Time interval between the completion of radiotherapy and robotic-assisted surgery among patients with stage I–III rectal cancer undergoing preoperative chemoradiotherapy

Background This aim of this study was to evaluate the effects of time interval between the completion of radiotherapy and robotic-assisted surgery on the outcomes among patients with rectal cancer undergoing preoperative concurrent chemoradiotherapy (CCRT). Methods In total, 116 patients with stage I–III rectal cancer who underwent preoperative CCRT and robotic-assisted surgery between September 2013 and February 2019 were enrolled. Patients were categorized into two groups based on the time interval: group A (10–12 weeks) and group B (≥ 12 weeks). Results Among the 116 enrolled patients, 98 (84.5%) had middle and lower rectal cancers. Two (1.7%) patients underwent abdominoperineal resection with a sphincter preservation rate of 98.3%. Thirty-seven (31.9%) patients had a pathologic complete response (pCR). The circumferential resection margin and distal resection margin were positive in 2 (1.7%) and 1 (0.9%) patients, respectively. Therefore, the R0 resection rate was 97.4%. A total of 24 (22.4%) patients experienced postoperative relapse and 12 (10.3%) patients died; these were slightly more common in group B than in group A (28.8% vs 15.8% and 15.3% vs 5.3%, respectively; both P > 0.05); however, this difference was nonsignificant. Three-year disease-free survival (DFS) and overall survival (OS) were 75% and 89%, respectively, among all patients. Non-significant trend of favorable 3-year DFS, 3-year OS, 3-year locoregional control rate and 3-year distant metastasis control rate were observed in group A compared with group B (all P > 0.05). Conclusion Robotic-assisted surgery after a longer interval is safe and feasible for patients with rectal cancer undergoing preoperative CCRT. The present study’s results suggested that the time interval of 10–12 weeks can be considered because comparable clinical and perioperative outcomes and preferable oncological outcomes were observed for interval of this length. However, future prospective randomized clinical trials are required to verify the present finding.


Introduction
In the past three decades, the treatment outcomes of rectal cancers have been substantially improved through novel therapeutic modalities and improved surgical approaches. The standard surgical approach for patients with rectal cancer has been total mesorectal excision (TME) surgery, as reported by Heald and Ryall [1] in 1982, because it remarkably improves the clinical outcomes of these patients. MacFarlane et al. reported a 5-year locoregional recurrence (LR) rate of 5% among patients receiving monotherapy with TME surgery [2]. However, Tepper JE et al. reported a high 5-year LR rate of 14% and poor 5-year overall survival (OS) of 64% among patients with locally advanced rectal cancer (LARC) undergoing curative surgery and postoperative concurrent chemoradiotherapy (CCRT) [3]. A German study reported a marked reduction in LR among patients receiving preoperative CCRT [4,5], and similar results have been previously reported [6][7][8]. Therefore, preoperative CCRT has since been the recommended as a standard treatment for patients with LARC.
Because of its downsizing and downstaging effects, preoperative CCRT reportedly serves as a potential treatment modality for patients with LARC to sequentially enhance the potential for R0 resection and the anal sphincter preservation rate [9, 10]. Furthermore, a pathologic complete response (pCR), an indicator of good clinical oncological outcomes, could be achieved through preoperative CCRT in approximately 8%-38% of cases [11][12][13][14][15][16][17][18]. The pCR rate would be affected by the duration of radiotherapy (i.e., short or long) [19][20][21], the interval between the completion of radiotherapy and surgery [16,17,[22][23][24][25][26][27][28], and the chemotherapy regimen [12-18, 24, 29] in preoperative CCRT. Increased tumor downstaging with no detrimental effect on toxicity and early clinical results have been reported among patients with a long interval between preoperative irradiation and surgery (6-8 weeks) compared with those with a short 2-week interval [22]. Since then, a 6-8 weeks "waiting" interval between preoperative radiotherapy and surgery has been preferred. We previously reported [23] a 31.6% pCR rate among patients with rectal cancer undergoing an intensified FOLFOX-based regimen with an interval of 10-12 weeks between radiotherapy completion and surgery in preoperative CCRT.
Because laparoscopic rectal surgery requires highly technically skilled surgeons experienced in minimally invasive surgery, this approach is not accepted worldwide as a standard surgical procedure for rectal cancer [30,31]. Robotic-assisted surgery offers numerous advantages including high-definition three-dimensional vision with up to 10× magnification, articulatory instruments, a surgeon-controlled camera platform, and stable traction provided by the robotic arm. Thus, more precise dissection can be performed in the confined pelvic cavity using the robotic system. Compared with conventional laparoscopic and open surgeries for rectal cancers, the clinical and short-term oncological outcomes of robotic surgery are more favorable [32][33][34][35].
Thus far, no consensus has been reached regarding the optimal interval between the completion of radiotherapy and robotic-assisted surgery in preoperative CCRT. Thus, we conducted a retrospective study to investigate the short-term clinical and oncological outcomes of patients with stage I-III rectal cancer who underwent preoperative CCRT and robotic rectal surgery with an interval of more than 10 weeks between the completion of radiotherapy and robotic-assisted surgery. Furthermore, we compared the effects of different intervals (10-12 weeks vs �12 weeks) on oncological outcomes.

Patients
We retrospectively analyzed prospective data collected from a single institution, namely Kaohsiung Medical University Hospital in Taiwan. The inclusion criteria were as follows: histologically proven rectal adenocarcinoma with tumor located within 15 cm from the anal verge, clinical stage I-III, preoperative CCRT with FLOFX regimen and long-course radiotherapy (LCRT), robotic-assisted surgery, and interval between the completion of radiotherapy and robotic-assisted surgery of � 10-week. In total 116 patients met the inclusion criteria and underwent preoperative CCRT followed by robotic-assisted TME with the single-docking technique using the da Vinci 1 Si surgical system (Intuitive Surgical, Inc., Sunnyvale, CA, USA) between September 2013 and February 2019 at the abovementioned hospital (Fig 1). All data were fully anonymized before they were accessed. This study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20200036). All patients routinely underwent preoperative colonoscopy and abdominal and pelvic computed tomography (CT) or high definition magnetic resonance imaging (MRI) for preoperative staging. Based on the distance from the anal verge, rectal cancer was categorized into upper (11-15 cm), middle (6-10 cm), and lower (� 5 cm). Patients with T3, T4, or N+ rectal cancer received preoperative CCRT, including a FOLFOX (i.e., 5-fluorouracil, leucovorin, and oxaliplatin) regimen every 2 weeks and LCRT (total 5000 cGy in 25 fractions), as previously described [23]. Patients with cT2 rectal cancer within 5 cm from the anal verge also received the same preoperative CCRT.
After radiotherapy, all patients continued the biweekly FOLFOX regimen until 2-3 weeks before robotic rectal surgery. Thereafter, abdominal and pelvic CT or high definition MRI was performed for restaging. Robotic-assisted TME was performed using the single-docking technique [36] if the rectal cancer was resectable. Patients with unresectable rectal cancer underwent an additional 3-4 cycles of FOLFOX and their rectal cancer was restaged through CT scan or MRI. The clinicopathological features and perioperative parameters including age; sex; histological type; TNM (tumor, node, and metastasis) classification; vascular invasion; perineural invasion; pre-CCRT, preoperative, and postoperative serum carcinoembryonic antigen (CEA) levels; interval between the completion of preoperative radiotherapy and robotic surgery; tumor location (distance from the anal verge); American Society of Anesthesiologists (ASA) score; and body mass index (BMI) were evaluated. TNM classification was determined in accordance with the criteria of the American Joint Commission on Cancer (AJCC) and International Union Against Cancer (UICC) [37]. The tumor regression grade (TRG) was evaluated in accordance with the AJCC and College of American Pathologists regression grade [38]. Perioperative outcomes, including surgical procedures, docking time, console time, operation time, estimated blood loss, duration of the first flatus passage, duration for resuming a soft diet, duration of postoperative hospital stay, and postoperative first day visual analog scale (VAS) pain score were evaluated.

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Time Interval between the completion of radiotherapy and robotic-assisted surgery After robotic-assisted surgery, adjuvant chemotherapy was administrated, as previously reported [22]. In summary, an additional 5-6 cycles of the FOLFOX regimen were administered every 2 weeks (12 perioperative cycles in total) for patients with following risk factors: (1) ypN+ (2) positive circumferential resection margin (CRM) or distal resection margin (DRM), and (3) ypT3-4. For patients with ypT1-2N0 lesions, fluoropyrimidine-based chemotherapy was administrated for up to 6 months of perioperative chemotherapy). Patients were regularly followed-up and their clinical outcomes and survival statuses were regularly recorded as our previous studies, as previously described [36].

Statistical analysis
All data were statistically analyzed using the Statistical Package for Social Sciences, Version 22 (SPSS Inc., Chicago, IL). All patients were followed up until their death or last follow-up. Based on the interval between the completion of radiotherapy and robotic-assisted surgery, patients were categorized into the following two groups: group A (10-12 weeks; 70-83 days) and group B (� 12 weeks; � 84 days).The docking time was defined as the time required to position the robot and secure the robotic arms to the corresponding port sites. The console time was defined as the total duration of any robotic-assisted surgical procedure using the robotic system. The operation time was defined as the time between the initial skin incision and wound closure completion. A P value of <0.05 indicated statistical significance. OS was defined as the time from the date of primary treatment to the date of death from any cause or last follow-up. DFS was defined as the time from the date of primary treatment to the date of diagnosis of recurrent or metastatic disease or the date of last follow-up. OS and DFS were determined using the Kaplan-Meier method, and the log-rank test was performed to compare time-to-event distributions.

Patient characteristics and perioperative outcomes
The baseline characteristics and perioperative outcomes of the 116 patients with rectal cancer who underwent preoperative CCRT followed by robotic-assisted surgery were summarized in Table 1. The median age and BMI of all patients were 63.5 (range, 28-88) years and 23.6 (range, 17.20-34.02) kg/m 2 , respectively. Of the 116 patients, 64 (55.2%), 34 (29.3%), 18 (15.5%) had lower, middle, and upper rectal cancers, respectively. There were 57 patients in the group A (10-12 weeks) and 59 patients in the group B (� 12 weeks). The median distance of the tumor from the anal verge was 5 (range, 1.0-15.0) cm, and there was no significant difference between the two groups (p = 0.215).
The most frequent surgical procedure was low anterior resection (LAR) (72/116, 62.1%), which was performed in 40 (70.2%) of group A patients and 32 (54.2%) of group B patients. Intersphenteric resection (ISR) with coloanal anastomosis was performed in 32 (33.7%) patients, which was performed in 17 (29.8%) of group A patients and 25 (42.4%) of group B patients. Abdominoperineal resection (APR) was performed in 2 (3.4%) of group B patients. Protective diverting loop transverse colostomy was performed for 56 (49.1%) patients, including 42 and 14 patients who underwent ISR and LAR, respectively. Furthermore, the sphincter preservation rate of all patients was determined from among 114 of 116 patients (98.3%). No significant differences between the two groups were observed in console time, operation time, estimated blood loss, duration of postoperative first flatus passage, duration for postoperative resuming a soft diet, postoperative hospital stay, and postoperative first day pain score (all P>0.05). Table 1. Baseline characteristics and perioperative outcomes of 116 patients who underwent preoperative CCRT followed by robotic rectal surgery.

Docking Time (minutes)
Mean ± SD a (range

Pathological and oncological outcomes
The pathological characteristics and oncological outcomes of all 116 patients are listed in Table 2. Preoperative clinical staging demonstrated that the majority of the patients with LARC were T3 in 91 (76.5%) patients, T4 in 19 (15.2%) patients, or N+ in 63 (77.6%) patients. T4 lesions were more common in group B than group A (23.7% vs 8.7%, respectively), but the difference was not significant (p = 0.092). No significant differences were observed in clinical T stage, N stage, and AJCC stage (all P>0.05). Furthermore, pCR (ypT0) was noted in 37 (31.9%) patients. Good tumor regression (TRG 0 and 1) was noted in 92 (79.3%) patients, and it was more common in group A than group B (82.5% vs 76.3%, respectively), but the difference was not significant (P = 0.411). Combined analysis of the pCR rate and the good tumor regression rate among all 132 patients with clinical stage I-III disease undergoing preoperative CCRT with FOLFOX regimen and robotic-assisted surgery revealed an optimal interval of 10-

Distance of distal resection margin (cm)
Mean ± SD c (range) 2.4 ± 1.6 (0. 12 weeks between the completion of radiotherapy and robotic-assisted surgery, because no clear benefits were observed for interval �12 weeks (Fig 2). The pCR rate and good tumor regression rate at the time interval of 10-12 weeks were 29.8% and 82.5%, respectively. DRM and CRM were positive in 1 (0.9%) and 2 (1.7%) patients, respectively. Therefore, R0 resection rate for primary rectal cancer was 97.4% (113/116 patients).
The median follow-up duration of 116 patients after primary treatment was 30.0 months (range: 11.4-83.4 months). Twenty-six (22.4%) patients experienced postoperative relapse, including local recurrence in 4 (3.4%) and distant metastases in 22 (19.0%) patients. Postoperative relapse was slightly more common in group B than in group A, but the difference was not significant (28.8% vs 15.8%, P = 0.093). Furthermore, 12 (10.3%) patients died after surgery; post-surgery death was slightly more common in group B than in group A, but this difference was not significant (15.3% vs 5.3%, P = 0.125). At a median follow-up duration of 30.0 months, 3-year DFS rate was 75% (Fig 3A) and the 3-year OS rate was 89% (Fig 3B). Moreover, the 3-year locoregional control rate was 96% (Fig 3C), and the 3-year distant metastasis control rate was 79% (Fig 3D). The 3-year DFS rate was higher in group A than in group B (80% vs 71%, Fig 3A), the 3-year OS rate was higher in group A than group B (92% vs 87%, Fig 3B), the 3-year locoregional control rate was higher in group A than group B (100% vs 93%, Fig 3C), and the 3-year distant metastasis control rate was higher in group A than in group B (80% vs 78%, Fig 3D); however, none of these differences were significant (all P > 0.05).

Postoperative complications
Postoperative complications are summarized in Table 3. Postoperative complications were observed in 27 patients (23.3%), and no significant difference between the two groups were

Discussion
This study revealed the short-term clinical and oncological outcomes of 116 patients with stage I-III rectal cancer who underwent preoperative CCRT and robotic rectal surgery with a �10 weeks interval between the completion of radiotherapy and robotic-assisted surgery.
Because this was a retrospective study, we did not calculate the sample size or power to reveal the real-world evidence of our clinical practices. These patients had a relatively high pCR rate (31.9%), R0 resection rate (97.4%), and sphincter preservation rate (98.3%). However, their overall postoperative complication rate (23.3%) and 3-year short-term oncological outcomes were consistent with those previously reported [39][40][41][42][43]. No significant differences were observed between the two groups in short-term oncological outcomes; hence, the time interval of 10-12 weeks between the completion of radiotherapy and robotic-assisted surgery can be considered as a safe interval, because no clear benefits were observed beyond this interval.  https://doi.org/10.1371/journal.pone.0240742.g003 Table 3. Postoperative complications in 116 patients who underwent preoperative concurrent chemoradiotherapy followed by robotic-assisted surgery.

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Time Interval between the completion of radiotherapy and robotic-assisted surgery Chemotherapy with a FOLFOX regimen was administrated during preoperative CCRT and was continued upon the completion of radiotherapy. In the German CAO/ARO/AIO-04 study, Rödel et al. evaluated the effect of the addition of oxaliplatin upon preoperative CRT followed by TME surgery 5-6 weeks after completion of CRT, and they reported a R0 resection and pCR rates of 94% and 17%, respectively when combining fluorouracil with oxaliplatin, and 95% and 13%, respectively, with fluorouracil alone [13,14]. They concluded that combinatorial treatment with oxaliplatin and a fluorouracil-based treatment was well-tolerated and increased the pCR rate. In a multicenter, phase II randomized controlled trial [18,29], Garcia-Aguilar et al. evaluated the effect of the supplementation of mFOLFOX6 cycles between chemoradiation and surgery. The pCR rate increased from 18% to 38% upon supplementation of 2, 4, and 6 mFOLFOX6 cycles; the risk of postoperative complications and surgical difficulty remained unaltered. Conversely, in a phase III randomized trial, Gérard et al. reported nonsignificant increases in the pCR rate from 13.9% to 19.2% and in CRM negative resection rate, from 87.3% to 92.3%, upon supplementation of oxalipatin [44], indicating that oxaliplatin supplementation did not have clinical benefits. In a systemic review and meta-analysis study, Yang et al. reported that administration of OX/FU regimen resulted in a significant higher pCR rate compared with the FU regimen [39]; however, no significant differences were observed between the two treatment regimens in the R0 resection rate and the positive CRM rate. Another meta-analysis of eight randomized control trials also reported a higher pCR rate in the oxaliplatin-based regimen group [40].
Preoperative rather than postoperative radiotherapy has been reported to reduce the LR rate and complication rate [4][5][6][7][8]. Preoperative radiotherapy may induce tissue swelling and local inflammation, which requires time to subside. Therefore, a longer interval between radiotherapy completion and surgery for higher degrees of tumor shrinkage. This study reported good tumor regression rate of 79.3% and pCR of 31.9% of rate with an interval �10 weeks between the completion of radiotherapy and robotic-assisted surgery. Furthermore, this study revealed a high R0 resection rate (97.4%). Garcia-Aguilar et al. reported that a modest increase in the pCR rate without an increase in postoperative complications may result from intensive neoadjuvant therapy and delayed surgery (�10 weeks vs 6-8 weeks) [18,29]. In a Chinese FOWARC randomized controlled trial, Deng et al. reported a pCR rate of 27.5%, good tumor regression rate of 68.5%, and R0 resection rate of 89.9% upon administration of an mFOL-FOX6 regimen during preoperative CCRT with a 52-day median interval between the completion of chemoradiotherapy and TME [15]. Sloothaak et al. [41] analyzed the database of the Dutch Surgical Colorectal Audit to evaluate the optimal interval between neoadjuvant CRT and surgery, and they reported the highest pCR rate (18.0%), T-downstaging rate (55.2%), and N-downstaging rate (55.2%) among patients with an interval of 10-11 weeks from the completion of CCRT. Lichthardt et al. retrospectively analyzed the German StuDoQ|Rectalcarcinoma registry and reported a prolonged interval (�8 and 8-10 weeks vs <6 and 6-8 weeks) between the completion of CCRT and oncological resection in patients with LARC is potentially beneficial in increasing the pCR and TRG rates without increasing perioperative morbidity [42]. Moreover, because of the relatively high T-downstaging rate, good tumor regression rate, and pCR rate observed in the current study, the positive CRM and DRM rates were 1.7% and 0.9%, respectively. However, the positive CRM rate reported by Lim et al. was 2.8% [28]; that reported in the GRECCAR-6 study was 10.8% [26,27]; and that reported by Law et al was 3.9%-6.6% [45]. Moreover, the overall positive DRM rate was 2.1% in the GRECCAR-6 study [26,27].
Because pCR and good tumor regression are indicators of favorable oncological outcomes for preoperative CCRT [12, 38,50], we analyzed the effects of time intervals on these factors. The pCR rate was the highest among patients with an interval of � 12 weeks (33.9%), whereas good tumor regression was superior among patients with an interval of 10-12 weeks (82.5%). Although good tumor regression was optimal among patients with an interval of < 8 weeks (100%), the number of patients in this group was too small (n = 8). Furthermore, preferable oncological outcomes including DFS, OS, 3-year locoregional control, and 3-year distant metastasis control were observed among patients with an interval of 10-12 weeks compared with those with an interval of � 12 weeks. These differences were nonsignificant, which might have resulted from small sample size. Therefore, based on the present results, 10-12 weeks may be considered as a safe interval between the completion of radiotherapy and robotic-assisted rectal surgery.
This study had several limitations. First, this was a single-center retrospective study with a small sample of 116 patients which probably was probably insufficient for highlighting differences between the two groups. Second, we did not evaluate the toxicity rates of preoperative CCRT; however, no treatment-related death occurred in and all patients completed the preoperative CCRT and postoperative chemotherapy. Third, the follow-up interval was relatively short, with a 30-month median follow-up duration; thus, only short-term (3-year) survival and oncological outcomes were documented. Fourth, we did not evaluate the postoperative outcomes of urinary, sexual functions, or anal functions.

Conclusions
An intensified multimodal preoperative treatment with a longer interval (�10 weeks) between the completion of radiotherapy and robotic-assisted surgery potentially increases the pCR rate and the good tumor regression rate; furthermore, preferable oncological outcomes were observed without any effects on the overall complication rate among patients with an interval of 10-12 weeks. Therefore, robotic-assisted surgery after a 10-12-week is safe and feasible for patients with rectal cancer undergoing preoperative CCRT. However, further studies with a longer follow-up duration are required to investigate the long-term oncological outcomes. Moreover, further prospective randomized clinical trials are required to validate the present results.