Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC
- Tawfik Giaddui1Email author,
- Wenzhou Chen1,
- Jialu Yu1,
- Liyong Lin2,
- Charles B. SimoneII2,
- Lulin Yuan3,
- Yutao U. T. Gong1,
- Q. Jackie Wu3,
- Radhe Mohan4,
- Xiaodong Zhang4,
- Jaques B. Bluett4,
- Michael Gillin4,
- Kevin Moore5,
- Elizabeth O’Meara6,
- Jennifer Presley6,
- Jeffrey D. Bradley7,
- Zhongxing Liao4,
- James Galvin6 and
- Ying Xiao2
Received: 25 January 2016
Accepted: 23 April 2016
Published: 4 May 2016
Abstract
Background
To establish the feasibility of the dosimetric compliance criteria of the RTOG 1308 trial through testing against Intensity Modulation Radiation Therapy (IMRT) and Passive Scattering Proton Therapy (PSPT) plans.
Methods
Twenty-six lung IMRT and 26 proton PSPT plans were included in the study. Dose Volume Histograms (DVHs) for targets and normal structures were analyzed. The quality of IMRT plans was assessed using a knowledge-based engineering tool.
Results
Most of the RTOG 1308 dosimetric criteria were achieved. The deviation unacceptable rates were less than 10 % for most criteria; however, a deviation unacceptable rate of more than 20 % was computed for the planning target volume minimum dose compliance criterion. Dose parameters for the target volume were very close for the IMRT and PSPT plans. However, the PSPT plans led to lower dose values for normal structures. The dose parameters in which PSPT plans resulted in lower values than IMRT plans were: lung V5Gy (%) (34.4 in PSPT and 47.2 in IMRT); maximum spinal cord dose (31.7 Gy in PSPT and 43.5 Gy in IMRT); heart V5Gy (%) (19 in PSPT and 47 in IMRT); heart V30Gy (%) (11 in PSPT and 19 in IMRT); heart V45Gy (%) (7.8 in PSPT and 12.1 in IMRT); heart V50% (Gy) (7.1 in PSPT and 9.8 in IMRT) and mean heart dose (7.7 Gy in PSPT and 14.9 Gy in IMRT).
Conclusions
The revised RTOG 1308 dosimetric compliance criteria are feasible and achievable.
Keywords
Introduction
Lung cancer is the main cause of cancer death in the United States (US) [1, 2]. In the year 2015, a total of 221,200 new cases and 158,040 deaths from lung cancer are estimated in the US [3]. Non-small cell lung cancer (NSCLC) accounts for about 80–85 % of these cases [1–3] and approximately 30 % of them are considered to be locally advanced, comprising both stage IIIA and IIIB in the current American Joint Committee on Cancer (AJCC) staging system [1]. Radiation therapy plus chemotherapy is the accepted standard of care for patients with locally advanced NSCLC. Proton therapy generally allows for reduced doses to organs at risk compared with photon therapy due to the physical properties of the proton beam, with essentially no dose delivered distal to the characteristic Bragg Peak [4, 5]. RTOG 1308 is a phase III randomized trial comparing overall survival after photon versus proton chemoradiotherapy for inoperable stage II-IIIB NSCLC. The trial’s purpose is to determine if proton therapy can improve overall survival over IMRT by reducing the risk of severe toxicity to organs at risk as compared to photon therapy, and new and more stringent dose constraints were employed [2]. The compliance criteria of clinical trials are often used as constraints for treatment planning and are used for plan scoring upon final review. The method used for designing compliance criteria should optimally examine a large number of treatment plans that are considered to be the result of a significant effort on the part of experienced treatment planners. In this paper, we assessed the feasibility of the new and more stringent dosimetric criteria of the RTOG 1308 trial using the IMRT and PSPT plans submitted during the design stage of the trial. This study aims at improving the efficiency of clinical trials launch by establishing realistic dose constraints in advance.
Methods and materials
Dosimetric compliance criteria for RTOG 1308 trial
RTOG 1308 dosimetric compliance criteria for target volumes and normal structures
RT Parameter | Per protocol | Variation acceptable |
---|---|---|
% of PTV covered by prescription dose | 95 % | ≥95 % of the PTV is covered by ≥95 % of the prescription dose |
% of ITV (motion-incorporated CTV) | 100 % | ≥99 % |
Maximum PTV dose PTV (0.03 cc) | ≤120 % RX | ≤125 % RX |
Minimum PTV dose (0.03 cc) | ≥85 % RX | ≥75 % RX |
Normal lung (Both lungs minus GTV) | V5 ≤ 60 % | V5 ≤ 65 % |
V20 ≤ 37 % | V20 ≤ 40 % | |
Mean dose < 20 Gy (RBE) | Mean Dose: ≤ 22 Gy (RBE) | |
Esophagus | Max dose: 74 Gy (RBE) ≤ 1 cc of partial circumference | Max dose: 74 Gy (RBE) ≤ 1.5 cc of partial circumference |
Brachial Plexus | V66 ≤ 2.0 cc | V66 ≤ 2.5 cc |
V70 ≤ 1.0 cc | V70 ≤ 1.5 cc | |
V74 ≤ 0.5 cc | V74 ≤ 1.0 cc | |
V75 ≤ 0.1 cc | V75 ≤ 0.5 cc | |
Spinal Cord | V50 < 0.03 cc | V52 < 0.03 cc |
Heart | V30 ≤ 50 % | 50 % ≤ V30 ≤ 55 % |
V45 ≤ 35 % | 35 % ≤ V45 ≤ 40 % |
Target definitions and treatment planning
The study investigated 26 patients, each of whom had an IMRT plan and PSPT plan and plans were chosen for consecutive patients. Clinical proton and photon plans were generated for each patient either with the intention of delivering the more optimal plan based on DVH parameters or as comparison plans for insurance purposes. The plans were submitted by two institutions, with the first institution (The University of Pennsylvania) submitting plans for 16 consecutive patients, and the second institution (MD Anderson Cancer Center) submitting plans for 10 consecutive patients. The contouring of normal structures and target volumes as well as motion management was performed in accordance with guidelines from RTOG 1308 at both institutions.
Volumes in cubic centimeters (cc) for all structures (target volume and normal structures) used in this study
Structure | Minimum | Maximum | Median | Mean ± SE |
---|---|---|---|---|
Target volume | 76.55 | 1160.83 | 420.5 | 548 ± 60 |
Normal Lung | 1328.66 | 5701.44 | 2860.8 | 3033 ± 183 |
Heart | 396.54 | 1084.13 | 676.96 | 671 ± 37 |
Esophagus | 21.59 | 66.97 | 33.73 | 35 ± 2 |
Spinal Cord | 14.25 | 71.59 | 37.95 | 39 ± 3 |
Quality assurance of treatment plans using knowledge-based engineering tool
The prescription dose was 66.6/1.8 Gy for plans that the first institution submitted and 74 Gy for plans that the second institution submitted. As such, all plans were scaled so that a prescription dose of 70/2 Gy RBE covered 95 % of the PTV (as per RTOG 1308 guidelines). The scaling factor for plans that the first institution provided ranged from between 1.06 and 1.12, and the scaling factor for plans that the second institution submitted ranged from between 0.93 and 1.00. The quality of all scaled plans was evaluated using a knowledge-based engineering (KBE) tool [12–14]. The tool generates dose volume histogram for OARs based on the patients’ anatomical information using predictive models. The predictive models correlates the anatomical features with the dose features embedded in the IMRT plans and was trained using a multi-institutional database of past high-quality plans. The OARs and their anatomical features were analyzed upon building the model and a stepwise multivariate regression was used to assess the significance of the features and establish the models that correlate anatomy features and dosimetry features. The details of the model building and evaluation is described in [13]. The model was later validated by comparing the DVHs predicted by the model with the actual DVHs of clinical plans for the following dosimetric parameters, V5Gy, V10Gy, V20Gy of Lung, mean dose of heart and esophagus. DICOM data (CT, RtPlan, RtDose and RtStruc) of all IMRT plans used in this study were imported to the KBE tool. The tool requires the matching of PTV and OARs names in the candidate plan with the names used in the models. The tool then generates a modeled dose volume histogram (DVH) for organs at risks for the evaluation plan in study. The predicted DVHs were compared with the planned DVHs to assess the quality of plans involved [15].
Data analysis
DVHs for all plans were analyzed using MIM Software, Inc. [16]. Dose parameters from the two types of plans were compared using a paired t-test. Differences were considered significant if p < 0.05 (two-sided).
Results
Quality assurance of photon IMRT plans using knowledge-based engineering tool
Comparison of OARs dosimetric criteria as estimated by the treatment planning system and the knowledge based engineering tool
Dosimetric Criteria | Treatment planning system | Knowledge based engineering tool |
---|---|---|
Spinal Cord Maximum Dose (Gy) | 40 ± 2 | 44 ± 2 |
Esophagus Maximum Dose (Gy) | 68 ± 3 | 75 ± 2 |
Heart V30 Gy (%) | 16 ± 4 | 15 ± 3 |
Heart V45 Gy (%) | 10 ± 3 | 9 ± 2 |
Lung V20Gy (%) | 27 ± 2 | 29 ± 2 |
Lung mean dose (Gy) | 17 ± 1 | 18 ± 2 |
Compliance of IMRT and PSPT plans to RTOG 1308 dosimetric criteria
Deviation unacceptable rates (expressed as percentage) for the different dosimetric criteria
Structure | Dosimetric Parameter | Photon IMRT | Proton PSPT |
---|---|---|---|
% of cases failed to meet the criteria | % of cases failed to meet the criteria | ||
PTV | % of PTV covered by RX | 0 | 0 |
PTV minimum | 23 | 28 | |
PTV maximum | 0 | 4 | |
Spinal Cord | Maximum dose | 4 | 0 |
Total Lung (both lungs – GTV) | V5 | 4 | 0 |
V20 | 4 | 0 | |
Mean dose | 12 | 4 | |
Heart | V30 | 8 | 0 |
V45 | 4 | 0 | |
Brachial Plexus | V70 | 10 | 5 |
V74 | 10 | 0 | |
V75 | 5 | 0 |
Photon IMRT and proton PSPT dose volume histogram analysis
Average dose volume histograms of IMRT and PSPT plans. a Target Volume. b Spinal Cord. c Esophagus. d Heart. e Normal Lung
Analysis of dose volume histograms of IMRT and PSPT plans
Structure | Photon IMRT | Proton PSPT | |||
---|---|---|---|---|---|
Median | Mean ± SE | Median | Mean ± SE | ||
PTV | % of PTV covered by RX | 95 | 95 | 95 | 95 |
PTV minimum | 57.0 | 56.7 ± 1.5 | 55.0 | 55.5 ± 1.4 | |
PTV maximum | 81.3 | 81.6. ± 0.7 | 79.9 | 80.9 ± 0.9 | |
Normal lung (total lungs – GTV) | Lung V5 | 42.6 | 47.2 ± 2.6 | 35.3 | 34.4. ± 1.6 |
Lung V20 | 27.9 | 28.1 ± 1.6 | 29.32 | 27.6 ± 1.5 | |
Mean Lung dose | 18.4 | 17.8 ± 0.9. | 18.3 | 16.4. ± 0.9. | |
Spinal cord | Spinal Cord maximum dose | 43.8 | 43.5 ± 1.4 | 37.9 | 31.7 ± 3.1 |
Heart | V5 | 39.4 | 47 ± 6 | 16.6 | 19. ± 3 |
V30 | 15.7 | 19 ± 4 | 9.7 | 11 ± 2 | |
V45 | 7.7 | 12.1 ± 2.7 | 7.4 | 7.8 ± 1.5 | |
V50 | 5.4 | 9.8. ± 2.3 | 6.5. | 7.1 ± 1.4 | |
V60 | 2.6 | 6.2 ± 1.5 | 4.2 | 6.7 ± 1.2 | |
V66 | 1.8 | 4.2 ± 1 | 2.9 | 4.7 ± 1.1 | |
Heart mean dose | 12.7 | 14.9 ± 2.4 | 6.7 | 7.7. ±1.4 | |
Maximum Dose | 78 | 69.3. ± 4.5 | 76.4 | 68.5. ± 4.4. | |
Esophagus | Mean dose | 20.1 | 22.7 ± 1.9 | 21.2 | 23 ± 2 |
Maximum dose | 76.2 | 73.2 ± 2.5 | 74.1 | 71. ± 3 | |
Brachial Plexus | V70 | 0 | 0.50 | 0 | 1.0 |
V74 | 0 | 0.27 | 0 | 0.10 | |
V75 | 0 | 0.18 | 0 | 0.11 |
Discussion
Quality assurance of treatment plans using knowledge-based engineering tool
The knowledge-based engineering tool is a quick and reliable tool for checking the quality of treatment plans. This tool [12] was trained using a multi-institutional dataset of high-quality plans to take into consideration the variations in the anatomies of patients, institutional protocols, and treatment techniques. Treatment plans are considered to be of good quality if their calculated dosimetric parameters are less than the values predicted by the tool or if they lie within the confidence level (uncertainty level) of the predicted ones. The quality of all IMRT plans was assessed using this tool. As indicated in Table 4, the values of various dosimetric parameters (volumes receiving a certain dose; mean dose and maximum dose of various structures) as calculated by the treatment plans were within the uncertainty of the values predicted by the tool, indicating that the quality of all plans are generally acceptable. This is a very important step for ensuring that the plans used for establishing the dosimetric criteria are not only acceptable but also of good quality, and it also indicates that the scaling of the plans to the prescription dose of RTOG 1308 did not affect their quality.
Compliance of IMRT and PSPT plans to RTOG 1308 dosimetric criteria
This study was conducted when designing the new and more strict dose constraints now in place for the RTOG 1308 clinical trial to test if these criteria are achievable; based on its findings, many criterion were relaxed (for example, the minimum dose of PTV) or removed (for example, the maximum heart dose of 74 Gy; this was removed after protocol enrollment already started based on the current study findings). Such a study represents a practical improvement in the trial planning processes. By establishing in advance that dosimetric compliance criteria are achievable across a variety of centers and techniques. RTOG and now NRG Oncology clinical trials usually specify two levels of constraints: per protocol and variation acceptable. Ideally, all plans are expected to meet the per-protocol constraints; however, plans are still considered acceptable if there is a minor deviation from the per-protocol constraints and it is still within the range of the variation-acceptable constraints. As a general rule, if the deviation unacceptable rates significantly exceed 10 %, the criterion has to be revised. The deviation unacceptable rates for all RTOG 1308 criteria were less than 10 %, with the exception of the PTVmin dose and mean lung dose (MLD). We compared the PTVmin of the plans with that required by the protocol (Table 2) and noticed that the deviations of the plans from the protocol were less than 5 % in four IMRT plans and ranged between 20 and 34 % in the other two cases. In the PSPT plans, the deviation ranged from between 2.9 and 4.7 % in two cases, ranged from between 8 and 12 % in four cases, and reached 20 % in one case. This effect is likely due to lack of a PTVmin institutional constraint at the time the plans were developed. The deviations of the IMRT plans that failed the MLD criterion from the protocol dose constraints ranged from between 11 and 20 %. Only one PSPT plan failed to meet the MLD criterion, and the deviation of the plan was 15 % from the protocol dose constraints. Such deviation unacceptable rates in some of the plans were dealt with using the protocol allowable variations (prescribing 95 % of the prescription dose to 95 % of PTV or using a prescription dose of 60 Gy instead of 70 Gy) [2].
Photon IMRT and proton PSPT dose volume histogram analysis
The trend of our results agreed qualitatively with those reported by Berman et al.[18] for lung V5Gy (%), mean lung dose, spinal cord maximum dose, and esophagus mean dose. However, a disagreement was observed between our results and Berman et al.[18] on the mean heart dose and the lung V20Gy (%): They reported 4.6 % higher mean heart dose in PSPT plans as compared with IMRT plans, whilst in our study, the mean heart dose was 48 % less in PSPT plans as compared with IMRT plans. The lung V20Gy (%) was 2.7 % higher in PSPT plans compared with in IMRT plans in Berman et al.’s [18], while it was 1.6 % higher in IMRT plans as compared with PSPT plans in our investigation. Chang et al. [19] compared photon and proton plans for stage III NSCLC patients and reported a reduction of 9–3 Gy (compared with 12 Gy in our investigation) in the spinal cord maximum dose and 3 Gy (compared with 1.31 Gy in our study) in the mean lung dose when proton beams were used as compared with IMRT. They also reported 15-17 % (12 % in our study) and 4 % (~0.5 % in our study) in lung V5Gy (%) and lung V20Gy (%), respectively. The prescription dose was different in Chang et al.’s [19] study; they used two different dose levels: 60–63 Gy (RBE) and 74 Gy (RBE) for protons and photons, respectively. Kesarwala et al. [20] examined the feasibility of intensity-modulated proton therapy (IMPT) for elective nodal irradiation in locally-advanced none small-cell lung cancer. They reported a mean lung dose of 17.2 ± 0.9 (Gy/CGE) (compared to 17.8 ± 0.9 Gy in our IMRT results) using photon IFRT and 11 ± 0.8 Gy/CGE (compared to 16.4 ± 0.9 Gy in our PSPT results) using IMPT; our results on IMRT are comparable to their results. They also reported lung V20Gy of 27.9 ± 1.6 % (compared to 28.1 ± 1.6 % in our IMRT plans) and 22.9 ± 1.5 % (compared to 27.6 ± 1.5 % in our PSPT plans). Our IMRT plans results are in good agreement with their results. However, there are some differences in the proton plans, as they used IMPT, which resulted in lower mean lung dose and lung V20Gy.
Conclusion
Most of the dosimetric criteria were achieved using the IMRT and PSPT plans, suggesting that the RTOG 1308 dosimetric compliance criteria are feasible and achievable despite the relatively high deviation unacceptable rate in the PTVmin dose compliance. The KBE QA tool indicated that the plans used in this study are of good quality. PSPT plans led to a significantly lower heart V5Gy (%), V30Gy (%), V45Gy (%), V50Gy (%), heart mean dose, lung V5Gy (%), spinal cord maximum dose, and esophagus maximum dose as compared with IMRT plans. PSPT led to a numerically slightly higher heart V60Gy (%), V66Gy (%), brachial plexus V70Gy (CC), and esophagus mean dose; however, these differences were within statistical uncertainty.
Declarations
Acknowledgement
This project was supported by grants U10CA180868, U10CA180822 and U24CA180803 and U24 RFA-CA-12-014 from the National Cancer Institute (NCI) and the Cure Grant from the Department of Health in Pennsylvania. Paper check services are acknowledged for proof reading the manuscript.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
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