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Department of Physics, St. Luke’s Radiation Oncology Network, St. Luke’s Hospital, Dublin, IrelandUCD School of Physics, University College Dublin, IrelandSt Luke’s Institute of Cancer Research, Dublin, Ireland
St Luke’s Institute of Cancer Research, Dublin, IrelandDepartment of Radiation Oncology, St. Luke’s Radiation Oncology Network, St. Luke’s Hospital, Dublin, Ireland
St Luke’s Institute of Cancer Research, Dublin, IrelandDepartment of Radiation Oncology, St. Luke’s Radiation Oncology Network, St. Luke’s Hospital, Dublin, Ireland
Department of Physics, St. Luke’s Radiation Oncology Network, St. Luke’s Hospital, Dublin, IrelandUCD School of Physics, University College Dublin, IrelandSt Luke’s Institute of Cancer Research, Dublin, Ireland
Hypo-fractionated lung Stereotactic Ablative Body Radiotherapy (SABR) has often been avoided when tumours are close to the chest wall. Our strategic objective was the reduction of fraction number, while maintaining target biological effective dose coverage without increasing chest wall toxicity (CWT) predictors.
Materials and methods
Twenty previously treated lung SABR patients were stratified into four cohorts according to distance from PTV to the chest wall, <1 cm, <0.5 cm, overlapping up to 0.5 cm and 1.0 cm. For each patient, four plans were created; a chest wall optimised plan for 54 Gy in 3 fractions, the clinical plan re-prescribed for 55 Gy in 5, 48 Gy in 3 and 45 Gy in 3 fractions.
Results
For a PTV distance of 0.5–0.0 cm, a reduction of the median (range) Dmax from 55.7 (57.5–54.1) Gy to 40.0 (37.1–42.0 Gy) Gy was observed for the chest wall optimised plans. The median V30Gy decreased from 18.9 (9.7–25.6) cm3 to 3.1 (1.8–4.5) cm3. For a PTV overlap of up to 0.5 cm, the Dmax reduced from 66.5 (64.1–70) Gy to 53.2 (50.6–55.1) Gy. The V30Gy decreased from 21.5 (16.5–29.5) cm3 to 14.9 (11.3–20.2) cm3. For the cohort with up to 1.0 cm overlap, there was a reduction in Dmax values of 9.9 Gy. The V30Gy for clinical plans, at 66.8 (18.7–188.8) cm3, decreased to 55.3 (15.5–149) cm3.
Conclusion
When PTVs are within 0.5 cm of chest wall, lung SABR dose heterogeneity can be used to reduce fraction number without increasing CWT predictors.
Stereotactic ablative body radiotherapy (SABR) is a well-established option to treat early-stage non-small cell lung cancer (NSCLC) with excellent local control rates and low incidences of acute/late toxicity [
]. To reduce Chest Wall Toxicity (CWT) related to treatment of tumours close to or overlapping with the chest wall, it is common practice to reduce the Biologically Equivalent Dose (BED) via an increased number of fractions and/or decreased total prescription dose. Our institutional practice, based on published guidelines [
] for peripheral tumours is to prescribe 54 Gy in three fractions (BED 151 Gy10) for tumours away from the chest wall (CW) and 60 Gy in five fractions (BED 132 Gy10) for tumours that are within 0.5 cm of, or that overlap with, the CW. However, published literature shows that lung SABR dose and fraction number for tumours close to the chest wall varies greatly in clinical practice, see Supplementary Table S1 [
Radiation-induced CWT, which includes chest wall pain (CWP) and rib fracture (RF), is a late adverse effect after lung SABR but there is considerable variation regarding its correlation with radiotherapy plan dose metrics. Two recent systematic reviews [
]. Analysis of pooled data identified chest wall distance, high dose to small volumes of ribs (e.g. Dmax, D0.5cm3, D5cm3) and dose to larger volumes (e.g., V30Gy and V40Gy) as predictors of chest wall toxicity. Ma et al [
] concluded there was no correlation between PTV (planning target volume) dose per fraction, number of fractions or BED and CWT, supported by Mutter et al whom found no predictive advantage for biologically corrected dose over physical dose [
] indicated that dose fractionation schemes might alter toxicity rates. Other clinical risk factors reported include gender, tumour location, body mass index and age [
UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.
There are risk adapted strategies that are designed to minimise fraction numbers, moving from 3 to 5 fractions only if CWT dose metrics exceed pre-defined levels [
]. The aim of our study was to refine such strategies by developing an approach that takes advantage of SABR dose heterogeneity to reduce fraction number. Uniquely this was to be achieved while maintaining target BED coverage without increasing reported chest wall toxicity (CWT) predictors. In addition, as distance to CW has been identified as a predictor of CWT, we aimed to refine this further by using a distance metric, potentially providing a more efficient way of arriving at the final solution.
2. Materials and methods
2.1 Patients and materials
Twenty previously treated lung SABR cases with tumours in close proximity to chest wall were identified, with ethics approval given for this retrospective study by the Saint Lukes Radiation Oncology Network (SLRON) Research Ethics Committee. The treatment plans for these patients are referred to as the treated clinical plans henceforth.
All patients underwent 4-dimensional computed tomography (4DCT) simulation, and the acquired datasets were binned into ten phases. In addition, maximum intensity projection (MIP) and average intensity projection (AVIP) datasets were generated. An internal gross tumour volume (iGTV) was defined on the AVIP as the combination of the GTV delineated at maximum inspiration, maximum expiration and on the MIP [
]. An isotropic iGTV to planning target volume (PTV) expansion of 5 mm was used. The chest wall was contoured on the AVIP, defined as an expansion of lungs by 2 cm but not medially. For all clinical plans coplanar or near-coplanar (maximum 15 degree couch tilt used) volumetric modulated arc therapy (VMAT) plans were generated on the AVIP for each patient with a prescription of 54 Gy in 3 fractions (for peripheral tumours with PTV distance to CW of > 0.5 cm) or 60 Gy in 5 fractions (for tumours within 0.5 cm of, or overlapping with CW) using Eclipse treatment planning system (Varian, Palo Alto, Ca.) V11 or V13 Acuros XB (AXB) (0·1 cm calculation grid and dose to medium). Each clinical plan was normalised to PTV D95% = 100%. As required, all clinical plans met PTV D99% > 90% with a dose maximum of < 140%. Where possible all clinical plans were optimised to ensure 1 cm3 of chest wall received<110% of prescription.
2.2 Plan optimisation
For each individual patient, four additional plans were created in addition to the original clinical plan, and chest wall dose parameters of Dmax, D0.5cm3, D1.0cm3, D5cm3, V30Gy and V40Gy were extracted from each. The additional plans consisted of the clinical plan re-prescribed for 55 Gy in 5 fractions, 48 Gy in 3 fractions, 45 Gy in 3 fractions as well as a chest wall optimised plan for 54 Gy in 3 fractions. Chest wall optimised plans were designed to separate out the prescription coverage of the GTV and the PTV, taking advantage of our allowable SABR plan dose heterogeneity. Plans were prescribed to GTV: D99% = 54 Gy (100%). They were also required to meet PTV: D95% ≥ 49.7 Gy (92%) and D99% ≥ 48 Gy (89%). A prescription of PTV D95% ≥ 49.7 Gy in 3 fractions was designed as it is equivalent in BED Gy10 to this institution’s standard prescription of 60 Gy in 5 fractions at 133 Gy10 and 132 Gy10. PTV D99% ≥ 48 Gy in 3 fractions was chosen as it is equivalent in BED Gy10 to our institutional standard coverage of 99% of PTV at BED 124.8 Gy10 and 124 Gy10 respectively (SeeTable 1). Fig. 1(a) shows an example of the dose distribution in a 60 Gy in 5 fraction treated clinical case and 1(b) the same case 54 Gy in 3 fraction chest wall optimised. For results cases were categorised in terms of PTV distance from chest wall in four groups: 0.5 – 1.0 cm, 0.0 – 0.5 cm, overlap with CW of up to 0.5 cm and overlap with CW of 0.5 – 1.0 cm, with PTV distances measured from the closest point of the PTV to the chest wall in the axial direction.
Fig. 1(a) Example of the dose distribution in a 60 Gy in 5 fraction clinical case; (b) Dose distribution in the same case prescribed to 54 Gy in 3 fraction but optimised for chest wall. The navy and red contours are the GTV and PTV respectively. The yellow isodose represents 60 Gy, pink isodose 54 Gy, green isodose 49.7 Gy (92% of 54 in 3 fractions), orange isodose 40 Gy and light blue 30 Gy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Prescription target coverage in terms of BED deliverable of the original clinical plans was at least maintained for the chest wall optimised 54 Gy in 3 fraction plans, as indicated by the tabulated prescription D99% of the GTV, the D95% and D99% of the PTV in terms of BED10, (Table 1).
In the patients where the PTV to CW distance was 0.5–1.0 cm, all clinical plan CW predictors with 54 Gy in 3 fractions were comparable to the chest wall optimised 54 Gy plans. A median V30Gy of 1.6 (range 0–3.5) cm3 was obtained and a V40Gy of zero for all plans (Fig. 2).
Fig. 2(a) Point dose chest wall dose results and (b) volumetric chest wall dose results of five patient cases with a PTV between 0.5 cm and 1 cm from chest wall. The asterisks illustrate the median, the whiskers the range of values with the 25%-75% quartiles enclosed in the box. All original clinical plans for each patient were planned with 54 Gy in 3 fractions with an average PTV volume in this cohort was 19.2 ± 1.0 cm3.
For patients where the PTV to chest wall distance was 0.0–0.5 cm, CW predictors of toxicity were highest in cases planned to 60 Gy in 5 fractions followed by the 55 Gy prescription. Chest wall optimised 54 Gy plans were comparable to the re-prescribed 48 Gy and 45 Gy plans (Fig. 3). Comparison of the original clinical plans to the chest wall optimised 54 Gy in 3 fraction plans showed a reduction in Dmax from 55.7 (57.5–54.1) Gy to 40.0 (37.1–42.0) Gy, in D0.5cm3 from 47.0 (43.7–48.7) Gy to 34.2 (32.3–35.4) Gy. The V30Gy for the original clinical plans was 18.9 (6.7–25.6) cm3, compared to 3.1 (1.8–4.5) cm3 for the chest wall optimised plans. Similarly, the V40Gy reduced from 3.2 (1.2–1.4) cm3 to zero.
Fig. 3(a) Point dose chest wall dose results and (b) volumetric chest wall dose results of five patient cases with distance from PTV to CW between 0.0 cm and 0.5 cm. All original clinical plans for each patient were planned with 60 Gy in 5 fractions with an average PTV volume in this cohort was 28 ± 7 cm3. The asterisks illustrate the median, the whiskers the range of values with the 25%-75% quartiles enclosed in the box.
In the patient cohort of up to 0.5 cm PTV overlap with chest wall, CW predictors of toxicity were highest with planned prescriptions of 60 Gy in 5 fractions. Chest wall optimised 54 Gy plans were comparable with 48 Gy prescription (Fig. 4). Comparison of the original clinical plans to the chest wall optimised 54 Gy in 3 fraction plans showed a reduction in Dmax of 66.5 (64.1) Gy to 53.2 (50.6–55.1) Gy and in D0.5cm3 from 58.9 (56.2–63.1) Gy to 48.9 (45.0–51.0) Gy. Volumetric V30Gy of 21.5 (16.7–29.5) cm3 for the original clinical plans reduced to 14.9 (11.3–20.2) cm3 for chest wall optimised plans. The V40Gy also reduced from 7.2 (6.0–9.8) cm3 to 4.3 (2.3–5.9) cm3.
Fig. 4(a) Point dose chest wall dose results and (b) volumetric chest wall results of five patient cases with an overlap of PTV and chest wall of up to 0.5 cm. All original clinical plans for each patient were planned with 60 Gy in 5 fractions with an average PTV volume in this cohort was 23 ± 13 cm3 (range 40.6–11.2 cm3). The asterisks illustrate the median, the whiskers the range of values with the 25%-75% quartiles enclosed in the box.
In the patient cohort of up to PTV 0.5–1.0 cm overlap with chest wall, median point dose metrics reduced from a Dmax of 67.1 (64.9–71.7) Gy to 57.2 (54.6–59.3) Gy and a D0.5cm3 of 64.1 (61.6–66.4) Gy to 54.0 (51.8–56.4) Gy between the original clinical and chest wall optimised cases (Fig. 5). The V30Gy average for clinical plans was 66.8 (18.7–188.8) cm3 and for the chest wall optimised method was 55.3 (15.5–149) cm3. The V40Gy for clinical plans was 37 (8.2–108.6) cm3 compared to 26 (6.6–66.8) cm3.
Fig. 5(a) Point dose chest wall dose results and (b) volumetric chest wall results of five patient cases with an overlap of PTV and chest wall of 0.5 cm – 1 cm. All original clinical plans for each patient were planned with 60 Gy in 5 fractions with an average PTV volume in this cohort was 52 ± 68 cm3 (range 11.5 cm3 − 177.5 cm3). The asterisks illustrate the median, the whiskers the range of values with the 25%-75% quartiles enclosed in the box.
This study developed a risk adaption approach using SABR dose heterogeneity to reduce fraction number when tumours are within 1 cm of CW, while minimising CW toxicity. BED equivalent prescription target coverage of the GTV and PTV is also maintained.
Previous evidence can be categorised into two groups; one correlating CW toxicity to a point dose and the other correlating CW toxicity with a volume dose. Taremi et al [
] with prescription doses of 54–60 Gy in 3 fractions showed a significant association between RF and Dmax in excess of 50 Gy, with D0.5cm3 of 60 Gy leading to a 50% risk of RF. Stam et al [
], with a median of 54 Gy in 3 fractions, also showed maximum rib point dose was the best predictor of fractures. They reported using NTCP modelling a TD50 (dose with 50% complication) of 375 Gy3 BED, concluding the risk of symptomatic rib fractures was significantly correlated with dose, with < 5% occurrence when Dmax < 225 Gy3 BED.
In several studies reviewing volumetric constraints, CW V30Gy appears to be the best predictor of CWT. Ma et al [
] recommended a V30Gy < 30 cm3 in cases where tumour coverage is not compromised. When this is not achievable V30Gy < 70 cm3 can be considered as acceptable. The rates of grade 2 or greater CWP for V30Gy < 30 cm3 and V30Gy < 70 cm3 have been reported to be 17% and 28% respectively, when delivering 48 – 60 Gy in 3–5 fractions [
] with 3 fractions or 5 fractions demonstrated that the CWT rates at 7% and 5% respectively were similar, once V30Gy (3 fraction) or V37Gy (5 fraction) < 30 cm3 chest wall constraints were applied.
There are two key differences in this study when compared with risk adapted publications. First, this method ensures, that prescription target coverage is maintained. Prescription target coverage must satisfy the D99% of the GTV of the original clinical plan and the D95% of the PTV. Table 1 shows that the BED based prescription coverage of the original clinical plans equates to the BED values for the chest wall optimised plans, exploiting the inherent heterogeneity of these plans. The clinical view in this institution is strongly in favour of maintaining current prescription BED levels. In support of these high BED levels, Manyam et al [
Effect of Tumor Location and Dosimetric Predictors for Chest Wall Toxicity in Single-Fraction Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.
] suggests that BED > 150 Gy may improve local control. An additional advantage of having a GTV indicator in the prescription is helping to harmonise dose prescription in lung stereotactic radiotherapy [
Second, our classification of patients according to the PTV to chest wall distance into the different categories used here shows a narrow range of CW predictors of toxicity within each cohort (Fig. 2, Fig. 3, Fig. 4). By retrospectively considering the CW metrics of five different plans for each patient, we have shown that there is merit to refining the risk management strategy by reference to distance from chest wall. Stephans [
] demonstrated that patients with CWT had tumours closer to the CW, with mean ITV (internal target volume) to CW distances of 2.6 vs 6.0 mm, p = 0.02, respectively.
Using the proposed novel chest wall dose optimisation 54 Gy in 3 fraction method for PTVs, no benefit is seen in CW predictors of toxicity for the 0.5 to 1 cm cohort. For this cohort, the V30Gy results are well below what is documented in literature to correlate with CWT and the V40Gy was zero for all plans.
In using this risk adapted strategy for PTV within 0.5 cm of chest wall, we can expect that the point dose and volumetric constraints to drop sufficiently, and to remain below tolerance level ie reduction in Dmax from 55.7 (57.5–54.1) Gy to 40.0 (37.1–42.0) Gy and V30Gy from 18.9 (6.7–9.7) cm3 to 3.1 (1.8–4.5) cm3. Indeed, such is the extent in the drop for the 0.5 – 0 cm cohort that in accordance with literature cited above, the difference could prove beneficial to CWT outcome, especially in a 3-fraction regime. Notably, the results of the chest wall optimised 54 Gy plans are comparable to 48 Gy and 45 Gy plans. This shows the benefit of the new heterogeneous method separate from the overall prescription reduction in dose from 60 to 54 Gy.
For the 0.5 cm PTV overlap cohort, the chest optimised method would typically mean that the resultant chest wall toxicity metrics could remain under the level at which an increase in fraction number would be recommended. Comparison of the original clinical plans to the chest wall optimised 54 Gy in 3 fraction plans shows a reduction in Dmax of 66.5 (64.1–70) Gy to 53.2 (50.6–55.1) Gy. Such a reduction would mean that we would be below the Dmax of our literature review and the suggested CW Dmax of 56.7 Gy for a three fraction regime within the VALOR trial, which is an ongoing randomised prospective trial designed to compare 54 Gy in 3 fractions to 56 Gy in 4 fractions or 57.5 Gy in 5 fractions, to include CWT outcomes. Also Jumeau et al [
] showed that in their three fraction group, the CW V30Gy for patients with CWT was 21 cm3, whereas it was 15 cm3 for patients without CWT (p = 0.012). A review of our volumetric results show the V30Gy of 21.5 (16.7–29.5) cm3 for the original clinical plans reduced to 14.9 (11.3–20.2) cm3 for chest wall optimised plans. In addition the V40Gy also reduced from 7.2 (6.0–9.8) cm3 to 4.3 (2.3–5.9) cm3, below the recommended V40Gy < 5 cm3.
In the cases where the GTV is in contact with the chest wall, both the point dose and volumetric results in the chest wall optimised plans, although reduced, may still be above acceptable dose volume constraints. The point dose metrics reduced significantly by a mean of 9.8 Gy. The mean point dose metrics reduced from a Dmax of 67.1 (64.9–71.7) Gy to 57.2 (54.6–59.3) Gy, between the original clinical and chest wall optimised cases.
Due to the extent of the overlap and the variability of the PTVs the same consistent level of CWT metric reduction is not seen in the volumetric results. The V30Gy average for clinical plans is 66.8 (18.7–188.8) cm3 and for the chest wall optimised method is 55.3 (15.5–149.0) cm3. The V40Gy for clinical plans is 36.9 (8.2–108.6) cm3 compared to 26 (6.6–66.8) cm3. Notably in this cohort there was a wide range of target volumes, with a mean PTV volume of 52 (range 11.5 cm3 − 177.5 cm3). Therefore, for this cohort, one can choose on a case by case basis to continue with the current clinical practice of 60 Gy in 5 fraction regime, de-escalate dose or use the chest wall re-optimisation method.
Our study has shown that there is merit to refining chest wall risk adapted schedules further. Based on this planning study, tumours with a PTV distance of between 0.5 cm to −0.5 cm from chest wall, can typically be treated with 54 Gy in 3 fractions optimised to reduce chest wall toxicity. Optimisation can be achieved through exploiting the heterogeneity of SABR plans using a BED adapted approach to maintain acceptable GTV and PTV coverage and reduce the known dose predictors of chest wall toxicity to acceptable limits. The potential benefit to the GTV overlap cohort will need to be evaluated on an individual basis.
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:
UK 2022 Consensus on Normal Tissue Dose-Volume Constraints for Oligometastatic, Primary Lung and Hepatocellular Carcinoma Stereotactic Ablative Radiotherapy.
Effect of Tumor Location and Dosimetric Predictors for Chest Wall Toxicity in Single-Fraction Stereotactic Body Radiation Therapy for Stage I Non-Small Cell Lung Cancer.
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