Efficacy of radioactive 125I seed implantation in treating inoperable or refused operation head and neck cancers.

PURPOSE: This study aims to observe the curative effect of radioactive 125I seed implantation in treating inoperable or refused operation head and neck cancer. METHODS: Data from 132 patients with head and neck malignant tumors underwent computed tomography-guided radioactive 125I seed implantation from April 2004 to August 2020 were analyzed retrospectively. The Kaplan-Meier method was used to calculate the local control and survival rates. The logarithmic rank test and the Cox proportional risk model were used for univariate and multivariate analysis, respectively. RESULTS: A total of 132 patients were enrolled. All tumors were confirmed to be malignant through pathological analysis. Herein, we revealed that the seeds were implanted at the primary tumor site (23 cases, representing 17.4%), recurrent (9 cases, representing 6.8%), or metastatic lymph nodes (100 cases, representing 75.8%). Three months after the operation, 96 patients were evaluated as effective, whereas 36 patients were considered ineffective. The median local control time was 16 months; the local rates at 6, 12, 18, and 24 months were observed to be 75%, 47%, 35%, and 22%, respectively. The study reports a median survival period (OS) of 15 months. Additionally, the survival rates at 6, 12, 18, and 24 months were 61%, 42%, 31%, and 27%, respectively. Regarding side effects, skin or mucosal toxicity occurred in 14 patients. Grade I skin toxicity occurred in seven cases (5.3%), grade IV skin toxicity in one case (0.8%), grade I mucosal ulcer in four cases (3.0%), and grade I dry mouth in four cases (3.0%). The multivariate analysis showed that short-term efficacy and tumor site were independent prognostic factors (P < 0.001, 0.006, respectively). Additionally, the multivariate analysis showed that the independent OS influencing factors included D90, the longest tumor diameter, and short-term efficacy (P = 0.017, 0.001, <0.001). CONCLUSION: Radioactive 125I seed implantation is a safe and effective salvage therapy for patients with inoperable or refused operation head and neck cancer.

CT-guided iodine-125 brachytherapy as salvage therapy for local-regional recurrent breast cancer.

Background: The treatment of local-regional recurrent breast cancer (BC) after external beam radiotherapy is challenging. We aim to evaluate the effectiveness and safety of computed tomography (CT)-guided percutaneous iodine-125 brachytherapy for local recurrent BC. Methods: We retrospectively analyzed 15 patients with local recurrent BC treated with CT-guided interstitial implantation of iodine-125 seeds. Regular contrast-enhanced CT was conducted to evaluate the tumor response. Follow-up survival, quality of life, and adverse events were analyzed. Results: Among the 15 patients, five were elderly patients (older than 80 years) and six were complicated with chronic underlying diseases. The median number of 125I seeds implantation was 33 (range: 20-130) with median dose 90 (D90, the minimum dose covering 90% of the target volume) of 108 Gy (range: 60-120 Gy). There was no significant difference in D90, V100 (the volume of the target receiving 100% of the prescription dose), and V150 (the volume of the target receiving 150% of the prescription dose) before and after operation (p > 0.05). The median follow-up was 14 months (range: 6-18 months). Six months after operation, the ORR was 66.7% (10/15) and the LCR was 93.3% (14/15). The 6- and 12-month survival rates were 100 and 41.6%, respectively, and the median survival time was 12.5 months. PS score decreased from 1.53 ± 0.81 to 0.53 ± 0.49. The pain score decreased from 2.87 ± 1.67 before operation to 1.07 ± 1.18 after operation, and the differences were statistically significant (p< 0.05). No severe complications occurred. Conclusions: CT-guided iodine-125 brachytherapy provided a safe and effective choice for recurrent BC with significant local therapeutic effects and minor complications, especially for elderly patients with chronic underlying disease and those who were not eligible for surgical resection and had failed to benefit from systemic therapy.

A new technique for trans-perirectal iodine-125 seed implantation in prostatic cancer guided by CT and 3D printed template: Two case reports.

Low-dose-rate prostate brachytherapy with permanent iodine-125 is an important curative treatment for low-risk prostate cancer, and it has been demonstrated that brachytherapy with permanent seeds is an effective treatment. However, differences in prostate volume, spatial location, and gland deformation between images obtained in the pre-planning phase and those obtained during the implantation procedure affect accurate delivery of the pre-planned dose. Furthermore, the complicated procedure could be a burden to elderly patients, for example, the risks associated with general anesthesia. In addition, ultrasound images are not as clear as computed tomography (CT) images with regard to identifying the location of seeds. Therefore, a new method for guidance during the procedure is urgently needed. Here, we have described a new method for precise trans-perirectal insertion of radioactive iodine-125 seeds in patients with prostate cancer under the guidance of CT and a 3D-printed template. These are some of the advantages of this technique over the standard procedure for seed implantation in the prostate: It requires only local anesthesia, the pre-planning phase can be completed before the procedure, and the operation time is considerably shorter. This report describes trans-pararectal iodine-125 seed brachytherapy for prostate cancer under local anesthesia and the guidance of a 3D printed template in two elderly patients. The dose parameters determined in the preoperative planning phase were verified postoperatively and found to be consistent. Further, the procedure was completely successfully with no major complications in both cases, and the patients' prostate-specific antigen levels were normal at the most recent follow-up conducted 50 months after the procedure. Therefore, this technique seems promising for prostate cancer brachytherapy, and its application needs to be researched and extended further in the future.

Case report: 125I seed implantation for rare malignant solitary fibrous tumor in the pelvic cavity: a case report.

Solitary fibrous tumor (SFT) is a rare spindle cell tumor, benign or low-grade malignant, with an extremely low possibility of occurrence of malignant solitary fibrous tumor (MSFT). Surgery is an effective way for treating SFT, but it is often difficult to resect completely due to a large size, with a high recurrence rate and mortality rate after operation. Additionally, SFT is relatively resistant to chemotherapy, and there is a lack of effective systemic drug treatment. These lead to certain difficulties in the treatment of SFT. We report a case of a rare MSFT in the pelvic cavity. With a history of recurrence after two surgeries, this patient underwent surgical removal combined with 125I seed implantation at our hospital in the context that the tumor could not be completely removed because it was large and adhered to surrounding tissues; after up to 43 months of progression-free survival (PFS), the patient underwent 125I seed implantation alone, and achieved a complete remission, with a PFS up to 35 months. 125I seed implantation can be a safe and effective treatment option for unresectable MSFT as well as a potential solution to repeated local recurrence.

Comparison of three-dimensional-printed template-guided and traditional implantation of 125I seeds for gynecological tumors: A dosimetric and efficacy study.

OBJECTIVE: The objective of the study was to compare the dose parameter and clinical efficacy of three-dimensional-printed template (3D-PT)-guided and traditional 125I seed implantation in treatment of gynecological tumors. MATERIALS AND METHODS: A total of 28 patients with gynecological tumors treated with radioactive seed implantation in Hebei General Hospital from January 2016 to December 2018 were retrospectively analyzed. Twelve patients (template group) were guided by 3D-PT and the remaining 16 patients (traditional group) were guided by computed tomography (CT) with traditional technique. Preoperative treatment plan (preplan) was completed through a treatment planning system. In the template group, 3D-PT was printed according to preplan and seeds were implanted under the guidance of 3D-PT and CT. In the traditional group, seeds were implanted under the guidance of single CT directly according to the preplan. Postoperative verification plan (post-plan) was completed. Dose-volume histogram (DVH) was calculated and D80, D90, V90, V100, and V150 were obtained according to DVH. Then, deviation of the dosimetric parameters D80, D90, V90, V100, and V150 between the preplan and postplan were compared within the two groups. The difference and percentage of difference of the above dosimetric parameters between the preplan and postplan within the two groups were calculated using the formula Xd = Xpost-plan- Xpre-plan, and Xd% = (Xpost-plan- Xpre-plan)/Xpre-plan × 100%. Doses were calculated to determine whether the differences there were statistically significant. Efficacy evaluation was completed according to RECISIT 1.1. Local control rate and effective rate of 2-months postplan were compared between the two groups. Survival analysis was completed by the Kaplan-Meier method. The patients were followed up for 12 months, and their survival rate was calculated and compared. RESULTS: There was no significant difference between the two groups for all the parameters, except for D80 of the preplan and postplan in the traditional group (P = 0.000). All the differences and percentage of difference were calculated and it was found that the Xd difference of D80 (P = 0.035), D90 (P = 0.023), V90 (P = 0.047), V100 (P = 0.032), and V150 (P = 0.031), as well as the Xd% difference of D80 (P = 0.032), D90 (P = 0.034), V90 (P = 0.042), V100 (P = 0.036), and V150 (P = 0.044) of the two groups was statistically significant, thus indicating that the dosimetric parameter fluctuation in the template group was more stable. The result of the curative effect after 2 months were as follows: the local control rate and effective rate of the template group were 100% (12/12) and 83.3% (10/12), while those of the traditional group were 100% (16/16) and 81.2% (13/16). There was no statistically significant difference in the curative effect between the two groups. After 6-27 months (median = 12 months) of follow-up, the median survival time of the template group and traditional group were 17 (10-23) and 16 (11-20) months, respectively, and the 1-year overall survival rate was 63% and 79% (P = 0.111), respectively, with no statistically significant difference observed. CONCLUSION: 3D-PT-guided 125I seed implantation is safe and effective in the treatment of gynecological tumors.

Dosimetry study of three-dimensional print template for 125I implantation therapy.

BACKGROUND: 125I seed implantation has been found to show good therapeutic effects on tumors. Recent studies showed that three-dimensional (3D) print template-assisted 125I seed implantation can optimize radiation dose distribution. This study aimed to compare the dose distribution differences in 125I seed implantation among 3D print noncoplanar template- (3DPNCT), 3D print coplanar template- (3DPCT) assisted implantation and traditional free-hand implantation. METHODS: We systematically searched the PubMed, EMbase, Cochrane Library, Wan Fang Med Online, China National Knowledge Infrastructure (CNKI) from the earliest to November 2020 without time or language restrictions. And the references of primary literature were also searched. The outcome measures were dosimetry and operation time. This meta-analysis was carried out using Stata 12.0. RESULTS: A total of 16 original articles were selected for inclusion. The differences of D90, D100, V90, and V100 values pre- and post-implantation with traditional free-hand implantation showed statistically significant (p < 0.05). The differences of D90, D100, V100, V150, V200, and D2cc of organs at risk (OAR) values pre- and post-implantation with 3D print template showed no statistically significant (p > 0.05). Compared with traditional free-hand implantation without any templates, 3D print template could improve postoperative D90 (Standard mean difference, SMD = 0.67, 95% confidence interval (CI) = 0.35 to 0.98, p < 0.001), D100 (SMD = 0.82, 95%CI = 0.40 to 1.23, p < 0.001), V90 (SMD = 1.48, 95%CI = 0.95 to 2.00, p < 0.001), V100 (SMD = 1.41, 95%CI = 0.96 to 1.86, p < 0.001), and reduce operation time (SMD = - 0.93, 95%CI = - 1.34 to - 0.51, p < 0.001). In three studies, both 3DPNCT and 3DPCT plans were designed for all patients. The prescribed dose and seed activity were same. Pooled analysis of D90, D100, V100, D2cc of OAR, number of seeds and number of needles showed no significant differences between 3DPNCT and 3DPCT groups (p > 0.05). However, in 3DPNCT group, V150 and V200 were increased (SMD = 0.35, 0.49; 95%CI = 0.04 to 0.67, 0.02 to 0.96; p = 0.028, 0.043); the number of through bone needles was reduced (SMD = - 1.03, 95%CI = - 1.43 to - 0.64, p < 0.001). CONCLUSIONS: Compared with traditional free-hand implantation, 3D print template-assisted 125I seeds implantation can optimize dose distribution and reduce the implantation time at the same time. Compared with 3D print coplanar template, 3D print noncoplanar template can increase the volume of high dose within tumor target and is more safer in the respect of puncture route.

Analysis of the efficacy and safety of iodine-125 seeds implantation in the treatment of patients with inoperable early-stage non-small cell lung cancer.

PURPOSE: To evaluate the efficacy and safety of iodine-125 (125I) seeds implantation for inoperable early-stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: PubMed, Cochrane Library, Embase, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched from inception until April 2020. Data were collected concerning overall survival, short-term efficacy, and complications. Meta-analysis was performed using R software (version 3.6.3). RESULTS: Nine studies involving 308 patients were included. Meta-analysis showed that the 1-, 2-, and 3-year survival rates were 0.98% (95% CI: 0.95-0.99%), 0.83% (95% CI: 0.77-0.89%), and 0.65% (95% CI: 0.55-0.75%), respectively; short-term local control rate (LCR) and effective rates were 0.99% (95% CI: 0.98-1.00%) and 0.92% (95% CI: 0.83-0.98%), respectively; 1-, 2-, and 3-year LCRs were 0.96% (95% CI: 0.83-1.00%), 0.94% (95% CI: 0.85-0.99%), and 0.95% (95% CI: 0.76-1.00%), respectively. Sub-group analysis of the prescribed dose found that when the prescribed dose was > 120 Gy, short-term efficacy and 1-year LCR were increased significantly (p < 0.01). The incidence of bleeding, pneumothorax, and radiation lung injury was 0.14% (95% CI: 0.07-0.21%), 0.19% (95% CI: 0.11-0.28%), and 0.00% (95% CI: 0.00-0.03%), respectively. Two studies involving 106 patients compared 125I seeds combined with chemotherapy versus chemotherapy alone for NSCLC. Results showed that compared with chemotherapy alone, 125I seeds combined with chemotherapy could improve short-term LCR (RR = 1.34, 95% CI: 1.09-1.65%, p = 0.005) and short-term effective rate (RR = 1.49, 95% CI: 1.14-1.96%, p = 0.004). CONCLUSIONS: 125I seeds implantation is safe and effective approach for the treatment of inoperable early-stage NSCLC, but high-quality clinical research is still needed to further confirm the findings.

125I brachytherapy seeds implantation for an inoperable large retroperitoneal leiomyosarcoma.

Retroperitoneal leiomyosarcoma is relatively uncommon. Leiomyosarcoma has accounted for about 5%-10% of soft-tissue sarcoma, and 1/2-2/3 of the primary lesions were retroperitoneal, with a cumulative 5-year survival rate of only 35%.Leiomyosarcoma is one kind of soft-tissue sarcoma with the lowest survival rates due to the invasive growth, difficult treatment, and poor prognosis.The present study reported a case of a 78-year-old male diagnosed as left retroperitoneal leiomyosarcoma, who had received three operations. Computed tomography (CT) demonstrated a mass of approximately 12.9 cm × 6.9 cm × 6.6 cm in his retroperitoneal region. The Eastern cooperative oncology group and numerical rating scale scores of pain were 1 and 5, respectively. Multiple treatment strategies were administered, including the application of drainage and125I seed implantation. A total of 90125I seeds were implanted into the tumor through repetitious operations, with 30 seeds each time. Treatment planning system was involved to calculate the source distribution.125I seeds with the activity of 0.5 mCi were implanted under the guidance of CT, and dosimetric verification was performed after the operation. D90 (90% minimum prescription dose received by target volume) was 40 Gy. Follow-up was performed after 6 months, and complete response was achieved in the local lesions. However, there was no evidence-based treatment currently and the majority of our knowledge was based on results from case reports, thus further studies would be required.

The effectiveness and prognostic factors of radioactive iodine-125 seed implantation for the treatment of cervical lymph node recurrence of esophageal squamous cell carcinoma after external beam radiation therapy.

PURPOSE: To analyze factors influencing the efficacy of 125I seed implantation in the treatment of in-field cervical lymph node recurrence of esophageal squamous cell carcinoma (ESCC) after external beam radiation therapy. MATERIAL AND METHODS: We conducted a retrospective review of 36 patients with in-field cervical metastatic lymph nodes recurrence of esophageal squamous cell carcinoma (CML-ESCC) after external beam radiation therapy treatment, who underwent 125I seed implantation in our department from 2013 to 2019. Previous cumulative external irradiation dose ranged from 20 to 66 Gy (median, 60 Gy). The post-implant efficacy was evaluated by response evaluation criteria in solid tumors (RECIST) version 1.1, and an adverse event was evaluated by the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Score (EORTC). COX proportional hazards model was used to analyze risk factors affecting effectiveness. RESULTS: Among 36 patients, 31 patients (86.1%) received fluorouracil-based chemotherapy (1-6 cycles) after 125I seed implantation. Local control rates at 3, 6, 12, and 24 months after implantation were 51%, 30%, 30%, and 18%, respectively, with a median of 9 months (95% CI: 6.106-11.894); survival rates after 3, 6, 12, and 24 months were 55%, 41%, 22%, and 22%, respectively, with a median of 8 months (95% CI: 5.753-10.247). Multivariate analysis showed that D90 and short-term efficacy were independent factors related to local control and survival rate (p = 0.005, < 0.001, 0.010, < 0.001). There were 2 cases (5.6%) with grade 1 skin toxicity, 1 case (2.8%) with grade 4 skin toxicity, 3 cases (8.3%) with grade 1 mucosal ulcer, and 3 cases (8.3%) with grade 1 xerostomia. CONCLUSIONS: 125I seed implantation as an effective salvage treatment shows definite efficacy and safety for patients with in-field cervical lymph node recurrence of ESCC after external beam radiation therapy.

Feasibility of three-dimensional-printed template-guided 125I seed brachytherapy and dosimetric evaluation in patients with malignant tumor.

OBJECTIVE: The objective of the study is to test whether three-dimensional (3D)-printed template can be used reproducibly for guiding malignant tumors brachytherapy and study the dosimetric consistency and adequacy between pre- and post-plan. MATERIALS AND METHODS: Between January and December 2016 in our hospital, a total of 14 patients underwent 3D-printed template-guided brachytherapy. All the patients were fixed into position using a vacuum cushion before undertaking a computed tomography (CT) scan. After the preplan was designed, the templates were printed. The tumors were punctured through predesigned needle holes. Following this, another CT scan was used to confirm the locations of needles, and then the 125 I radioactive seeds were implanted into the tumor according to the preplan. Postplan was performed after the operation. Data of the D90 (minimum absorbed dose of 90% target volume), V90 (90% prescription dose coverage volume percentage of target volume), V100, V150, and seed number pre- and post-operation were collected and compared. RESULTS: The mean D90, V90, V100, V150, and seed number preoperation were 94.96 ± 16.43 Gy, 94.64% ± 1.43%, 91.21% ± 1.59%, 65.01% ± 5.78%, and 46.67 ± 21.87, respectively. The mean D90, V90, V100, V150, and seed number postoperation were 91.97 ± 17.54 Gy, 93.35% ± 2.45%, 89.35% ± 3.21%, 63.40% ± 6.36%, and 46.60 ± 22.85, respectively. No significant difference between pre- and post-operation was observed across the data (P >0.05). CONCLUSION: For immobilized malignant tumors, 3D-printed template can be used reproducibly. The dose parameters in preplan can be achieved easily and satisfactorily by 3D-printed template guided brachytherapy, and it may become an easily reproducible standardized procedure in the future.

Preliminary investigation of computed tomography-guided iodine-125 seed implantation treatment efficacy in patients with iliac lymph nodes metastases.

OBJECTIVES: The objective of this study is to assess the technical feasibility, safety, and efficacy of computed tomography (CT)-guided iodine-125 (125 I) seed implantation to treat malignant iliac lymph node metastases. MATERIALS AND METHODS: In this retrospective study, 11 patients with a total of 11 iliac lymph node metastases were implanted with 125 I seeds (14.8-25.9 MBq) under CT-guidance, both the seed quantity and distribution were measured with a computerized treatment planning system. Treatment effects and adverse events were evaluated. RESULTS: 125 I seeds were successfully implanted in all patients, and the minimum peripheral dose of seeds was ranged from 30 to 110 Gy (median of 75 Gy). The median follow-up period was 11 months (ranged 3-39 months). Follow-up at 2 months after implantation revealed partial response in eight patients, stable disease in two patients, and progressive disease in one patient. The overall response rate and the local tumor control rate at 2 months were 72.73% and 90.91%, respectively. The rates of refractory pain and leg edema relief were 100% and 50% within 2 weeks after treatment, respectively. Survival rate at 1 year was 45.45%. No peri-interventional mortality or major complication was observed. CONCLUSION: 125 I seed implantation was a safe and effective technique for minimally invasive treatment for iliac lymph node malignant metastasis.

Precision dose measurement of 125I seed in solid water through SPECT/CT detecting.

PURPOSE: The aim of the study is to study the feasibility of gamma-ray-detection-based precision dose measurement of 125I seed brachytherapy in solid water. MATERIALS AND METHODS: Seven group 125I seeds with different activities were put into a hole in the center of solid water individually. Each group had ten seeds, and the seed activity ranged from 1.48 × 107 Bq to 3.7 × 107 Bq. Single-photon emission computed tomography/computed tomography (SPECT/CT) was used to scan the seeds perpendicular to the long axis of the seed, with a slice thickness of 3.75 mm. The radioactive count values (x) of the radioactive concentration around the seeds were collected at a distance of 1-15 mm from the center of the seeds, while the corresponding doses (Y) (Gy) were calculated. SPSS 18.0 was used to analyze the relationship between the count value and the dose. RESULTS: With the same seed activity, the count values became smaller according to the distance from the center of the seeds. The count values at the same point had an increasing trend according to the activity. This is similar to the doses calculated at the same point. There was an exponential relationship between the dose around the 125I seeds, and the radioactive count value detected by SPECT/CT. Correlative curves between the dose and radioactive count value detected by SPECT/CT of different-activity 125I seeds were fitted. The formulas of the dose and radioactive count with different seed activity were in the form of Y = b0 (b1)x. The constant b0 ranged from 1.48 to 3.93, according to the seed activity, while b1 was 1.006 for every seed's activity. CONCLUSION: The count value around the 125I seed can be detected accurately by SPECT/CT, and then can be quantified. This study provided useful experiment data for the precision measurement of 125I seed implantation. Radiation detection-based dose measurement may become a new noninvasive technology for the dynamic dosimetry verification method after brachytherapy.

125I seeds implantation for an elderly patient of skin squamous cell carcinomas with ulcer guided by ultrasound.

The skin squamous cell carcinoma (SCC) is a kind of malignancy of keratinocytes. SCC was originated within the epidermis or relevant appendages, which commonly occurred on sunlight exposure sites, such as the head and neck. This case report described an 85-year-old female patient with skin SCC at the right frontal, accompanied with skin ulcer. This patient suffered from indications that were not suitable for surgical resection, including old age, Alzheimer's disease (AD), lacunar infarction, hydropericardium, and some other concomitant diseases. In addition, the external beam radiotherapy was rejected by the relatives of this patient. Then, the patient received 125I seeds interstitial brachytherapy guided by bedside ultrasound. The tumor response was evaluated based on the response evaluation criteria in solid tumors version 1.1 criteria. Complete response was achieved 4 months after brachytherapy. No complications and recurrence were observed during 8-month follow-up. As the sole modality, the 125I seeds implantation could be a reasonable and safe alternative for treating skin SCC with ulcer, especially for the elderly patients.

Three-dimensional-printed individual template-guided 125I seed implantation for the cervical lymph node metastasis: A dosimetric and security study.

OBJECTIVE: The objective of this study is to evaluate the dosimetric accuracy and pathway safety of the three-dimensional (3D)-printed individual template-guided 125I seed implantation for the treatment of cervical lymph node metastasis. MATERIALS AND METHODS: A total of 15 consecutive patients with cervical lymph node metastasis were enrolled during September 2015-July 2017 (12 patients had a history of external beam radiotherapy, with the mean dose of 63 Gy), who undergone radioactive seed implantation guided by the 3D-printed individual template. The preplan was completed based on contrast-enhanced computed tomography images, and then, the 3D-printed individual template was printed according to the preplan. After the operation, the real-time dose verification was completed: the D90 was ranged from 60 to 113 Gy with median of 93 Gy and the number of seeds was ranged from 21 to 76 with median of 53. To observe the intraoperative complications and postoperative complications in 3 days, we collected and compared the deviation of the number of seeds, target volume, and dosimetric parameters (D90, V90, V100, and V150) between preplan and postoperative plan. RESULT: Intraoperatively, each template was observed to exactly fit and lock on the lamina, and the operation was successfully completed. No intraoperative complications and postoperative complications were observed in 3 days. There was no significant difference in P values between the two groups for all the parameters (P > 0.05). CONCLUSION: The 3D-printed individual template-guided 125I seed implantation for the cervical lymph node metastasis has not only reduced the dosimetric differences between pre- and postplan but also lowered the difficulty of puncture, indicating that it was a safe and accurate guidance approach.