation.
OAR, organ-at-risk; Dmax, maximum point dose to an organ or tumor target; D1cc, minimal dose received by the highest irradiated volume of 1 mL; V33, volume receiving 33 Gy or more; V35, volume receiving 35 Gy or more; N/A, not applicable.