Of 500 patients treated for rectal cancer at the University Hospital of Tours between January 2010 and December 2018, 70 patients with rectal cancer and SLM were selected. Exclusion criteria were an unachievable R0 resection (on rectum and SLMs), extra-hepatic localization, intraoperatively discovered hepatic localization, liver metastases appearing more than 6 months after rectal cancer diagnosis. SLMs were defined as all liver lesions discovered before or simultaneously with primary rectal cancer. Patients had a thoraco-abdominal CT scan and a liver magnetic resonance imaging (MRI) scan as part of the extension assessment. Rectal cancer assessment included clinical examination (digital pelvic exam, anoscopy) and paraclinical investigations (complete colonoscopy with biopsies, rectal endoscopic ultrasound (EUS), pelvic MRI). Evaluation of T stage was dependent on EUS, according to Hildebrandt et al.  and preoperative liver and pelvic MRI. These investigations confirmed rectal cancer location (low, 0 to 5 cm from the anal verge; mid, 5 to10; upper, 10 to 15) and assessed lymph node involvement.
Preoperative treatment-oncologic bridge treatment (figure 1A et 1B and Figure 1 supplementary data)
5 fluorouracil or capecitabin-based Chemotherapy (CT) (5FU) were administered concomitantly with RT to 16 patients according to our guidelines for patients with mid/low rectal tumors and/or T3/4 rectal tumors. Short-course RT was chosen for 14 patients to have closely sequenced sessions because of the extent of the hepatic disease, age, or personal reasons. 22 patients underwent CT alone because of no indication for RT and six patients underwent RT alone because of CT contra-indications. Twelve patients underwent surgery without neoadjuvant treatment: ten because of small-sized rectal tumours and liver SLM, two because of cardiology-related contra-indications. Overall, 58 out of 70 patients had a neoadjuvant treatment, 39 in the staged surgery group and 19 in the simultaneous group. Twelve patients did not receive any NA treatment because of small size tumours or contraindications. Concerning the neoadjuvant treatment in each group, 5 fluorouracil or capecitabin-based chemotherapy were administered concomitantly with RT (50 Gy in 25 fractions over five weeks) according to institutional recommendations for patients with mid/low rectal tumors and/or T3/4 rectal tumors. Short-term RT was chosen because of the extent of liver disease, age, or social reasons to have closely sequenced therapy sessions. CT alone was performed when there was no need for rectal RT and RT alone was performed because of CT contraindications.
Concerning the staged surgery group, bridge treatment was CT alone for 5 patients mostly depending on SLM size, associated in six cases with a pre-operative portal embolization. Twenty patients had CT alone after second surgery, and 13 patients had CT only after both surgeries were performed, including two patients who underwent hepatic stereotaxic RT. Decision to deliver post-operative CT was based on tumor histologic type and/or surgical margins. Concerning the simultaneous surgery group, 18 patients underwent adjuvant CT, with no stereotaxic RT associated, based on tumor histologic type and/or surgical margins.
Evaluation of tumor response
All patients had a clinical re-evaluation six weeks after the end of neo-adjuvant therapy with standard clinical examination (digital exam, anal examination). EUS was performed by the same team as the initial evaluation. Evolution of pre-treatment T and N staging was re-evaluated by pelvic MRI scan according to the 1.1 version RECIST criteria . SLMs were reevaluated after neoadjuvant treatment by CT scan and MRI scan.
Choice of surgical procedure
Patients underwent a simultaneous approach, either through laparotomy or laparoscopy, if the surgical procedure on the liver was not a major hepatectomy (<3 segment of liver). On the contrary, if liver metastases implied a major hepatectomy (>3 segment or required a preoperative embolization), a two-staged approach was preferred.
Moreover for the low and advanced rectal cancer requiring abdominal perineal resection or coloanal anastomosis, surgical stage approached was preferred.
Patients underwent mechanical bowel preparation before surgery. For rectal surgery, laparoscopic approach was the standard approach. For T4 tumors, open approach was preferred . A medial-to-lateral approach was used. Specimens were retrieved from abdominal cavity via a small abdominal incision . Mechanical colorectal or manual colo-anal anastomoses (side-to-end or end-to-end) were performed depending on tumor level. Total or partial intersphincteric resection for very low rectal cancer was performed whenever feasible. Otherwise, a perineal abdominal amputation was performed. Upper rectal cancer underwent partial mesorectal excision with a 5 cm margin from the lower limit of the tumor. Other patients underwent standard TME. A protective loop ileostomy was performed routinely for mid and low rectum tumours.
Surgery was performed for curative intent. Whenever necessary, liver resection was combined with radiofrequency ablation (RFA). Major hepatectomy was defined as a liver resection comprising 3 or more contiguous liver segments. Portal vein embolization was considered if calculated remaining liver volume was insufficient (< 30% total liver volume) . Two-stage hepatectomy involved initial resection of all left liver metastases with ligation of the right portal vein or embolization of the right portal vein in the postoperative period. Four to 6 weeks after first surgery, a right or extended hepatectomy was performed. Liver transection was carried out using squeeze-clamp technique and ultrasound dissection to expose residual vessels or glissory sheaths, which were ligated with 4-0 vicryl or sealed using LigaSure technology [33, 34, 35, 36]. Intraoperative ultrasonography was routinely performed to guide SLM resection.
Primary tumors were analyzed using a standardized protocol . TNM classification was used according to the 8th edition of American Joint Committee of Cancer (AJCC). Circumferential and distal resection margins were defined as positive (R+) if less than 1 mm and negative (R0) if more than 1 mm to the tumor.. Total or partial mesorectal excision, colloid component degree, differentiation grade, vascular, lymphatic or perinervous emboli, liver fibrosis, liver steatosis and capillary obstruction syndrome were stated in pathology report.
Anastomotic leakage was defined and graded according to the International Study Group of Rectal Cancer . Any clinical (sepsis, peritonitis, emission of gas, pus, or feces from the pelvic drain, purulent discharge per anus, or rectovaginal fistula) and/or biological suspicion of AL led to an early CT-scan. Management included antibiotics, radiologic or transanal drainage, and/or early abdominal redo surgery . Patients presenting with postoperative bile leakage were treated with antibiotics and radiological or surgical drainage . Short-term 30-day postoperative complications were ranked according to Clavien Classification .
Recurrence-free and overall survivals were analyzed. Postoperative follow-up included clinical, biochemical, and radiological assessments every three months during first postoperative year, then every six months up to five years postoperatively and every year up to ten years. Surviving patients were assessed for disease recurrence and site of recurrence. Follow-up data were obtained from medical records and direct patients’ consultation.
Propensity score matching (PSM) using nearest-neighbor method was performed to match patient who underwent simultaneous resection of liver metastasis to those who underwent staged procedures. PSM model was generated using preoperative risk factors reported to impair patient’s survival, namely, surgical difficulty (i.e., minor, or major hepatectomy) and underlying liver fibrosis. Qualitative variables are presented in percentages and compared using χ2 test with Bonferroni correction whenever necessary. Quantitative variables are presented in medians and interquartile range and compared using Student or Wilcoxon test. Kaplan-Meier method was used to estimate recurrence-free survival and overall survival, which were compared using the Log-rank test. Continuous variables were compared using ANOVA or nonparametric ANOVA tests. This study was conducted according to the ethical standards of the Committee on Human Experimentation of our institution and reported according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines .