Association of Image-Guided Navigation With Complete Resection Rate in Patients With Locally Advanced Primary and Recurrent Rectal Cancer

This nonrandomized controlled trial evaluates the resection margin rates as well as the safety and usability of a newly developed image-guided navigation technique among patients who underwent a rectal cancer resection.

Meaning Image-guided navigation appeared to be associated with an increase in radical resection margin rates in recurrent rectal cancer resection and thereby may improve patient outcomes.

+ Invited Commentary + Supplemental content Introduction
Surgical resection is the main treatment for patients with rectal cancer. This procedure can be challenging, especially in patients with primary advanced disease in which the mesorectal fascia is threatened and tissue planes are disrupted by tumor ingrowth, fibrosis, or radiation. Despite improved neoadjuvant treatment and refinement of surgical techniques, the proportion of tumorpositive resection margin rates remains 10% to 15%. 1,2 Previous studies have shown that a positive resection margin rate is associated with high local recurrence and low survival rates. 3,4 Surgical resection in patients with local recurrence is even more challenging because of fibrotic scar tissue of the previous operation. Rectal cancer recurrence is often accompanied by tumor ingrowth in surrounding tissue and organs, requiring extensive surgical procedures such as pelvic exenteration.
These procedures are associated with high tumor-positive resection margin rates of 38% to 62%, major complication rates of 32% to 60%, and 30-day mortality rates of 0% to 16%. [5][6][7][8][9][10][11] A possible means to improve the safety and effectiveness of surgical procedures for locally advanced and recurrent rectal cancer could be image-guided navigation. This technique provides surgeons with real-time intraoperative feedback on the position of surgical instruments in reference to the intraoperative anatomy, including tumor borders. As such, the technique could improve the complete removal of tumors without damaging the surrounding healthy structures. 12 In an investigation of whether image-guided navigation was possible in more advanced rectal resection, a novel electromagnetic surgical navigation system was developed for pelvic malignant neoplasms. This system was shown to be safe, feasible, and accurate. 13 In the current study, we evaluated the clinical performance of this image-guided navigation technique. We hypothesized that surgical navigation during advanced and recurrent rectal cancer resection would allow for the full use of preoperative imaging during the surgical procedure and would improve surgical outcome by a higher complete resection rate compared with results in a historical cohort. Moreover, we examined the safety and usability of this intraoperative technique.

Study Design and Patient Selection
We conducted a prospective, single-center nonrandomized controlled trial at the Netherlands Cancer Institute-Antoni van Leeuwenhoek, a tertiary referral hospital in Amsterdam, the Netherlands, to evaluate the use of an electromagnetic navigation system during abdominal surgical procedures. This trial consisted of individuals with locally advanced primary or recurrent rectal cancer who underwent a resection with image-guided navigation between February 1, 2016, and September 30, 2019. This study was approved by the institutional review board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek. All patients provided written informed consent. We followed the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) reporting guideline.

JAMA Network Open | Surgery
The inclusion criteria for the prospective cohort were as follows: diagnosis of either locally advanced primary or recurrent rectal cancer for which a radical resection was judged by surgeons as challenging, patient age of 18 years or older, suitability for contrast-enhanced computed tomography scanning, and scheduled abdominal surgical procedure at the Netherlands Cancer Institute-Antoni van Leeuwenhoek. Patients with metal pelvic implants or with a pacemaker were excluded because they could alter the preoperative imaging. Locally advanced primary rectal cancer was defined as T3 or T4 tumors extending close to (<2 mm) or invading the mesorectal fascia, as shown on rectal magnetic resonance imaging. Recurrent rectal cancer was defined as cancer that recurred in the pelvic area after earlier treatment. The inclusion and exclusion criteria are reported in the trial protocol (Supplement 1), and the patient selection diagram is shown in Figure 1.
The prospective or navigation cohort who underwent a resection with image-guided navigation was compared with a historical or conventional cohort. Patients with locally advanced primary or recurrent rectal cancer; who were aged 18 years or older; and who received rectal resection without the navigation system between January 1, 2009, and December 31, 2015, were eligible for inclusion in the historical cohort. Clinical data were collected retrospectively from medical records and then anonymized. The historical group was well balanced with the navigation group, and no significant differences in baseline characteristics were found between the 2 cohorts. Permission to collect the retrospective data was granted by the institutional review board of the Netherlands Cancer Institute-Antoni van Leeuwenhoek.

Image-Guided Navigation
Full details of the navigation setup have been published elsewhere. 13

Study End Points
The primary end point of this study was the complete resection rate, measured by the number of tumor-negative resection margin rates. After primary rectal cancer resection, a tumor larger than 1 mm of the circumferential resection margin rate was defined as radical (R0). After recurrent rectal cancer resection, the resection margin rate was defined as radical (R0) when no tumor cells reached the border of the inked resection specimen.
The secondary end points were safety and usability of the system. Safety was evaluated by the number of navigation system-associated surgical adverse events. Intraoperative surgical complications not associated with the navigation system were also reported. Usability was assessed from responses to a questionnaire completed by the participating surgeons after each procedure.
The questionnaire consisted of 2 parts. The first part tested surgical usability with the 10-item System Usability Scale (SUS), with 5 response options ranging from strongly disagree to strongly agree. The 10 questions on the SUS can result in a total score of 0 to 100 points, representing the surgeon's level of satisfaction with the novel technique (ie, from highly unusable to highly usable 14 ).
An SUS score of 70 points or higher is considered good, with a high chance of acceptance of the technology by the surgeons. 15 The second part of the questionnaire compared the effectiveness  The planning computed tomography scan, with segmentations in the coronal, sagittal, and axial planes, and the 3-dimensional model are shown. The surgical pointer is shown in the 3-dimensional model and orthogonal views (highlighted with arrowheads). The tumor is segmented in green, the ureters in yellow, and the vessels in blue/red.

Statistical Analysis
No sample size calculations were performed. All analyses were performed in SPSS, version 25.0 (IBM Corp

Results
In total, 64 patients were included in the prospective cohort ( Figure 1    Patients in the navigation cohort showed significantly lower tumor-positive margin rates after recurrent rectal cancer resection compared with patients in the historical cohort (21.1% vs 51.2%; P = .047). For the locally advanced rectal cancer resection, the difference was not significant (7.1% vs 15.8%; P = .69) (Figure 4).
After recurrent rectal cancer resection, intraoperative complications occurred in 6 patients: abdominal bleeding (n = 2) and ureter injury (n = 4). No significant differences in intraoperative complications were found between the navigation and historical cohorts.
When comparing the prospective cohort to the historical cohort, no significant difference was observed between the 2 groups (Table). Despite this finding, we analyzed the potential implication of the less-balanced characteristic, neoadjuvant chemotherapy. After controlling for neoadjuvant therapy in a logistic regression model for patients with recurrent rectal cancer, the use of imageguided navigation was associated with complete resection margin rates (odds ratio [OR], 4.10; 95% CI, 1.07-15.78; P = .04). After locally advanced primary tumor resection, the use of image-guided

Discussion
Patients with locally advanced primary or recurrent rectal cancer who underwent a surgical procedure with image-guided navigation showed high complete resection rates. The system was demonstrated to be safe, and no navigation system-associated complications were observed. In patients with recurrent rectal cancer, image-guided resection was associated with increased resection margin rates, even after adjustment for neoadjuvant therapy. Surgeons rated the navigation setting more favorably vs the conventional setting and stated that the technique improved decisiveness and simplified complex procedures.
Image-guided navigation in pelvic surgical procedures has been described previously. 13,[16][17][18][19] Two separate groups investigated the feasibility of navigation in pilot studies for Transanal Minimal Invasive Surgery-Total Mesorectal Excision (TAMIS-TME). [16][17][18][19] Both groups concluded that navigation was feasible and safe, with satisfactory accuracy for clinical use. Although promising results were shown, only small patient cohorts of 1 to 3 patients were evaluated. One study tested image-guided navigation in a large group. 13 Outcomes of this pilot study were encouraging, showing the navigation system was safe, feasible, and accurate (mean target registration error: 4.0 mm). However, the study included a wide variety of pelvic tumors and mainly focused on the feasibility and accuracy of the navigation system. 13 The current study aimed to evaluate the clinical outcomes of surgical navigation specifically in patients with rectal cancer. To our knowledge, this is the first study to compare the resection margin rates of patients receiving rectal resection with or without image-guided navigation.
In this study, a significant difference was found in surgical resection margin rates between the navigation and historical cohorts in patients with recurrent rectal cancer. The positive resection margin rate in the historical control cohort was in line with the margin rates in other studies, varying between 38% and 62%. 9,10,20 With image-guided navigation, the percentage of positive resection margin rate was 21.1%. In patients with locally advanced primary rectal cancer, no significant difference was found between the navigation and the historical cohorts. This similarity could be explained by the generally much lower positive resection margin rates in primary rectal cancer  Integration of new surgical techniques requires the evaluation of safety and usability. In this study, no navigation system-associated complications were observed, a finding that is consistent with previous results. 13 The usability of the system was given an SUS score of 75 points, and surgeons preferred the navigation setting over the conventional setting in all questions. Moreover, the time required for setting up the navigation system in this study was limited compared with the time reported in other studies, in which setup required 25 to 47 minutes. 17,19 All of these results suggest that the navigation system that we analyzed is safe and intuitive with a high chance of clinical acceptance outside of the research setting.

Limitations
This study has some limitations. First, the nonrandomized trial design used to compare a prospective cohort with a historical cohort has inherent methodological shortcomings. However, the historical control group that we selected was well balanced with the navigation cohort, with no differences in baseline characteristics. Nonetheless, relevant differences in the characteristics existed between the 2 groups, although none of them were statistically significant. Therefore, even though the analysis plan did not specify any adjusted analysis, we decided to adjust for neoadjuvant therapy. Second, this was a single-center study with small sample sizes in the navigation cohort. Third, a dedicated clinical implementation team that gave technical support was highly involved, and it remains unclear whether the navigation system would generate the same results if transferred to other hospitals.
Fourth, the resection margin rates could have been altered by the performance of the individual surgeons and the resulting quality of the total mesorectal excision specimen. Because of the retrospective setup of the historical cohort and the small sample size, these variables could not be taken into account. Nevertheless, the implications may be limited given that, in our institution, resections are performed by a team of 2 experienced surgeons in rectal cancer, and the results of the mesorectal resection specimen are discussed on a weekly basis in a multidisciplinary meeting.

Conclusions
Image-guided navigation appeared to be safe and was associated with an increase in radical resection margin rates in recurrent rectal cancer resection. To our knowledge, this study was the first to compare resection margin rates in patients with rectal cancer who underwent resection with imageguided navigation and those who received resection without navigation. Participating surgeons gave high ratings to the improved decisiveness regarding resection margin rates and tumor localization associated with the navigation technique.