Background: We sought to establish a conversion curve to convert the RBE-weighted doses calculated by local effect model I (LEM) (LEM RBE-weighted doses) in patients with locally recurrent nasopharyngeal carcinoma (rNPC) to the RBE-weighted doses calculated by microdosimetric kinetic model (MKM) (MKM RBE-weighted doses). We also converted the LEM dose constraints (RBE-weighted dose constraints in LEM plans) for the brain stem, spinal cord, and optic nerve based on this curve. Methods: Data from 20 patients with rNPC receiving carbon-ion radiotherapy (CIRT) in our hospital were collected. LEM in Raystation (V8A, Raystation, Sweden) was used to generate treatment plans. The clinical target volume CTV1 (GTV + 5 mm) was given 3 Gy (RBE) per fraction. Ninety-nine percent of target volumes should be covered by 95% of the prescriptions; the maximum doses of the brainstem and spinal cord were < 45 Gy (RBE) and < 30 Gy (RBE), respectively. The doses covering 20% volumes of optical nerves/chiasms D20 were < 30 Gy (RBE). Then physical doses of the LEM plans were recalculated by using MKM in Raystation to generate MKM plans. A series of conversion factors (i.e., the ratio of LEM RBE-weighted dose to MKM RBE-weighted dose) was then obtained by using an isovolumetric dose method. The LEM plan prescriptions (LEM prescription) and dose constraints of the organs at risk (OARs) (OAR constraints) were converted to the corresponding MKM prescriptions and dose constraints using this conversion curve. Results: For the CTV1 fractional RBE-weighted dose prescription of 3.00 Gy (RBE) and CTV2 of 2.70 Gy (RBE) in LEM plans, the conversion factors (LEM RBE-weighted dose/MKM RBE-weighted dose) were 1.37 (CI 95% 1.35–1.39) and 1.46 (1.41–1.51), respectively. The average conversion factors from 1.37 (CI 95% 1.33–1.41) to 3.09 (2.94–3.24) corresponded to the LEM fractionated doses from 2.86 Gy (RBE) to 0.24 Gy (RBE), including the doses constraining upon OARs. LEM RBE-weighted doses of 30 Gy (RBE) and 45 Gy (RBE) in 21 fractions were converted to MKM RBE-weighted doses of 16.64 Gy (RBE) and 30.72 Gy (RBE) in 16 fractions. Conclusions: This conversion curve could be used to convert LEM RBE-weighted doses to MKM RBE-weighted doses for patients with rNPC receiving CIRT, providing dose references for re-irradiation therapy.
Keywords: Carbon ion radiotherapy; LEM I; MKM; RBE-weighted doses
Previous studies [[
To refer to the clinical experience of NIRS, the LEM group used the new LEM prescription converted from the corresponding MKM prescription while still using the original unconverted MKM OAR constraints [[
This work not only focused on targets in patients with rNPC but expanded to OAR stand. We also compared our experience with RBE-weighted dose constraints for patients with rNPC with those in NIRS [[
We randomly selected 20 local patients with rNPC who underwent CIRT at our hospital from June 2016 to December 2017.
Target definition [[
Prescription: Information obtained from selected patients is listed in Table 1. Their dose per fraction was the same 3.00 Gy (RBE) of CTV1 and 2.70 Gy (RBE) of CTV2. Since the dose conversion is only related to the dose per fractions [[
Table 1 The irradiation parameters (stage and LEM dose prescription) for all the patients
Patient TNM Stage Clinical stage LEM prescription/Gy (RBE) Fraction P01-P03 T4N0M0 IV 63 21 P04-P06 T3N1M0 III 63 21 P07 T3N0M0 III 63 21 P08 T2N0M0 II 63 21 P09 T1N0M0 I 63 21 P10-P12 T4N0M0 IV 60 20 P13 T3N0M0 III 60 20 P14 T2N0M0 II 60 20 P15 T1N0M0 I 60 20 P16 T4N0M0 IV 57 19 P17 T3N0M0 III 57 19 P18 T2N1M0 II 57 19 P19 T3N2M0 III 54 18 P20 T3N0M0 III 54 18
This study was performed using the Raystation (V8A, Raysearch, Sweden) treatment planning system, which incorporates both MKM and LEM. The RBE-weighted doses calculated by LEM and MKM are hereafter referred to as the LEM RBE-weighted dose and MKM RBE-weighted dose. Plans of selected patients, based on LEM, were first generated as LEM plans. The plan pass criteria [[
Table 2 OAR constraints under MKM obtained from the conversion curve
OAR constraints/Gy (RBE) LEM constraint (21 fractions) LEM constraint (16 fractions) MKM constraint (16 fractions) 70% NIRS constraints Conversion factor Brain stem Dmax 45.00 43.68 30.72 (30.71–30.73) 28.00 1.42 (1.40–1.44) Spinal cord Dmax 30.00 29.28 16.64 (16.63–16.65) 21.00 1.76 (1.74–1.78) Optic nerve D20 30.00 29.28 16.64 (16.63–16.65) 19.60 1.76 (1.74–1.78)
Graph: Fig. 1 The flowchart of treatment planning and dose conversion
Graph: Fig. 2 Left side: transversal view of one patient LEM and MKM RBE-weighted dose distributions with CTV1 (red), CTV2 (green) and brain stem (cyan) contours. The orange coverage is 95% of the prescribed dose. Right side: corresponding dose volume histograms (DVHs) of CTV1 (red), CTV2 (green) and brain stem (cyan) in LEM plans (solid line) and MKM plans (dash line)
Wang [[
Previous scholars [[
For the dose conversion outside CTV, we first defined the dose area of interest outside the CTV as the CTV 20 mm extension (exclude CTV), which includes all the OAR adjacent to the CTV. Then, 56 isodose curves of 60.00 Gy (RBE) to 5.00 Gy (RBE) were selected in the LEM plans of 13 patients, whose fractional doses ranged from 2.86 Gy (RBE) to 0.24 Gy (RBE). The volume of each isodose line was obtained, and then the corresponding MKM RBE-weighted dose of the same volume was found in the MKM plan. A series of conversion factors were obtained according to the definition.
For patient 01, the RBE-weighted isodoses for the LEM plan were: 2.86 Gy (RBE), 2.81 Gy (RBE), 2.76 Gy (RBE), etc. The corresponding volumes of these isodoses are 8.25 cubic centimeters (cc), 12.12 cc, 17.27 cc. For the same volume, the RBE-weighted isodoses in MKM plan were 2.05 Gy (RBE), 2.00 Gy (RBE), and 1.95 Gy (RBE), whose conversion factors in such LEM RBE-weighted doses were 1.39, 1.41, and 1.42.
Most patients with head and neck tumors in NIRS received 16 fractions of radiation, while the methods of this study used 21 fractions, as described above. Since the total dose in multi-fraction irradiations depends more on the size of dose-per-fraction for late, rather than for early, damage to normal tissues [[
Table 3 now presents the results of conversion factor inside CTV for 20 patients. P20 did not have CTV2 since the plan was a boost treatment after irradiation with proton. Based on the 20 cases, the average conversion factors were 1.37 (CI 95% 1.35–1.39) and 1.46 (1.41–1.51) for LEM RBE-weighted dose 3.00 Gy (RBE) of CTV1 and 2.70 Gy (RBE) of CTV2. The corresponding MKM RBE-weighted doses were 2.18 (2.15–2.21) Gy (RBE) and 1.85 (1.79–1.91) Gy (RBE). According to the fitting results of the Fossati curve [[
Table 3 CTV prescription (3 Gy (RBE) of CTV1 and 2.7 Gy (RBE) of CTV2) in LEM plans (LEM prescription) and corresponding conversion factor of 20 patients
LEM prescription Conversion factor P01–P20 3.0 Gy (RBE) 1.35 1.38 1.33 1.37 1.38 1.40 1.36 1.34 1.38 1.39 1.39 1.37 1.39 1.36 1.39 1.36 1.38 1.39 1.38 1.35 2.7 Gy (RBE) 1.67 1.45 1.42 1.47 1.45 1.45 1.45 1.44 1.44 1.45 1.47 1.46 1.47 1.44 1.46 1.41 1.44 1.45 1.46 /
As the conversion factors were obtained by the isovolumetric dose method, Fig. 3 shows the conversion curve outside the CTVs based on our results. The horizontal axis is the fractional dose (0.24–2.86 Gy (RBE)/fraction), and the vertical axis is the conversion factor corresponding to LEM to MKM [1.37 (CI 95% 1.33–1.41) to 3.09 (2.94–3.24)].
Graph: Fig. 3 Conversion curve from LEM to MKM for dose region outside CTV in 20 patients with rNPC (black solid line represents the average value and dashed lines the 95% confidence interval (CI))
Figure 4 shows the dose distributions of the LEM plan and corresponding MKM plan from a patient with rNPC. Three low, medium, and high dose lines of 31.50 Gy (RBE) (Volume covered by 50% of the prescription dose, V50), 50.40 Gy (RBE) (V80), and 56.70 Gy (RBE) (V90) are displayed under LEM plan as shown in Fig. 4a, whose volumes are 3.33 cubic centimeters (cc), 2.00 cc, and 0.24 cc, respectively. Figure 4b shows the corresponding isodose lines of 15.81 Gy (RBE), 33.11 Gy (RBE), 39.61 Gy (RBE) of the MKM RBE-weighted dose in the same volume. Using the conversion curve to obtain the conversion factor, we could deduce that the dose distributions of 15.73 Gy (RBE), 32.59 Gy (RBE) and 39.90 Gy (RBE) in the recalculated MKM plan (21 fractions) were the same as that of the three-dose lines in the LEM plan (as shown in Fig. 4c). Considering the error of the conversion factor curve, the image is only slightly different (Fig. 4b, c).
Graph: Fig. 4 The RBE-weighted dose distribution (three dose lines) from a patient with rNPC in LEM plan (a), the dose distribution in recalculated MKM plan (b) and the dose distribution using the conversion curve in MKM plan (c); b and c are nearly identical
The OAR limits of the carbon ion plan for patients with rNPC [[
The conversion factor in targets have a possible deviation > 1%. This is considered reasonable since the patient's target area involves a combination of various factors (target size, dose, depth of target area, beam configuration, etc.). The conversion curve outside CTV is also consistent with the previous findings of the other scholars [[
This study was performed on patients with rNPC. Compared with patients with primary tumors, patients with rNPC had a significantly reduced tolerated doses to the organ. The conversion study was mainly based on the physical parameters of the carbon-ion beam (i.e., tumor size and location, beam setup, etc.). The radio-resistance of rNPC was not considered in the RBE calculation and conversion. However, since rNPC has OARs like the brain stem, spinal cord, and the optic nerve for head and neck cancers, the converted results should be applicable to other head and neck tumors with similar locations. However, different cancers carry slightly different conversion factors (ongoing research). Although NIRS has not reported any experience with treating rNPC, data collected over the long-term indicate normal tissue damage after the initial treatment of head and neck tumors. Based on Nieder's study [[
During follow-up—up to December 2018—none of patients in this study had serious neurotoxic side effects. This further verified the safety of the dose constraints for important nerve endangering organs (brainstem, spinal cord, visual pathway) during guiding clinical treatment. Therefore, we continued to use these OAR constraints. Follow-up to 2017 showed that the total rNPC group in our center had a survival rate of 82.2% without local progression [[
The patient plan used in the study was not generated by the original Syngo treatment plan system, but rather generated in Raystation. Although the plan itself meets the clinical plan evaluation criteria, it still differs from the actual treatment plan. This may affect the target and OAR dose conversion results. Our method of converting OAR constraints from our 21-fraction treatment to the NIRS 16-fractions treatment involved converting the LEM RBE-weighted dose from 21 to 16 fractions using the LQ model. We then converted from the LEM 16-fractions dose to the MKM 16-fraction dose using the conversion curve. The conversion results still need to be validated by subsequent clinical studies.
Using the isovolumetric dose method, we converted the LEM RBE-weighted doses for actual patients with rNPC into MKM RBE-weighted doses in targets, moreover, established a conversion curve extended to OAR stand.
The OAR constraints on rNPC that we experienced at our center were proven safe after converting to MKM RBE-weighted dose, referred to NIRS and considering re-irradiation. Either LEM or MKM CIRT could allow our constraints to safely treat rNPC without additional conversion studies. What's more, the dose constraints for other critical organs or re-irradiations could be derived or verified following our formula. The LEM or MKM clinical experiences could be translated using the corresponding biophysical model. This reduces the overall cost for deriving the OAR constraints for the whole CIRT community.
We greatly appreciate the generosity of Raysearch Company, who provided the treatment planning system (V8A, Raystation, Sweden).
ZLW designed and carried out the work, analyzed data, and was a major contributor in writing the manuscript. WWW designed the work, analyzed data, and substantively revised the manuscript. HJY designed the work, acquired, and analyzed data. LJD and KL designed the work and revised the manuscript. All authors read and approved the final manuscript.
This work was supported by The National Key Research and Development Program of China (2017YFC0108603); and Science and Technology Commission of Shanghai Municipality Research Project (19411951000).
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.
As a retrospective study, the work was approved by the Shanghai Proton and Heavy Ion Center Institutional Review Board.
Not applicable.
The authors declare that they have no competing interests.
• CIRT
- Carbon-ion radiotherapy
• CTV
- Clinical target volume
• CNAO
- National Center of Oncological Hadrontherapym, Italy
• cc
- Cubic centimeter
• GTV
- Gross tumor volume
• LEM
- Local effect model
- LEM prescription
- Prescription in LEM plan
- LEM RBE-weighted dose
- RBE-weighted dose calculated by means of LEM
• LQ
- Linear-quadratic
• MKM
- Microdosimetric kinetic model
- MKM RBE-weighted dose
- RBE-weighted dose calculated by means of MKM
• NIRS
- National Institute of Radiobiological Sciences
• OAR
- Organ at risk
- OAR constraints
- RBE-weighted dose constraints on OARs
• PTV
- Planning target volume
• rNPC
- Recurrent nasopharyngeal carcinoma
• SPHIC
- Shanghai Proton and Heavy Ion Center
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By Liwen Zhang; Weiwei Wang; Jiyi Hu; Jiade Lu and Lin Kong
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