The Accuracy and Dosimetry of Individualized 3D-Printing Template Assisted I125 Radioactive Seed Implantation for Recurrent/Secondary Head and Neck Cancer

Background: Individualized 3D-printing template (3D-PT) is developed to facilitate I 125 radioactive seed implantation (RSI), while most of the previous studies were focused on the ecacy and safety proles, study on the accuracy of I 125 RSI is lacking. Therefore, the aim of this study is to evaluate the accuracy of intraoperative needle puncture and post-plan dosimetry of individualized 3D-PT assisted I 125 RSI for recurrent/secondary head and neck cancer. Methods: From February 2017 to January 2020, clinical data of 41 patients (mean age, 58.5 ± 16.1 years; 28 males) with recurrent (48.8%)/secondary (51.2%) head and neck cancer underwent individualized 3D-PT assisted I 125 RSI under CT guidance in our institute were retrospectively reviewed. Results: A total of 430 needles [mean, 10.5 (range 3–17) per patient] were inserted. Technical success rate was 100% without major complication. The mean needle’s entrance deviation was 0.090 cm (95% Condence Interval, 0.081–0.098). The mean intraoperative depth and angular of the needle were consistent with that of pre-plan (6.23 ± 0.24 vs. 6.21 ± 0.24 cm, p = 0.903; 83.14 ± 3.64 vs. 83.09 ± 3.66 degrees, p = 0.985, respectively). The mean deviation between the needle’s pre-planned and intraoperative depth and angular were 0.168 ± 0.024 cm and 1.56 ± 0.14 degrees, respectively. The post-plan dosimetry parameters, including D90, D100, V100, V150, V200, conformity index, external index, and homogeneity index, were all well coordinate with pre-planned dosimetry without signicant deference (all p (cid:0) 0.05). Conclusion: Within the limitation of this study, individualized 3D-PT assisted I 125 RSI may be accurate obtaining favorable post-plan dosimetry for patients with recurrent/secondary head and neck cancer, further prospective study is warranted. plan tumor volume; Post-CTV, target volume.


Background
Brachytherapy (BT) is a speci c form of radiotherapy (RT) consisting of the precise placement of radioactive sources directly placed into or next to the tumor [1]. Currently, BT has the potential to deliver an ablative radiation dose (>100Gy) directly to the target volume with the advantage of a rapid dose falling-off and consequently sparing of adjacent organs [2,3]. BT was recommended by both The Head and Neck Working Group of the European Brachytherapy Group and American Brachytherapy Society as one of the treatments for head and neck cancers [4,5]. I 125 radioactive seed implantation (RSI) may be safely used for recurrent/secondary head and neck cancer as a salvage therapy providing a high local tumor control and preservation of organ functions [6][7][8][9].
The challenge is how to deliver the I 125 seeds into the target volume accurately per pre-plan, spares the vital organ structure, and obtains focused radiation on the lesion. Owing to the dense critical organs and tissues (e.g. eyes, major vessels, and nerve) in head and neck region, the accuracy of needle puncture during I 125 RSI and post-plan dosimetry was extremely critical for patients with head and neck cancer.
The needle's deviation between pre-plan and intraoperative puncture may occur even under the image guidance, which leads to mis-implantation of the I 125 seeds and unnecessary radiation and damage to surrounding critical organs/tissues.
Recently, Individualized 3D-printing template (3D-PT) was developed to facilitate I 125 RSI for head and neck cancer in order to improve the accuracy, optimize post-plan dosimetry, and shorten the RSI duration [8][9][10][11][12]. However, most of the previous studies involving 3D-PT assisted I 125 RSI were focused on the e cacy and safety pro les, e.g. local control and survival [6][7][8]13]. Only 2 studies involving accuracy of intraoperative needle puncture and dosimetry after I 125 RSI were published for head and neck cancer [11,14]. Indicated by these existed evidence, 3D-PT assisted I 125 RSI may provide satis ed accuracy and postplan dosimetry without additional perioperative complications [8,11,14], while cases reported in these studies was limited with small sample sizes. Here, the aim of the study is to evaluate the accuracy of intraoperative needle puncture and post-plan dosimetry of individualized 3D-PT assisted I 125 RSI for patients with recurrent/secondary head and neck cancer in our institute.

Study design
The electronic database of our institute was searched and reviewed to identify eligible patients. Patients who underwent 3D-PT assisted I 125 RSI under CT guidance for the treatment of recurrent/secondary head and neck cancer between February 2017 to January 2020 were included. The indications for 3D-PT assisted I 125 RSI were as follows: (i) Residual/recurrent/secondary head and neck cancer after surgery; (ii) Progressive/recurrent/secondary head and neck cancer after EBRT and/or chemotherapy. The contraindications were as follows: (i) Active infection; (ii) The diameter of largest tumor > 7 cm or any active concomitant distant cancer; (iii) Karnofsky Performance Score < 70 or predicted life span < 3 months; (iv) Approach of I 125 RSI deemed not available revealed by preoperative CT/MRI; (v) International normalized ratio > 2; and (vi) Pregnancy/mental disorder or any somatic comorbidities of clinical concern.
The technical success rate, number of needles inserted and seed implanted, the mean needle's entrance deviation, the depth and angular of the pre-planned and intraoperative needle insertion, and pre-planned and post-plan dosimetry pro les were recorded. Subgroups analysis by cancer type (recurrent/secondary) and implantation site (head/neck, bounded by the connecting line of the lower margin of the jaw, the mandibular angle, the tip of the mastoid process, superior nuchal line, and the external occipital carina) were conducted. Technical success was de ned as successful needle insertion and implantation of I 125 seed in the targeted volume per pre-plan/intraoperative plan. The mean needle's entrance deviation was de ned as the super cial distance between the pre-planned needle's entrance point and the actual intraoperative needle's entrance point on CT images after fusing the pre-planned and intraoperative CT images into the same coordinate axis on the BT Treatment Planning System (BT-TPS). Then the needle's depth and angular were directly calculated and extracted from the BT-TPS. The needle's depth was de ned as the tip of the pre-planned/inserted needle to the template surface when the needle is deemed in place during the retrusive seed implantation. The needle's angular was de ned as the angle between the pre-planned/inserted needle in place and the horizontal axis. The pre-planned and post-plan dosimetry parameters, including the prescription dose (PD), seed number, gross tumor volume (GTV), D90, D100, V100, V150, V200, conformity index (CI), external index (EI), and homogeneity index (HI) were recorded and compared. D90 and D100 refer to the dose delivered to the 90% or 100% of GTV, respectively. V100, V150, and V200 refer to the percentage of GTV receiving 100% or 150% or 200% of prescription dose, respectively.
The individualized pre-plan data in the BT-TPS was then transferred into 3D imaging and reverse engineering software (Beijing Feitian Industries Inc and Beijing University of Aeronautics and Astronautics, Beijing, China) for digital modeling of individualized 3D-PT. After that, the modeling data was optimized with postprocessing using Magics 19.01 software (Materialise Company, Belgium) and the individualized 3D-PT was nally produced by using 3D light-cured rapid-forming printer RS6000 (Shanghai Liantai 3D Technology Company, Shanghai, China). The 3D-PT with 3 mm thickness contained individualized information such as body-surface characteristics of the target region, localization markers, and entrance hole for 18-gauge needle [16], Fig. 1.

Intraoperative seed implantation
All RSI procedures were performed with local anesthesia under the CT guidance. After skin preparation and sterilization, the 3D-PT was aligned to the target region according to the outline characteristics, reference line on the 3D-PT, surface positioning line, and positioning laser, Fig. 2A-B. Then CT scan was performed to con rm the exact tting of 3D-PT in position according to the pre-plan data in BT-TPS. Malposition identi ed between the pre-plan data and the current CT image was adjusted in real-time and then 2-3 locking needles (18-gauge) followed by the seed implantation needles (18-gauge) were percutaneously inserted via the pre-planned holes on the 3D-PT, Fig. 2C-D. After all the needle were deemed in place, the I 125 seeds were implanted and delivered using the Mick applicator in a retrusive manner with 0.5/1.0 cm interval according to the pre-plan and intraoperative re-plan, which was made and executed if necessary, Fig. 2E-H.

Postoperative veri cation
All patients were re-evaluated immediately with CT scan after I 125 RSI to validate the post-plan distribution of the I 125 seeds and rule out potential perioperative complications. Then, the CT images were transferred to BT-TPS to verify post-plan dosimetry, Fig. 3. Dosimetry parameters including D90, D100, V100, V150, V200, CI, EI, and HI were evaluated. All RSI procedures were performed in accordance with relevant guidelines and regulations, as also described in published study [6,7].

Statistical analysis
Continuous variables were compared using paired t-test between pre-plan data and intraoperative data/post veri cation data. As 84.2% of the cancer in the head was recurrent cancer and 81.8% of the cancer in the neck was secondary cancer, subgroups analysis by cancer type and implantation site were further conducted in multivariate analysis using linear regression model. A 2-sided p-value < 0.05 was considered as statistically signi cant difference. Statistical analyses were performed using SPSS software (version 26.0; SPSS, Chicago, IL, USA).

Discussion
The present study evaluated the accuracy of intraoperative needle puncture and post-plan dosimetry of individualized 3D-PT assisted I 125 RSI for recurrent/secondary head and neck cancer. As a result, the mean needle's entrance deviation was < 0.1 cm. The mean needle's intraoperative depth and angular were well consistent with pre-plan without signi cant deference. The post-plan dosimetry parameters, including D90, D100, V100, V150, V200, CI, EI, and HI, were also well coordinate with pre-plan without signi cant deference. Therefore, this study indicated that the accuracy of needle puncture and post-plan dosimetry was satis ed for individualized 3D-PT assisted I 125 RSI in patients with recurrent/secondary head and neck cancer.
Since the introduction of 3D-PT in the clinical practice, few studies investigate the accuracy of needle puncture during 3D-PT assisted needle related interventions [14,17]. As revealed by a non-inferiority randomized clinical trial that enrolled 200 patients for localizing small pulmonary nodules [17], localizer deviation did not signi cantly differ between the 3D-PT assisted group and CT-guided group (mean, 8.7 vs. 9.6 mm; p = 0.36). The mean procedural durations were 7.4 minutes for the 3D-PT assisted group and 9.5 minutes for the CT-guided group (P < 0.001). The mean CT related radiation dose was 229 mGy × cm in the 3D-PT assisted group and 313 mGy × cm in CT-guided group (p < .001) [17]. Indicating that the use of the 3D-PT for placement of pulmonary localizer showed e cacy and safety that were not substantially worse than those with the CT-guided alone, while signi cantly simplifying the procedure and decreasing patient CT related radiation exposure.
For patients with head and neck cancer, the relative stable craniocerebral structure may fascinate the usage of individualized 3D-PT and the deviation of needle puncture during RSI maybe prone to be smaller than that of localizing pulmonary nodules. Ming-Wei Huang et al [14] reported 25 patients with head and neck tumors implanted with I 125 radioactive seeds under the assistance of 3D-PT. The mean entrance deviation for all inserted needles was 1.18 ± 0.81 mm varying from 0.857 ± 0.545 to 1.930 ± 0.843 mm at different sites and was signi cantly smaller in the parotid and maxillary regions (belong to head region), which is signi cant smaller than that of localizing pulmonary nodules mentioned above and seems similar to that of reported here (0.81-0.98 mm). In the present study, needle's entrance deviation was also signi cantly different in patients with implantation in head and neck region and in patients with recurrent cancer and secondary cancer in multivariate analysis, but was only larger in patients with recurrent cancer in univariate analysis. Meanwhile, in the study by Ming-Wei Huang et al [14], the mean angular deviation was 2.08 ± 1.07 degrees varying from 1.85 ± 0.93 to 2.73 ± 1.18 degrees at different sites and was signi cantly larger (indicating less accurate placement) in the sub-mandibular and upper neck area (neck region), than in the other regions (head region), which also seems similar to that reported here (1.56 ± 0.14 degrees). Interestingly, in the current study, needle's angular deviation was lager in patients with cancer in the neck region than in the head region, and also lager in patients with secondary cancer than reccurent cancers in univariate analysis. However, in multivariate analysis, both needle's pre-planned and intraoperative deviation of depth and angular have no statistical signi cance involving both cancer type and implantation site. This may be owing to the in uence of other potential factors as R 2 of the linear regression turns out to be < 0.1, which means little weightiness. Therefore, whether the accuracy of 3D-PT assisted RSI varies by cancer type or implantation site, further high-quality study is needed before conclusion is drawn.
As for dosimetry pro le, in the above study of Ming-Wei Huang et al [14], the D90 was larger than that of pre-plan and ranged from 122 Gy to 198 Gy (mean 163.8 ± 22.6 Gy), which seems higher than that reported here (range, 90-170; mean, 136.1 ± 7.7 Gy). The V100 was larger than 95% and the V150 was less than 50% in all patients and other pre-plan and post-plan dosimetric data (e.g. V150, V200, CI, EI, and HI) was not reported in their study. In a study by Ji Z et al [16] comparing the dose distributions of postplan data with pre-plan for 3D-PT assisted RSI, a total of 14 patients with malignant tumors (majority located in pelvic cavity) were enrolled. The average post-plan D90, V100, and V150 were smaller than the pre-plan ones, and average post-plan V200 and minimum peripheral dose of GTV were larger than the preplan ones, however, there was no statistical difference in any these parameters between the two groups except for V100 (p = 0.027). Sun et al [18] compared the dosimetric data between pre-plan and post-plan veri cation in 3D-PT assisted CT-guided RSI for thorax movement tumors. All of the included dosimetry parameters changed slightly, while the difference was also not statistically signi cant (all p > 0.05).
Yansong Liang et al [13] reported the dosimetric accuracy of 3D-PT assisted I 125 RSI for the treatment of cervical lymph node metastasis in 15 patients. There was also no signi cant difference for all the parameters (D90, V90, V100, and V150) between pre-plan and post-plan veri cation (all p > 0.05). Similarly, as also revealed in the current study, the post-plan dosimetry was completely meet the requirements of the pre-plan for 3D-PT assisted RSI without signi cant deference.
The present study has several limitations. First, this was a retrospective study and therefore prone to potential selection bias. Second, the absence of a control group limits evaluation of the superiority of 3D-PT assisted CT-guided RSI over bare-handed CT-guided RSI. Third, the needle's depth and angular was calculated after fusing the pre-plan and intraoperative CT images into the same coordinate axis on BT-TPS, suffered from potential fusion error. However, this is the only way to compare pre-plan data with intraoperative data. Fourth, in subgroup analysis for implantation site, further re ned subregion classi cation, e.g. the parotid and masseter region, maxillary and paranasal region, the retromandibular region, and submandibular and upper neck region, was not applied in the present study, limited by the power of statistics in such small group of patients. Finally, there was dilemma in grouping the tumors located at the boundary of head and neck region (submandibular and upper neck area), which may stretch over both head and neck region and were mainly classi ed according to location of the lesion center, leading to potential distraction of the results.

Conclusion
Within the limitation of this study, individualized 3D-PT assisted I 125 RSI may be accurate obtaining favorable post-plan dosimetry for patients with recurrent/secondary head and neck cancer, further prospective study is warranted. National Key Research and Development Plan of China (Grant No. 2019YFB1311300) to JJ W supports the implementation (e.g. labor cost and data collection) and publication of the project.
Competing interests: The authors declare that they have no con ict of interest.
Ethics approval: The retrospective study was approved by Peking university Third Hospital Medical Science Rearch Ethics Committee and the requirement to obtain written informed consent was waived.
Consent to participate: Not applicable.

Consent for publication:
Not applicable.
Availability of data and materials: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Code availability: Not applicable.
Authors' contributions: BQ, PJ and JJ W conceived and designed the study. BQ, ZJ, HT S, JH F, WY L, and YX S performed the data collection and are responsible for statistical analysis. BQ and PJ wrote the paper. JJ W reviewed and edited the manuscript. All authors read and approved the manuscript.