1. Introduction
Gastric cancer is the fifth most common malignant disease worldwide, with more than one million new cases per year, according to recent statistics from 185 countries [
1]. Gastric carcinoma is also the fourth leading cause of cancer mortality globally, following lung, colorectal and liver cancers [
1]. Complete tumor and regional lymph node resection is the primary treatment approach for patients with stomach cancer [
2]. The curative or palliative surgical resection may be applied in 50–60% of these subjects during the first disease stage [
2]. Macdonald et al. [
3] showed that postoperative chemoradiotherapy for gastric cancer significantly improves overall and relapse-free survival compared to those associated only with surgery.
Adjuvant radiation therapy administered with concurrent chemotherapy is currently recommended for patients suffering from gastric cancer [
4]. Radiation-related toxicity remains a concern for these patients subjected to the above treatment option [
3,
4]. The target volume in gastric cancer usually has large dimensions [
5], and it is surrounded by many healthy organs with high radiosensitivities, such as kidneys, liver, heart, bowel and lungs. Special consideration needs to be given in the selection of the proper radiation therapy plan, ensuring adequate tumor control with minimal adverse events. The radiobiological optimization of treatment plans using biologically related models should supersede the well-known plan evaluation based on physical dose quantities [
6]. Limited data have been published about the radiobiological metrics associated with the therapeutic irradiation of gastric cancer. Mondlane et al. [
7] found that proton therapy reduced the normal tissue control probability (NTCP) of the left kidney with respect to volumetric modulated arc therapy (VMAT) with 6 MV photons. Photon and proton irradiation led to similar NTCPs for all other organs-at-risk (OARs). Sharfo et al. [
8] showed that the automated VMAT plans result in lower NTCPs of kidneys and liver compared to manual VMAT planning with 10 MV photons. To our knowledge, no attempts have been made to investigate the impact of radiation therapy technique and photon beam energy on the tumor control probability (TCP) and NTCP related to gastric cancer irradiation.
The objectives of this study were (a) to determine the TCP and NTCP from three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiation therapy (IMRT) and VMAT for gastric cancer with different photon beam energies, and (b) to develop a new software package providing automatic calculation of the above radiobiological parameters derived from the treatment plans.
3. Results
3.1. Dosimetric Comparison of Treatment Plans
The isodose curves associated with 3D-CRT, IMRT and VMAT plans for gastric cancer are presented in
Figure 4. The dose parameters for the PTV and eight different OARs derived from treatment plans on XCAT phantoms representing an adult male and female are shown in
Table 3 and
Table 4, respectively. The V
42.
75Gy for the PTV in 3D-CRT plans varied from 95.8% to 98.3% by the beam energy and the phantom used. The respective value for plans with intensity-modulated beams was at least 99.9%. IMRT plans led to HI and CN values of 1.03–1.04 and 0.84–0.87, respectively. The corresponding parameters from VMAT were similar and equal to 1.03–1.04 and 0.85–0.87. The 3D-CRT plans led to a HI of 1.08–1.10, whereas the CN was 0.35–0.61.
The Dav received by the left lung, right lung, heart, left kidney, right kidney and liver from 3D-CRT plans for gastric cancer generated on both humanoid phantoms was 4.1–6.8 Gy, 2.3–4.6 Gy, 9.4–17.6 Gy, 12.0–15.7 Gy, 9.9–12.6 Gy and 21.5–22.6 Gy, respectively. The corresponding doses from IMRT and VMAT were 5.5–8.4 Gy, 4.0–7.0 Gy, 10.2–16.5 Gy, 10.6–12.8 Gy, 9.3–11.0 Gy and 19.5–21.2 Gy, respectively. The Dmax values to the spinal cord from 3D-CRT, IMRT and VMAT were 31.1–35.6 Gy, 33.1–37.7 Gy and 32.3–36.7 Gy, respectively. The V10Gy, V20Gy and V30Gy for both lungs from 3D-CRT were found to be smaller than those from IMRT and VMAT plans. The opposite result was found for the Vi parameters of right and left kidneys, liver and bowel. The V30Gy for the heart associated with conformal radiotherapy of a female patient with gastric cancer was lower than that from IMRT and VMAT. The above was not observed for treatment plans generated on the XCAT phantom representing an adult male.
3.2. Radiobiological Comparison of Treatment Plans
No difference was detected between the manual calculations of both TCP and NTCP and the respective software-based calculations. The time for any software calculation took less than 40 s. The TCP and NTCP of an adult male undergoing radiation therapy for gastric cancer, as obtained by the new software tool, are presented in
Table 5. The radiobiological parameters for an irradiated female with stomach carcinoma are shown in
Table 6. The TCP range from 3D-CRT plans created on both phantoms was 48.5–50.2%, depending upon the photon beam energy used. The TCPs from IMRT and VMAT varied from 51.3 to 51.5%. The NTCP for lungs, heart, kidneys, liver, bowel and spinal cord due to 3D-CRT of male patients with gastric cancer was (4.8 × 10
−5–7.4 × 10
−1)%. The corresponding ranges from IMRT and VMAT were (9.2 × 10
−6–3.3 × 10
−1)% and (1.3 × 10
−5–2.7 × 10
−1)%. The NTCPs derived from 3D-CRT, IMRT and VMAT plans created on a phantom simulating an average female were (3.4 × 10
−7–5.2 × 10
−1)%, (5.3 × 10
−6–2.9 × 10
−1)% and (5.9 × 10
−6–2.4 × 10
−1)%, respectively.
4. Discussion
The quality of any particular radiotherapy plan and the subsequent comparison of plans usually relies on radiation dose and dose-volume parameters. The report of the therapy physics committee of the American Association of Physicists in Medicine previously suggested the use of biologically-based models for treatment planning [
6]. The TCP and NTCP indices may reflect more closely the clinical outcome of radiation therapy compared to physical dose-volume quantities [
6]. The above radiobiological indices have been widely employed for the analysis and evaluation of radiation therapy plans [
27,
28,
29]. However, many treatment planning systems can not directly provide TCP and NTCP calculations. The determination of these quantities on the basis of the EUD model requires the extraction of DVHs from the planning systems and, then, the combination of histogram data with mathematical equations and model parameters. This procedure takes considerable time making its use to be rather difficult in everyday clinical practice.
This study introduced a new software tool for calculating the TCP and NTCP from radiation therapy plans. This tool was not limited to the needs of the present study related to gastric cancer and the surrounding OARs. It was designed to give calculations of radiobiological parameters for different tumor sites and different critical organs. Moreover, its design enabled the TCP and NTCP determination for any fractionation schedule. The DVH data of the target volume or any OAR, as obtained by the treatment planning system, was directly introduced into the software tool without any processing or modification. Organ- and tumor-specific parameters were introduced into the software environment to facilitate the EUD calculation and the subsequent determination of the TCP and/or NTCP. The user had to simply define the OAR or tumor site and the dose per fraction. The accuracy of the software results was verified against manual calculations of the above biological indices. The proposed software tool may be routinely used as a clinical aid in the radiobiological comparison of any treatment plans. The user intervention in this process is minimal. The tool may directly give quick and automatic calculations of TCP and NTCP values. Further research is needed to investigate the application of the software tool to centers equipped with treatment planning systems different from that used in this work.
The newly developed software tool was applied for the radiobiological comparison of photon plans for gastric cancer. The target volume in radiotherapy for gastric malignancies has multi-concave shapes, and its size may vary widely from patient to patient. Jansen et al. [
30] found a PTV range from 634 cm
3 to 1677 cm
3. The analysis of treatment plans obtained by consecutive gastric cancer patients undergoing radiation therapy may not lead to representative dose results for the average subject. The previously reported guidelines of radiotherapy treatment planning [
31] pointed out that some planning studies may benefit from the in-depth and profound examination of a few representative cases. The treatment plans of this study were created on two different computational XCAT phantoms simulating average adult male and female patients. The anatomies of the XCAT phantoms were properly adjusted to represent the 50th percentile of United States adult subjects aged 18–64 years [
9]. Data from ICRP publication 89 [
32] dealing with anatomical and physiological values of reference individuals were employed to determine the organ volumes of both phantoms.
Three dimensional-CRT plans were generated with 6, 10 and 15 MV X-rays on both XCAT phantoms. Photon beam energies of 6 MV and 10 MV were used for the IMRT and VMAT planning. The generated treatment plans were considered clinically acceptable, and they fulfilled the dose constraints for the examined OARs. The IMRT and VMAT plan led to almost the same TCP values, which were always higher than those related to 3D-CRT. The TCP difference between the intensity-modulated treatment techniques and conformal radiotherapy was found to be 4.0–6.0% for females treated for the gastric difference. The minimum difference for irradiated males was 2.2%. The calculated TCP values were consistent with those reported by Mehri-Kakavand et al. [
19], who examined patients subjected to radiotherapy for gastro-esophageal junction cancer.
The NTCP values for the spinal cord and the critical abdominal organs, including left and right kidneys, liver and small bowel associated with IMRT and VMAT, were systematically lower than those from 3D-CRT for gastric cancer irrespective of the patient’s gender and the beam energy employed. Conventional conformal radiation therapy on a phantom simulating an adult female resulted in smaller NTCPs for both lungs and heart with respect to advanced intensity modulated treatment methods. Similar results were found only for the left and right lungs based on the analysis of treatment plans created on a phantom representing a typical male. It should be noted that the NTCP values derived from all treatment plans for gastric cancer created on the two different XCAT phantoms were found to be small. The vast majority of these values were lower than 0.01%. One exception was the NTCP of the liver, which varied from 0.24% to 0.74%. The NTCP of the left kidney for males subjected to 3D-CRT was also more than 0.03%.
Comparing the biological indices from plans generated with different photon beam energies, useful conclusions were drawn about the optimal energy selection for radiotherapy for gastric cancer. The TCP and NTCP from 3D-CRT with 15 MV photons were lower than those associated with treatment plans created with both 6 and 10 MV X-rays. The photon beam energy had no effect on the TCP values derived from both IMRT and VMAT plans. However, the use of 10 MV instead of 6 MV photons for IMRT and VMAT for gastric cancer reduced the NTCP to five to six out of eight OARs examined in this work.