Optimization of dose distributions of target volumes and organs at risk during stereotactic body radiation therapy for pancreatic cancer with dose-limiting auto-shells

Medical records of patients with pancreatic cancer receiving SBRT in our center from October 2016 to April 2017 were reviewed. All patients received clinical examinations and abdominal CT or MRI scanning. The inclusion criteria were as follows: diagnose confirmed by pathological examinations; locally advanced pancreatic cancer; patients with resectable or borderline resectable cancer intolerant of surgical resections; age ranging from 18 to 75 years old; tumor located in the pancreatic head with maximum diameter < 5 cm; ECOG ≤2; all patients receiving the same prescription dose. The following exclusion criteria were used: patients with a history of radiotherapy prior to the SBRT; metastatic pancreatic cancer.

SBRT was delivered via CyberKnife, an image-guided frameless stereotactic robotic radiosurgery system (Accuray Corporation, Sunnyvale CA). The treatment planning process was carried out with a dedicated treatment planning system, Multiplan version 4.0.2 (Accuray Inc.).

The sequential method was applied for all plans in the investigation. The inverse treatment-planning algorithm was performed to maximize the minimum dose to target volume or the mean dose, known as “optimize coverage (OCO)” in the system. The upper bounding constraints of the OAR were restricted to the following doses during the optimization (volume of interest limits, VOI limits): spinal cord: 3Gy; stomach: 15Gy; intestine: 14Gy; duodenum: 14Gy. In order to minimize the maximum doses to the critical structures, the above limits were stricter than those reported in the American Association of Physicists in Medicine guidelines in TG-101 [10]. The optimization of monitor unit (MU) was performed as follows: total MU: 90,000; max MU per beam: 500; max MU per node: 1500. This could reduce isodose lines showing up as streaks in the direction of beam entry points, and hot spots in the vicinity of the beam entry points just below the skin surface [11].

The procedure of CyberKnife was similar to our previous study [12, 13]. Gross tumor volume (GTV) was delineated as a radiographically evident gross disease by contrast CT acquired from the portal-venous phase. At the discretion of the physician, clinical target volume (CTV) encompassing areas of the potential subclinical disease spread was also designated. In most cases, the CTV equaled GTV. A 2–5 mm expansion margin was included to determine the planning target volume (PTV). When the tumor was adjacent to critical organs, the expansion of PTV outside of CTV in this direction should be avoided. Therefore, the margin expansion was allowed to be nonuniform. References of normal tissue constraints were according to the American Association of Physicists in Medicine guidelines in TG-101 [10].

Each patient treatment plan was re-generated with 3 shells, 5 shells and 7 shells, respectively. All the patients received the same prescription dose (37.5Gy/5f). At least 90% of PTV should be covered by the prescription dose. The prescription isodose line was limited to 70–80%, which would restrict the tumor D_max. The prescription isodose line of each patient in 3-shell, 5-shell and 7-shell plan was the same. Shells were determined based on the expansions of PTV margins (Details shown in Table 1). The dose limitations between every two shells were assigned (Table 2) in order to obtain desired dose fall-off without compromising coverage significantly. The distance from the PTV margin to each shell was 5 mm, 15 mm and 30 mm in 3-shell group, respectively; 2 mm, 5 mm, 15 mm, 30 mm and 60 mm in 5-shell group, respectively; 2 mm, 5 mm, 10 mm, 15 mm, 30 mm, 60 mm and 100 mm in 7-shell group, respectively. Beam reduction in the system was utilized to restrict beam numbers, remove low-weighted beams and reoptimize with the remaining beams to keep the plan quality, which resulted in ensuring the same number of beams in the three plans. The plans were calculated by Monte Carlo algorithm with high resolution and the uncertainty was 1%.

Parameters selected for evaluation of doses of target volumes included conformity index (CI), new conformity index (nCI), heterogeneity index (HI), gradient index (GI), coverage, volumes encompassed by 100% isodose line (100% PD-V), volumes encompassed by 50% isodose line (50% PD-V) and volumes encompassed by 30% isodose line (30% PD-V). Crucially, the formula of calculation of CI was: \( \mathrm{CI}=\frac{prescription\ isodose\ volume\ \left( PIV,{cm}^3\right)}{tumor\ volume\ encompassed\ prescription\ isodose\ line\ \left( TIV,{cm}^3\right)} \). The nCI was calculated as follows: \( \mathrm{nCI}=\frac{CI}{coverage} \), in which coverage was defined as the ratio of target volumes covered with prescription dose to the target volume. The HI was determined by the following formula: \( \mathrm{HI}=\frac{D_{max}}{R_{xDose\kern0.5em }} \), in which R_xDose was the prescription dose. The definition of GI was the ratio of the volume of half the prescription isodose to the volume of the prescription isodose [14]. Evaluations of doses to OAR included the maximum dose (D_max) and volume doses. D_max was defined as the dose of a 0.035-cc or less. The dose volume of the intestine, stomach and spinal cord was the dose of a 5-cc volume (D_5cc), 10-cc volume (D_10cc) and 0.35-cc volume (D_0.35cc). Doses of a 5-cc and a 10-cc volume were investigated in the case of the duodenum. In addition to these OAR, doses to the spleen were also studied, including the mean dose (D_mean), the dose of a half spleen volume (D_50%) and the volume receiving 5Gy (V₅) and 10Gy (V₁₀). However, 2 patients had splenectomy. Hence, dose evaluations were only performed in 18 patients.

A total of 20 patients were enrolled in the investigation. The median age was 64.5 years old. The prescription dose was 37.5Gy/5f (BED₁₀ = 65.625Gy, biological effective dose, α/β = 10). The median GTV and PTV was 26.95cm³ and 36.33cm³, respectively. The beam number ranged from 150 to 210 and the median was 186.

With the increase of shell number, the CI, 100% PD-V and 30% PD-V significantly decreased (CI: 3-shell vs 5-shell: 1.12 ± 0.05 vs 1.10 ± 0.04, P <  0.001; 5-shell vs 7-shell: 1.10 ± 0.04 vs 1.09 ± 0.03, P = 0.024; 3-shell vs 7-shell: 1.12 ± 0.05 vs 1.09 ± 0.03, P <  0.001) (100% PD-V: 3-shell vs 5-shell: 38.92 ± 12.31 vs 38.45 ± 12.85, P = 0.036; 5-shell vs 7-shell: 38.45 ± 12.85 vs 37.73 ± 12.62, P = 0.002; 3-shell vs 7-shell: 38.92 ± 12.31 vs 37.73 ± 12.62, P <  0.001) (30% PD-V: 3-shell vs 5-shell: 344.53 ± 119.93 vs 312.90 ± 110.18, P <  0.001; 5-shell vs 7-shell: 312.90 ± 110.18 vs 299.15 ± 106.41, P = 0.006; 3-shell vs 7-shell: 344.53 ± 119.93 vs 299.15 ± 106.41, P <  0.001). Additionally, there was significant difference between 3-shell and 5-shell, 3-shell and 7-shell with respect to nCI and GI. Furthermore, the 50% PD-V was smaller in 7-shell compared with that of 3-shell and 5-shell. And the tumor coverage in 7-shell was better than that of 3-shell and 5-shell (Table 3).

The doses to normal tissue were shown in Table 4. After restriction of doses to OAR with different shells, D_5cc of the intestine, D_10cc of the stomach and D_max of the spinal cord was lower in 7-shell than those in 3-shell (D_5cc of the intestine: 3-shell vs 7-shell: 15.50 ± 2.10 vs 14.95 ± 2.51, P = 0.003; D_10cc of the stomach: 3-shell vs 7-shell: 14.32 ± 1.74 vs 13.97 ± 2.23, P = 0.020; D_max of the spinal cord: 3-shell vs 7-shell: 7.12 ± 1.20 vs 6.63 ± 0.89, P = 0.046), though only a trend of decrease of D_10cc of the stomach and D_max of the spinal cord was found when the number of shell increased.

Crucially, in addition to the conventional OARs, the dose-volume parameters of the spleen were further investigated. There was no significant difference between the three groups regarding D_mean, V₅ and D_50%. Nevertheless, V₁₀ was much smaller in 7-shell group than that in 3-shell group.

Given that one patient with a large tumor abutting to the spleen, invading the splenic hilar, the radiation dose was much higher than that for other patients. Therefore, the further analysis of V₁₀ precluded the patient was performed. It was also shown that V₁₀ was smaller in 7-shell group compared with 3-shell group (3-shell: 0 ± 1.31; 5-shell: 0 ± 1.30; 7-shell: 0 ± 0.82; 3-shell vs 5-shell, P = 0.367; 5-shell vs 7-shell: P = 0.156; 3-shell vs 7-shell: P = 0.024). An exemplary image showing the comparison of dose contributions between the three shells, five shells and seven shells plan was illustrated (Fig. 1).